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2,337,600 |
Central nervous system manifestations in VHL: genetics, pathology and clinical phenotypic features.
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This review focuses on CNS hemangioblastomas in von Hippel-Lindau (VHL) disease. The pathogenesis of these lesions remains unclear to date; however, biallelic inactivation of the VHL tumor suppressor gene is thought to be an important step. These benign tumors occur frequently in patients with VHL disease and produce symptoms by mass effect either by the tumor itself or an accompanying cyst or edema. Furthermore, cases of spontaneous hemorrhage have been described. Genetic testing for VHL germline mutations is recommended in all patients with hemangioblastoma and yearly screening, including MRI of the brain and spine, is recommended for all VHL disease patients. Treatment of these tumors is mainly surgical. In general, surgery is indicated in symptomatic hemangioblastomas and eventually also in asymptomatic tumors that exhibit radiographic progression. However, since most VHL disease patients harbor multiple lesions, a careful individual decision must be made in each case. The tumors can usually be completely removed by dissection in the plane between tumor and CNS tissue and coagulating and cutting of the numerous feeding vessels with low power. As long as consequent yearly surveillance is performed and lesions are adequately treated in time, the prognosis of CNS hemangioblastomas in VHL disease is good. Preoperative neurological deficit, however, will not improve after surgery in most patients. Local tumor recurrences are rare.
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2,337,601 |
Multiple endocrine neoplasia type 2.
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Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant inherited cancer syndrome. Predisposition to MEN 2 is caused by germline mutations of the RET proto-oncogene on chromosome 10q11.2 [1]. There are three clinically distinct forms of MEN 2 syndrome -- MEN 2A, familial medullary thyroid carcinoma (FMTC), and MEN 2B. In all of these subtypes, medullary thyroid carcinoma (MTC) is a key. MEN 2A is the most common subtype of MEN 2. Clinical features of the MEN 2A syndrome include medullary thyroid carcinoma (MTC) and/or C-cell hyperplasia (CCH) in almost all affected individuals, pheochromocytoma (approximately 50%) and hyperparathyroidism (HPT) (15-30%). MEN type 2B is the most aggressive of the MEN 2 variants and accounts for approximately 5% of all cases of MEN 2. MEN 2B is similar to MEN 2A but is characterized by the earlier onset of the disease and by developmental abnormalities. In FMTC, the third form of MEN 2, MTC is the only clinical feature. Introduced in recent years and still developing genetic testing of individuals at highest hereditary risk of MEN 2 syndrome holds the possibility of early detection and improved treatment and prognosis.
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2,337,602 |
Growth hormone injections improve bone quality in a mouse model of osteogenesis imperfecta.
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Systemic growth hormone injections increased spine and femur length in a mouse model of OI. Femur BMC, cross-sectional area, and BMD were increased. Smaller gains were produced in vertebral BMC and cross-sectional area. Biomechanical testing showed improvements to structural and material properties in the femur midshaft, supporting expanded testing of growth hormone therapy in children with OI.</AbstractText>Osteoblasts in heterozygous Cola2oim mutant mice produce one-half the normal amounts of the alpha2 strand of type I procollagen. The mice experience a mild osteogenesis imperfecta (OI) phenotype, with femurs and vertebrae that require less force than normal to break in a biomechanical test.</AbstractText>Subcutaneous injections of recombinant human growth hormone (rhGH) or saline were given 6 days per week to oim/+ mice between 3 and 12 weeks of age, in a protocol designed to simulate a trial on OI children.</AbstractText>rhGH injections promoted significant weight gain and skeletal growth compared with saline-treated control animals. Femur and spine lengths were increased significantly. Significant increases at the femur midshaft in cortical BMD (2.2%), BMC (15.5%), and cross-sectional area (13%) were produced by rhGH treatment. Increases in the same cortical bone parameters were measured in the metaphyseal region of the femur and in tail vertebrae, but lumbar vertebrae showed significant increases in BMC (9.6%) and cross-sectional area (10.1%) of trabecular bone. Three-point bending testing documented functional improvements to the femur mid-shafts. GH treatment produced significant increases in bone stiffness (23.7%), maximum load (30.8%), the energy absorbed by the femurs to the point of maximum load (44.5%), and the energy to actual fracture (40.4%). The ultimate stress endured by the bone material was increased by 14.1%.</AbstractText>Gains in bone length, cross-sectional area, BMD, BMC, structural biomechanical properties, and strength were achieved without directly addressing the genetic collagen defect in the mice. Results support expanded clinical testing of GH injections in children with OI.</AbstractText>
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2,337,603 |
Myopathy with skeletal asymmetry and hemidiaphragm elevation is caused by myotubularin mutations.
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The authors report two families with a myopathy phenotype affecting only women, marked by asymmetric weakness, skeletal asymmetry, and an elevated hemidiaphragm. One family had a mutation in a stop codon in exon 9 of the myotubularin gene, and the other had a splice site mutation in exon 13. Both families had manifesting and nonmanifesting carriers. Skewed X-inactivation appeared to explain the clinical manifestations in only one of the two families.
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2,337,604 |
LGMD2I presenting with a characteristic Duchenne or Becker muscular dystrophy phenotype.
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LGMD type 2I, caused by mutations in the fukutin-related protein, is a common form of LGMD. The phenotype resembles Duchenne/Becker muscular dystrophy. A point mutation, L276I has been found in all patients with LGMD2I studied so far. The authors screened for this mutation in 102 sporadic cases of Duchenne/Becker mutation-negative patients and found 13 patients with LGMD2I.
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2,337,605 |
Patterns of inheritance in familial ALS.
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We investigated 185 families with ALS for evidence of anticipation and mitochondrial inheritance. Although initial analysis demonstrated significant anticipation of age at death between generations in patients with familial ALS, further analysis demonstrated features of regression to the mean, suggesting that the perceived differences are the result of bias. In addition, there was no evidence of an effect of preferential maternal inheritance, which would have supported transmission of mitochondrial DNA mutations.
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2,337,606 |
High incidence of genetic human transmissible spongiform encephalopathies in Italy.
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To assess the incidence and mortality rates of genetic transmissible spongiform encephalopathy (TSE) diseases in Italy.</AbstractText>The authors have sequenced the prion protein gene (PRNP) in 643 patients referred to the Italian Registry of Creutzfeldt-Jakob disease (CJD) and related disorders between 1993 and 2002. Crude age- and sex-specific incidence and mortality rates were calculated. Differences in morbidity from genetic TSE diseases in the 20 Italian regions were assessed by the standardized morbidity ratio (SMR).</AbstractText>A total of 130 cases were classified as genetic TSE diseases with a mean yearly incidence rate of 0.28 cases per million people. Genetic TSE diseases represent 17.7% of all TSE diseases, including sporadic, iatrogenic, and variant CJD. The most frequent mutation was the V210I (n = 54), and the second most common the E200K (n = 42). Mortality rates for genetic TSE diseases did not increase in any of the age groups under examination over the 10 years of surveillance. The analysis of regional distribution of genetic cases by place of birth revealed that in Campania and Calabria regions the number of genetic TSE cases was higher than in other regions.</AbstractText>In Italy the incidence of genetic transmissible spongiform encephalopathy (TSE) diseases is the second highest among European countries. Genetic analysis is important for a correct classification of patients with TSE.</AbstractText>
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2,337,607 |
A novel mutation (K317M) in the MAPT gene causes FTDP and motor neuron disease.
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Frontotemporal dementia with parkinsonism is often linked to chromosome 17 and is related to mutations in the MAPT gene. In some families the genetic basis is still unknown. The authors report two pedigrees with FTDP-17 harboring a novel mutation (K317M) in exon 11 in the MAPT gene.</AbstractText>The authors identified two apparently unrelated pedigrees with an autosomal dominant neurodegenerative condition. Thirteen patients were examined and eight autopsies were performed.</AbstractText>Mean age at onset was 48 years. Mean disease duration was 6 years. Dysarthria often heralded the disease. All cases had parkinsonism and pyramidalism and half of them had amyotrophy. Behavioral or personality changes were not a prominent feature. Cognitive decline appeared late in the evolution. Neuropathologically, a massive degeneration of the substantia nigra without Lewy bodies was a constant finding. A variable degree of frontotemporal atrophy was found. Corticospinal tract degeneration and anterior horn neuron loss were present in six of seven autopsies in which the spinal cord was examined. An extensive deposition of abnormal tau protein in a mixed pattern (neuronal, glial) was observed. Pick's bodies were not seen. Biochemical analysis of tau revealed two bands of 64 and 68 kDa.</AbstractText>Genetic analysis revealed the same novel mutation (K317M) in exon 11 of the MAPT gene in both pedigrees. A common haplotype between members of the two pedigrees suggests that they belong to the same family.</AbstractText>
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2,337,608 |
APOE genotype, cholesterol level, lipid-lowering treatment, and dementia: the Three-City Study.
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To examine the association of plasma cholesterol levels, lipid-lowering agent (LLA) intake, and APOE genotype with dementia prevalence.</AbstractText>The Three-City Study is a population-based cohort of 9,294 subjects selected from the electoral rolls of three French cities (Bordeaux, Dijon, Montpellier). Baseline examination included extensive assessment of exposure to vascular risk factors (including cholesterol levels and LLA use [statin or fibrate]) and clinical diagnosis of dementia.</AbstractText>Two percent of participants were demented at baseline. Overall 32.4% of participants had hyperlipidemia, and 15.6% were prescribed statins and 13.7% fibrates. After adjusting for age, gender, education level, and study center, the odds ratio (OR) for dementia was observed to be lower among LLA users (OR = 0.61, 95% CI = 0.41 to 0.91) compared with subjects taking no LLAs. There was no differential effect between statin and fibrate users. The odds for dementia were increased in subjects with hyperlipidemia (OR = 1.43, 95% CI = 1.03 to 1.99). Further adjustment for potential confounders did not modify these associations. In addition, the association between LLA intake and dementia was not modified by APOE genotype, whereas hyperlipidemia was significantly associated with increased dementia prevalence only in non-epsilon4 carriers and non-Alzheimer disease cases. Finally, in participants taking LLAs, the odds for dementia were decreased only in those having normal lipid levels.</AbstractText>This observational study provides further evidence that lipid-lowering agents are associated with decreased risk of dementia, whereas hyperlipidemia is associated with increased odds for non-Alzheimer-disease-type dementia. These effects appear to be independent of all major potential confounders.</AbstractText>
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2,337,609 |
The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2.
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Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), or Nasu-Hakola disease, is a presenile dementia associated with loss of myelin, basal ganglia calcification, and bone cysts. It is caused by recessively inherited mutations in two genes encoding subunits of a cell membrane-associated receptor complex: TREM2 and DAP12. The clinical course of PLOSL has not been characterized in a series of patients with TREM2 mutations.</AbstractText>The authors compare neurologic and neuroradiologic follow-up data of six patients carrying TREM2 mutations with PLOSL due to defective DAP12 genes. The authors review the known mutations in these two genes.</AbstractText>Mutations in DAP12 and TREM2 result in a uniform disease phenotype. In Finnish and Japanese patients with PLOSL, DAP12 mutations predominate, whereas TREM2 is mutated more frequently elsewhere.</AbstractText>Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy should be considered in adult patients under age 50 years with dementia and basal ganglia calcification. Radiographs of ankles and wrists, and DNA test in uncertain cases, confirm the diagnosis.</AbstractText>
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2,337,610 |
UCHL1 is associated with Parkinson's disease: a case-unaffected sibling and case-unrelated control study.
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To avoid the possible confounding effect of population stratification, we employed a discordant sibling study design and a liberalization of the sibling transmission disequilibrium test to confirm the association of the S18Y variant of the ubiquitin carboxi-terminal hydrolase L1 (UCHL1) gene with Parkinson's disease (PD). The study included 497 case-control pairs (427 case-unaffected sibling pairs and 70 case-unrelated control pairs). Analyses confirmed a significant inverse association of the UCHL1 S18Y polymorphism with PD overall (OR=0.18, 95% CI=0.05-0.64, p=0.002, recessive model) and in several strata.
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2,337,611 |
The GABA type A receptor alpha5 subunit gene is associated with bipolar I disorder.
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Several genetic studies have revealed that bipolar disorders are linked with the chromosomal locus of 15q11-q13, where the gamma-aminobutyric acid (GABA) receptor alpha5 subunit gene (GABRA5) locates. GABA is one of the major neurotransmitters that may be involved in the pathogenesis of bipolar disorder. Five polymorphisms in the GABRA5 gene, -754C>T in the promoter region, IVS1-21G>A, IVS2-26T>A, (*)302C>T in 3'-UTR of exon 5, and a CA repeat polymorphism in the 3' flanking region were examined in a Japanese population. IVS1-21G>A exhibited significant differences in the distribution of the genotype and allele frequency in bipolar I disorder patients but not in bipolar II disorder patients, compared with control subjects. The haplotype analysis showed that IVS1-21G>A/IVS2-26A>T was associated with bipolar I disorder, and the IVS1-21A/IVS2-26T haplotype was a negative risk factor for susceptibility to the disorders (odds ratio: 0.57, 95% confidence interval: 0.44-0.73). These results suggest that the GABRA5 gene may confer susceptibility to bipolar I disorder.
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2,337,612 |
Lack of evidence for association between the serotonin transporter gene (SLC6A4) polymorphisms and autism in the Chinese trios.
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Serotonin regulates several aspects of brain development, and it is involved in a range of behaviors frequently disturbed in autistic disorder. The serotonin transporter is a critical component of the serotonergic system. The serotonin transporter gene (SLC6A4) is of special interest given the nature of the biological findings and the reported effects of selective serotonin reuptake inhibitors of autistic symptoms. So far the genetics researches of the SLC6A4 gene have given conflicting results. The aim of study was to investigate the association between the SLC6A4 gene and autism in the Chinese Han population. The present study was conducted with the detection of three single nucleotide polymorphisms (SNP(S)) located within the SLC6A4 gene by using the polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) analysis. We performed a family-based association study of these polymorphisms in 175 Chinese Han family trios. Linkage disequilibrium (LD) measurement (D') analysis showed the presence of LD between markers across the locus. No significant evidence of association was found at any of the markers detected by using the transmission disequilibrium test (TDT) and haplotype analyses in all samples and male samples. Our findings suggest that it is unlikely that DNA variations in the SLC6A4 gene play a significant role in the genetic predisposition to autism in the Chinese Han population or that allelic heterogeneity at the SLC6A4 loci dilutes potential disease-allele association.
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2,337,613 |
Clinical pharmacogenetics of immunosuppressive drugs in organ transplantation.
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Organ transplantation has become an important additional option for patients with organ failure. Immunosuppressive drugs showing a very narrow therapeutic window have to be administered. Different transporters and metabolic pathways are responsible for absorption and metabolism of these drugs; for instance, the P-glycoprotein (P-gp) pump regulates the absorption of a drug, and its metabolism is catalyzed by cytochrome P450s (CYPs). As the phenotypes of P-gp or the CYPs are predetermined by their genotypes, genetic testing prior to drug therapy may help to predict the drug doses required. This review describes polymorphisms of the genes coding for P-gp and CYPs, and focuses on the compounds cyclosporin and tacrolimus. It is hoped that this information might help to judge the value of pharmacogenetic testing prior to immunosuppressive therapy in solid organ transplantation.
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2,337,614 |
Testing hypotheses regarding the genetics of adaptation.
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Many of the hypotheses regarding the genetics of adaptation require that one know specific details about the genetic basis of complex traits, such as the number and effects of the loci involved. Developments in molecular biology have made it possible to create relatively dense maps of markers that can potentially be used to map genes underlying specific traits. However, there are a number of reasons to doubt that such mapping will provide the level of resolution necessary to specifically address many evolutionary questions. Moreover, evolutionary change is built upon the substitution of individual mutations, many of which may now be cosegregating in the same allele. In order for this developing area not to become a mirage that traps the efforts of an entire field, the genetic dissection of adaptive traits should be conducted within a strict hypothesis-testing framework and within systems that promise a reasonable chance of identifying the specific genetic changes of interest. Continuing advances in molecular technology may lead the way here, but some form of genetic testing is likely to be forever required.
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2,337,615 |
Application of genomewide SNP arrays for detection of simulated susceptibility loci.
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The prospect of SNP-based genomewide association analysis has been extensively discussed, but practical experiences remain limited. We performed an association study using a recently developed array of 11,555 SNPs distributed throughout the human genome. A total of 104 DNA samples were hybridized to these chips with an average call rate of 97% (range 85.3-98.6%). The resulting genomewide scans were applied to distinguish between carriers and noncarriers of 37 test variants, used as surrogates for monogenic disease traits. The test variants were not contained in the chip and had been determined by other methods. Without adjustment for multiple testing, the procedure detected 24% of the test variants, but the positive predictive value was low (2%). Adjustment for multiple testing eliminated most false-positive associations, but the share of true positive associations decreased to 10-12%. We also simulated fine-mapping of susceptibility loci by restricting testing to the immediate neighborhood of test variants (+/-5 Mb). This increased the proportion of correctly identified test variants to 22-27%. Simulation of a bigenic inheritance reduced the sensitivity to 1%. Similarly adverse effect had reduction of allelic penetrance. In summary, we demonstrate the feasibility and considerable specificity of SNP array-based association studies to detect variants underlying monogenic, highly penetrant traits. The outcome is affected by allelic frequencies of chip SNPs, by the ratio between simulated "cases" and "controls," and by the degree of linkage disequilibrium. A major improvement is expected from raising the density of the SNP array.
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2,337,616 |
High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients.
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Morbus Osler or HHT (hereditary hemorrhagic telangiectasia) is a disorder of the fibrovascular tissue that is inherited in an autosomal dominant way with frequency rates between 1:2,500 and 1:40,000. The disease provokes malformations of the blood vessels sometimes resulting in life-threatening complications. Presently, two genes involved in the development of HHT have been identified: ACVRL1 and ENG. Both of them encode proteins that belong to the TGF-beta receptor complex family and play an essential role in the formation of the vascular system. Recently, several mutations in ACVRL1 and ENG have been described in other European populations. However, no data concerning mutation frequencies in the German population have been reported so far. Therefore, we screened our collective of German HHT patients (28 single cases and 11 familial cases) for mutations in both genes by direct sequencing. We detected 11 mutations already described elsewhere and 19 novel ones. Furthermore, evidence for the pathogenic role of four new missense mutations was collected by screening a healthy control collective using RFLP analysis. Interestingly, the majority of ACVRL1 mutations represented missense mutations, whereas mutations in ENG mostly resulted in a shortened protein. Our results demonstrate the importance of ACVRL1 and ENG mutations in German HHT patients displaying mutation frequencies over 80%.
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2,337,617 |
Subtelomeric rearrangements in the mentally retarded: a comparison of detection methods.
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In recent years, subtelomeric rearrangements, e.g., chromosome deletions or duplications too small to be detected by conventional cytogenetic analysis, have emerged as a significant cause of both idiopathic and familial mental retardation. As mental retardation is a common disorder, many patients need to be tested on a routine basis. In this review, we will discuss the different methods that have been applied in laboratories worldwide, including multiprobe fluorescence in situ hybridization (FISH), multiallelic marker analysis, multiplex amplifiable probe hybridization (MAPH), multiplex ligation-dependent probe amplification (MLPA), quantitative real-time PCR, comparative genomic hybridization (CGH), and multicolor FISH, including spectral karyotyping (SKY), subtelomeric combined binary ratio labeling FISH (S-COBRA FISH), multiplex FISH telomere integrity assay (M-TEL), telomeric multiplex FISH (TM-FISH), and primed in situ labeling (PRINS).
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2,337,618 |
Male BRCA1 and BRCA2 mutation carriers: a pilot study investigating medical characteristics of patients participating in a prostate cancer prevention clinic.
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Male BRCA1 and BRCA2 mutation carriers are at an increased risk to develop prostate cancer and are subject to screening protocols for high-risk men. The utility of targeted screening, and the clinical and pathological features associated with prostate cancer, have received little attention in this population.</AbstractText>We report on the clinical screening and pathological characteristics of a group of 19 men with BRCA1 or BRCA2 mutation, as compared to an age-matched group of men with a family history of prostate cancer.</AbstractText>Mutation carriers were significantly more likely to have an elevated PSA at first visit (P = 0.03). Prostate cancer was twice as likely to be diagnosed in mutation carriers although this difference was not statistically significant (P = 0.55).</AbstractText>Prostate cancer surveillance of BRCA1 and BRCA2 mutation carriers is warranted. Further research on larger cohorts is needed to evaluate whether unique pathological prostate cancer characteristics exist in these men.</AbstractText>Copyright 2005 Wiley-Liss, Inc.</CopyrightInformation>
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2,337,619 |
Diagnostic DHPLC Quality Assurance (DDQA): a collaborative approach to the generation of validated and standardized methods for DHPLC-based mutation screening in clinical genetics laboratories.
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Genetic testing in a clinical diagnostic environment must be subject to rigorous quality control procedures, in order to ensure consistency and accuracy of results. Denaturing high performance liquid chromatography (DHPLC) has become a standard prescreening tool for mutation detection, offering very high efficiency and sensitivity of detection. Despite the relatively simple software-assisted assay setup, DHPLC is a complex assay, and quality control is reliant on ensuring optimal instrument performance, excellent assay design and validation, and sufficient user training and proficiency to interpret results. We describe here a unique collaborative effort by a group of diagnostic clinical genetics laboratories with DHPLC expertise who, together with the manufacturer of one of the most widely used DHPLC platforms, have generated standard operating procedures (SOPs) for instrument operation and maintenance, and for mutation detection by DHPLC. We also describe the validation of a disease-specific SOP for DHPLC assisted mutation screening of the MECP2 gene associated with Rett syndrome. The proposed SOP was validated, and used independently in two laboratories to introduce MECP2 testing. In addition, we provide empirically derived normal ranges for the WAVE System Mutation Standards, which are essential for optimal instrument performance. This effort was initiated to try to standardize DHPLC-based mutation screening procedures across laboratories, and so increase the overall quality of this testing method. This endeavor will thus save each laboratory from having to generate SOPs on their own, which is a lengthy and laborious task. In this respect, we define "generic" SOPs as procedures that are easily adaptable to the individual laboratories' quality systems.
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2,337,620 |
A weighted cohort approach for analysing factors modifying disease risks in carriers of high-risk susceptibility genes.
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The authors propose a novel approach to evaluate the effects of risk factors on disease risks in carriers of high-penetrance alleles in disease susceptibility genes. Most studies to date have utilised data collected on carriers identified through ongoing genetic testing programs. The advantage of this approach is that it allows relatively large numbers of affected and unaffected carriers to be identified rapidly. However, genetic testing is targeted at individuals with a strong family history of disease, so that the selection of carriers is not random with respect to disease status. Risk factors are often analysed by standard cohort analysis methods, but these can be biased in retrospective studies if subjects are selected on the basis of phenotype. To overcome this problem, a weighted cohort approach is proposed, under which individuals are weighted according to certain sampling probabilities in order to mimic a true cohort. The method is illustrated by analyses of data from the International BRCA1/2 Carrier Cohort Study (IBCCS). Simulations demonstrate that the method gives rate ratio estimates that are close to unbiased provided that the absolute disease risks are well estimated. The power to detect associations is, however, reduced compared with an unweighted approach.
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2,337,621 |
The genetics of thin basement membrane nephropathy.
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The diagnosis of thin basement membrane nephropathy (TBMN) usually is made on the basis of the clinical features or the glomerular membrane ultrastructural appearance. Only now are we beginning to understand the genetics of TBMN and the role of diagnostic genetic testing. The similarity of clinical and glomerular membrane features first suggested TBMN might represent the carrier state for autosomal-recessive Alport syndrome. This was confirmed subsequently by the demonstration that 40% of families with TBMN have hematuria that segregates with the corresponding locus ( COL4A3/COL4A4 ), and identical mutations occur in both conditions. To date, about 20 COL4A3 and COL4A4 mutations have been shown in TBMN, and these mainly are single nucleotide substitutions that are different in each family. The families in whom hematuria does not appear to segregate with the COL4A3/COL4A4 locus cannot all be explained by de novo mutations, and nonpenetrant or coincidental hematuria. This suggests a further TBMN locus. In patients with persistent hematuria, testing for COL4A3 and COL4A4 mutations to diagnose TBMN is problematic because of the huge size of these genes, their frequent polymorphisms, and the likelihood of a further gene locus. It is far more practicable to perform genetic testing to exclude or confirm X-linked Alport syndrome because this condition is the major differential diagnosis of TBMN and has a very different prognosis.
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2,337,622 |
Multiple endocrine neoplasia type 2B and Hirschsprung's disease.
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Multiple endocrine neoplasia type 2B and Hirschsprung's disease are genetic disorders characterized by gross and/or microscopic pathology of the enteric nervous system and associated dysmotility. A specific missense mutation in the RET proto-oncogene is the etiology of multiple endocrine neoplasia type B, in contrast to very complex multigenetic defects that underlie Hirschsprung's disease, which include overt mutations and more subtle changes in the RET locus. In this review, the molecular genetics of the 2 conditions are discussed, and the clinical implications of existing data and future studies are summarized.
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2,337,623 |
Molecular characterization of TEM-type beta-lactamases identified in cold-seep sediments of Edison Seamount (south of Lihir Island, Papua New Guinea).
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To determine the prevalence and genotypes of beta-lactamases among clones of a metagenomic library from the cold-seep sediments of Edison seamount (10,000 years old), we performed pulse-field gel electrophoresis, antibiotic susceptibility testing, pI determination, and DNA sequencing analysis. Among the 8,823 clones of the library, thirty clones produced beta-lactamases and had high levels of genetic diversity. Consistent with minimum inhibitory concentration patterns, we found that five (16.7%) of thirty clones produced an extended-spectrum beta-lactamase. 837- and 259-bp fragments specific to blaTEM genes were amplified, as determined by banding patterns of PCR amplification with designed primers. TEM-1 was the most prevalent beta-lactamase and conferred resistance to ampicillin, piperacillin, and cephalothin. TEM-116 had a spectrum that was extended to ceftazidime, cefotaxime, and aztreonam. The resistance levels conferred by the pre-antibiotic era alleles of TEM-type beta-lactamases were essentially the same as the resistance levels conferred by the TEM-type alleles which had been isolated from clinically resistant strains of bacteria of the antibiotic era. Our first report on TEM-type beta-lactamases of the pre-antibiotic era indicates that TEM-type beta-lactamases paint a picture in which most of the diversity of the enzymes may not be the result of recent evolution, but that of ancient evolution.
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2,337,624 |
Patients with a family history of cancer: identification and management.
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A family history of certain malignancies, especially breast, ovarian, colorectal, and prostate cancers, can place persons at increased risk of developing these cancers. By constructing a pedigree that includes 3 generations, family physicians can identify patients at increased risk because of family cancer history. Persons at increased cancer risk because of family history warrant a surveillance strategy for early detection. Genetic professionals represent an important resource in assessing genetic risk and possible testing. Persons identified as being at increased risk of various cancers based on their family history should understand the surveillance plan that is recommended and the importance of maintaining a healthy lifestyle and remaining up to date on other cancer screening tests.
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2,337,625 |
Primary pulmonary synovial sarcoma confirmed by molecular detection of SYT-SSX1 fusion gene transcripts: a case report and review of the literature.
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This is a case report of a rare patient with primary pulmonary synovial sarcoma. The patient was a 58-year-old woman who presented with a well-defined giant mass in the right lower field on a chest radiograph. A malignant pulmonary tumor was suspected and consequently a right middle and lower lobectomy was performed. Grossly, the tumor measured 10 x 8 x 7 cm, was whitish-yellow in color and friable with hemorrhage. Histologically, the tumor showed a dense proliferation of spindle cells. In some areas, a herringbone-like pattern with coagulation necrosis of large size was noted. Immunohistochemically, the tumor cells were focally positive for cytokeratin and epithelial membrane antigen (EMA). As these features suggested a monophasic synovial sarcoma, we looked for the presence of SYT-SSX fusion gene transcripts using RNA samples from the paraffin-embedded tissue. A reverse transcription-polymerase chain reaction (RT-PCR) amplified a single 118 bp fragment characteristic of the SYT-SSX1 fusion gene transcripts. As no tumor was found at other sites, it was diagnosed as primary pulmonary synovial sarcoma. Molecular testing proved to be very helpful or necessary when monophasic spindle cell synovial sarcoma was recognized in uncommon/unexpected sites. In our review of primary pulmonary synovial sarcomas confirmed by molecular detection of SYT-SSX fusion gene transcripts, the SYT-SSX2 fusion protein expression correlates with poorer prognosis. This is in contrast to the association between the SYT-SSX1 fusion protein expression and poorer prognosis in soft tissue synovial sarcomas.
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2,337,626 |
Ensemble dependence model for classification and prediction of cancer and normal gene expression data.
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DNA microarray technologies make it possible to simultaneously monitor thousands of genes' expression levels. A topic of great interest is to study the different expression profiles between microarray samples from cancer patients and normal subjects, by classifying them at gene expression levels. Currently, various clustering methods have been proposed in the literature to classify cancer and normal samples based on microarray data, and they are predominantly data-driven approaches. In this paper, we propose an alternative approach, a model-driven approach, which can reveal the relationship between the global gene expression profile and the subject's health status, and thus is promising in predicting the early development of cancer.</AbstractText>In this work, we propose an ensemble dependence model, aimed at exploring the group dependence relationship of gene clusters. Under the framework of hypothesis-testing, we employ genes' dependence relationship as a feature to model and classify cancer and normal samples. The proposed classification scheme is applied to several real cancer datasets, including cDNA, Affymetrix microarray and proteomic data. It is noted that the proposed method yields very promising performance. We further investigate the eigenvalue pattern of the proposed method, and we discover different patterns between cancer and normal samples. Moreover, the transition between cancer and normal patterns suggests that the eigenvalue pattern of the proposed models may have potential to predict the early stage of cancer development. In addition, we examine the effects of possible model mismatch on the proposed scheme.</AbstractText>
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2,337,627 |
Clinical advances in the diagnosis and therapy of the interstitial lung diseases.
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The last century experienced remarkable advances in the classification, diagnosis, and understanding of the pathogenesis of the interstitial lung diseases. Technological advances, particularly physiologic testing, lung imaging studies, bronchoalveolar lavage, surgical lung biopsy, and histopathologic assessment, improved our understanding of these entities. In particular, the advent of high-resolution computed tomography, the narrowed pathologic definition of usual interstitial pneumonia, and recognition of the prognostic importance of separating usual interstitial pneumonia from other idiopathic interstitial pneumonia patterns have profoundly changed the approach to these processes. Most recently, genetic medicine, the use of new technologies (e.g., microarrays, mass spectroscopic analysis of proteins, and laser capture microdissection), and the development of animal models have had a major impact on understanding the pathogenesis and potential molecular targets for interfering with fibrogenesis. This article highlights some of the advances and changes in clinical practice that took place in the management of patients with interstitial lung diseases over the last century.
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2,337,628 |
Interallelic class switch recombination contributes significantly to class switching in mouse B cells.
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Except for the expression of IgM and IgD, DNA recombination is constantly needed for the expression of other Ig classes and subclasses. The predominant path of class switch recombination (CSR) is intrachromosomal, and the looping-out and deletion model has been abundantly documented. However, switch regions also occasionally constitute convenient substrates for interchromosomal recombination, since it is noticeably the case in a number of chromosomal translocations causing oncogene deregulation in the course of lymphoma and myeloma. Although asymmetric accessibility of Ig alleles should theoretically limit its occurrence, interallelic CSR was shown to occur at low levels during IgA switching in rabbit, where the definition of allotypes within both V and C regions helped identify interchromosomally derived Ig. Thus, we wished to evaluate precisely interallelic CSR frequency in mouse B cells, by using a system in which only one allele (of b allotype) could express a functional VDJ region, whereas only interallelic CSR could restore expression of an excluded (a allotype) allele. In our study, we show that interchromosomal recombination of V(H) and Cgamma or Calpha occurs in vivo in B cells at a frequency that makes a significant contribution to physiological class switching: trans-association of V(H) and C(H) genes accounted for 7% of all alpha mRNA, and this frequency was about twice higher for the gamma3 transcripts, despite the much shorter distance between the J(H) region and the Cgamma3 gene, thus confirming that this phenomenon corresponded to site-specific switching and not to random recombination between long homologous loci.
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2,337,629 |
Expression, purification, and functional testing of recombinant CYR61/CCN1.
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The human cysteine-rich protein 61 (CYR61/CCN1) belongs to the CCN family of genes which plays an important role in cellular processes such as proliferation, migration, adhesion, and differentiation. These extracellular matrix signaling molecules consist of a modular structure and contain 38 conserved cysteine residues. Previously, we have shown that CYR61 is expressed in human osteoblasts and is regulated by bone-relevant growth factors. The protein also plays a role in angiogenesis. The open reading frame was cloned into a baculovirus expression vector and transfected into SF-21 insect cells. Recombinant protein was expressed as a fusion protein with the Fc-domain of human IgG and purified using affinity chromatography on protein G-Sepharose columns. The chorioallantoic membrane assay verified that blood vessel formation was stimulated by rCYR61. Additionally, human primary mesenchymal stem cells, osteoblasts, and endothelial cells responded to CYR61 treatment by a markedly stimulated proliferation. rCYR61-Fc represents a tool to elucidate its role in cells of the bone microenvironment.
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2,337,630 |
Skeletal dysplasias.
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This review is intended to help the neonatologist who is asked to see a baby or speak to parents who are expecting a baby with signs of a generalised disturbance of bone growth and/or modelling. In this review, we will: define a skeletal dysplasia; discuss the presenting features of a skeletal dysplasia in pregnancy and the newborn period; suggest a clinical approach to find the correct diagnosis; discuss the management of the neonate with a skeletal dysplasia; summarise the clinical features of the most common dysplasias; outline some pitfalls and difficulties in counselling the parents of the baby; and give information on further sources of information about skeletal dysplasias.
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2,337,631 |
Testing the trend towards specialization in herbivore-host plant associations using a molecular phylogeny of Tomoplagia (Diptera: Tephritidae).
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Herbivorous insects are abundant and diverse and insect-host plant associations tend to be specialized and evolutionarily conserved. Some authors suggested that generalist insect lineages tend to become specialists, with host specialization leading to an evolutionary dead-end for the parasite species. In this paper, we have examined this tendency using a phylogenetic tree of Tomoplagia (Diptera: Tephritidae), a parasite of asteracean plants. We have tested the trend towards specialization in different hierarchical degrees of host specialization. The topology of the tree, the inference of ancestral hosts, and the lack of directional evolution indicated that specialization does not correspond to a phylogenetic dead-end. Although most Tomoplagia species are restricted to a single host genus, specialization does not seem to limit further host range evolution. This work emphasizes the advantages of the use of different levels of specialization and the inclusion of occasional hosts to establish a more detailed scenario for the evolution of this kind of ecological association.
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2,337,632 |
The genetic-environmental etiology of parents' perceptions and self-assessed behaviours toward their 5-month-old infants in a large twin and singleton sample.
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Given the importance of parenting for the child's early socio-emotional development, parenting perceptions and behaviours, and their correlates, should be assessed as early as possible in the child's life. The goals of the present study were 1) to confirm, in two parallel population-based samples, including a large sample of twins, the factor structure of a new self-administered questionnaire assessing both parents' specific parenting perceptions and behaviours toward their 5-month-old infants (i.e., parental self-efficacy, perceived parental impact, parental hostile-reactive behaviours and parental overprotection), 2) to identify the specific risk factors associated with the negative side of these parenting dimensions, 3) to document the genetic-environmental etiology of these parenting dimensions through the twin method.</AbstractText>Parents (2,122 mothers and 1,829 fathers) of 5-month-old infants, and parents of 5-month-old infant twins (510 families) completed the questionnaire (28 items). The data were submitted to a series of confirmatory factor analyses. The contribution to parenting of a variety of risk factors was examined in the two samples using regression analyses. A series of quantitative genetic analyses were performed to quantify the different sources of variation in parenting.</AbstractText>A consistent factor structure was found across informants and across samples. There were significant mean differences in parenting between mothers and fathers, as well as between parents of twins and parents of singletons. A differentiated pattern of association with risk factors was found for each dimension of parenting. The twin analyses revealed that shared environment accounted for each parenting dimension. Maternal hostile-reactive behaviours were also moderately related to genetic factors in the child and this association was mainly mediated by the infant difficultness.</AbstractText>The overall pattern of results was consistent with Belsky's (1984) view of parenting as multiply determined. The longitudinal follow-up of these families should provide the means for testing developmental models about the determinants and outcomes of these parenting dimensions.</AbstractText>
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2,337,633 |
The Abantu phenotype in the ABO blood group system is due to a splice-site mutation in a hybrid between a new O1-like allelic lineage and the A2 allele.
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Many phenotypic variations in the expression of blood group A have been explained by variations in gene structure, but unresolved samples are frequently encountered in the reference laboratory. Among ABO subgroups, A(bantu) has the highest frequency in a specified population. The molecular basis of this phenotype is now described.</AbstractText>Blood from Black donors phenotyped as A(bantu) was subjected to genomic ABO screening and direct sequencing of polymerase chain reaction (PCR)-amplified ABO exons 1-7 and introns 2-6. Total RNA was extracted and ABO cDNA was synthesized by reverse transcription (RT)-PCR. Control material comprised Black South African, Swedish, Jordanian and Brazilian blood samples with common phenotypes.</AbstractText>Genomic ABO typing indicated the presence of an A(2) allele in each A(bantu) donor, in combination with an O allele. No previously reported mutations associated with weak A or B expression were found. Direct sequencing indicated the common A(2) sequence with a single nucleotide deletion (AGGT>AGT) at the exon 4/intron 4 junction, predicted either to disrupt the reading frame (resulting in a premature stop codon) or to cause erroneous splicing (resulting in the exclusion of exon 4 from the mRNA). O mRNA, but no transcripts from the A(bantu) allele, could be detected. Surprisingly, the splice-site mutation was also found in approximately 5% of O alleles in Black South Africans, but not in other blood donors, or in non-O(1) alleles. Utilizing intron polymorphisms, the A(bantu) allele was shown to be a recombination between a new allelic lineage (O(1bantu)) and A(2), with a cross-over region near exon 5.</AbstractText>The A(bantu) phenotype is caused by an O(1bantu)-A(2) hybrid at the ABO locus.</AbstractText>
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2,337,634 |
Yeast evolution and comparative genomics.
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Recent sequencing efforts and experiments have advanced our understanding of genome evolution in yeasts, particularly the Saccharomyces yeasts. The ancestral genome of the Saccharomyces sensu stricto complex has been subject to both whole-genome duplication, followed by massive sequence loss and divergence, and segmental duplication. In addition the subtelomeric regions are subject to further duplications and rearrangements via ectopic exchanges. Translocations and other gross chromosomal rearrangements that break down syntenic relationships occur; however, they do not appear to be a driving force of speciation. Analysis of single genomes has been fruitful for hypothesis generation such as the whole-genome duplication, but comparative genomics between close and more distant species has proven to be a powerful tool in testing these hypotheses as well as elucidating evolutionary processes acting on the genome. Future work on population genomics and experimental evolution will keep yeast at the forefront of studies in genome evolution.
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2,337,635 |
An efficient construction of conditionally replicating adenoviruses that target tumor cells with multiple factors.
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Despite the enormous potential of conditionally replicating adenoviruses (CRAs), the time-consuming and laborious methods required to construct CRAs have hampered both the development of CRAs that can specifically target tumors with multiple factors (m-CRA) and the efficient analysis of diverse candidate CRAs. Here, we present a novel method for efficiently constructing diverse m-CRAs. Elements involving viral replication, therapeutic genes, and adenoviral backbones were separately introduced into three plasmids of P1, P2, and P3, respectively, which comprised different antibiotic resistant genes, different ori, and a single loxP (H) sequence. Independently constructed plasmids were combined at 100% accuracy by transformation with originally prepared Cre and specific antibiotics in specific Escherichia coli; transfection of the resulting P1+2+3 plasmids into 293 cells efficiently generated m-CRAs. Moreover, the simultaneous generation of diverse m-CRAs was achieved at 100% accuracy by handling diverse types of P1+2 and P3. Alternatively, co-transfection of P1+3 and P2 plasmids into Cre-expressing 293 cells directly generated m-CRA with therapeutic genes. Thus, our three-plasmid system, which allows unrestricted construction and efficient fusion of individual elements, should expedite the process of generating, modifying, and testing diverse m-CRAs for the development of the ideal m-CRA for tumor therapy.
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2,337,636 |
Inheritance of seed dormancy in Tibetan semi-wild wheat accession Q1028.
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Tibetan semi-wild wheat (Triticum aestivum ssp. tibetanum Shao) is one of the Chinese endemic hexaploid wheat genetic resources, distributed only in the Qinghai-Xizang Plateau of China. It has special characters, such as a hulled glume and spike disarticulation. However, seed dormancy, another important character for wheat resistance to pre-harvest sprouting, was rarely reported. Seed dormancy of more than 10 Tibetan semi-wild wheat accessions was evaluated, and their germinations were 0% or near 0% with both treatments of threshed seeds and intact spikes at hard dough stage. Tibetan semi-wild wheat accession Q1028 was investigated for its seed dormant characters by testing the seed germination percentages of intact spikes, seeds with bract powder, normal seeds, seeds with pierced coat, and sectioned embryos. It was observed that embryo dormancy of Q1028 accounted for its seed dormancy. Using threshed seeds and intact spikes at hard dough stage, the inheritance of seed dormancy was carried out using the F1, F2, F3 and F2BC1 populations of the cross between Q1028 and a wheat line 88-1643, susceptible to preharvest sprouting. The germinations of seeds and intact spikes in F1 plants were 1.0% and 0.9%, respectively. It indicated that seed dormancy of Q1028 was inherited as a dominant trait. From the genetic analysis of the F2, F3 and F2BC1 populations it was found that the strong seed dormancy of Q1028 was controlled by two dominant genes.
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2,337,637 |
Autosomal dominant cerebellar ataxias in Spain: molecular and clinical correlations, prevalence estimation and survival analysis.
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The genetic and clinical profile of autosomal dominant cerebellar ataxias (ADCA) displays marked geographical and ethnical variability.</AbstractText>We have analysed the molecular and clinical correlations in an ethnically homogeneous sample of 30 Spanish ADCA kindreds. Minimal point prevalence for the region of Cantabria was estimated.</AbstractText>Seventy per cent of the families harboured known mutations. Areflexia, slow saccades and hypopallesthesia predominated in SCA2; nystagmus, pyramidal signs or areflexia restricted to the legs in SCA 3; and retinal degeneration, pyramidal signs and slow saccades in SCA 7. Anticipation and intergenerational instability were greater in SCA 7. Length of expansions and age at onset were inversely correlated in all SCA subtypes. Larger expansions correlated with areflexia in SCA 2, with pyramidal signs in SCA 3 and with early visual impairment in SCA 7. Survival was similar among the different SCA subtypes. Prevalence of ADCA in Cantabria was 1.6 cases per 100,000 population.</AbstractText>This report shows the epidemiological, clinical and genetic profile of ADCA in Spain, providing additional data regarding the broad clinical heterogeneity of these disorders and the variability of the genotype-phenotype correlations.</AbstractText>
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2,337,638 |
G309D and W437OPA PINK1 mutations in Caucasian Parkinson's disease patients.
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To determine whether the G309D and W437OPA mutations in PINK1 gene are present in American Caucasian population of patients with Parkinson's disease (PD).</AbstractText>We searched for the G309D and W437OPA mutation by sequencing the regions of interest in the PINK1 gene in 237 unrelated Caucasian patients.</AbstractText>None of the 237 samples showed the G309D or W437OPA mutations.</AbstractText>The G309D and W437OPA mutations in PINK1 gene probably do not represent common causes of familial or sporadic PD in a Caucasian population.</AbstractText>
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2,337,639 |
Predictive genetic testing for Alzheimer's disease: impact upon risk perception.
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The aim of this study was to determine the impact on risk perceptions of disclosing genetic test results used to estimate the risk of Alzheimer's disease (AD). Adult children (n = 149) of people with AD were randomized to one of two groups--Intervention group: lifetime risk estimates of AD based on age, gender, family history, and Apolipoprotein E (APOE) genotype;</AbstractText>lifetime risk estimates of AD based on the same risk factors excluding APOE genotype. Perceptions of personal risk (PPR) for AD were assessed six weeks after risk assessments. PPR were correlated with actual lifetime risk estimates (r = 0.501; p < 0.0001). After controlling for lifetime risks communicated to participants, age, and number of affected relatives, PPR scores among those with an epsilon4-positive test result (the test result associated with increased AD susceptibility) (adjusted mean: 3.4 (SD: 0.7)) were not different from the PPR scores in the CONTROL GROUP (adjusted mean: 3.4 (SD: 0.7) (F1,91= 1.98; p = 0.162). Again, controlling for lifetime risk estimates, age, and number of affected relatives, the PPR score of those receiving an epsilon4-negative test result was significantly lower (adjusted mean: 3.1 (SD: 0.8)) than those in the CONTROL GROUP (adjusted mean: 3.4 (SD: 0.7) (F1,95 = 6.23; p = 0.014). Perceptions of risk of developing AD are influenced by genetic test disclosure in those receiving epsilon4-negative, but not those receiving epsilon4-positive test results. Despite the reduced perceptions of risk in the former group, there was no evidence of false reassurance (i.e., perceiving risks as equal to or lower than population risks of AD), although this possibility should be assessed in other testing contexts.</AbstractText>
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2,337,640 |
The role of dental evaluation and cephalometric analysis in the diagnosis of Williams-Beuren syndrome.
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Williams-Beuren syndrome (WS) is a genetic condition with an incidence of 1 in 20,000-50,000 live births. The syndrome consists of supravalvular aortic stenosis, characteristic dysmorphic facial features named "elf face" and intellectual disability. Early diagnosis of the syndrome is important since many of its features require treatment, and the prognosis can be dramatically improved by early recognition and management. This developmental disorder is well known to be clinically heterogeneous, making diagnosis difficult if based on the clinical picture. However, genetic testing is expensive and it is not cost effective to screen all patients based on clinical suspicion. Our goal was to develop a novel clinical screening method that would be sensitive, specific, inexpensive and readily available. We performed cephalometric analysis and dental evaluation of 33 patients with genetically proven WS. Cephalometric analysis of soft tissues showed that with normal SNA, SNB and ANB angles, the lips were in front of the line of harmony. This finding was present in all WS patients (n = 33) but in none of the age-matched controls (n = 100). No other differences were found between WS and control patients. This cephalometric finding is specific and sensitive for WS and can be used in the diagnostic procedure, whereas none of the conventional dental evaluations are useful.
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2,337,641 |
Legal implications of pharmacogenomics regarding drug trials, drug labeling, and genetic testing for drug prescription: an international approach.
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Pharmacogenomics applies genomic technology to discover and develop drugs as well as to treat patients more effectively. This article addresses legal questions raised by pharmacogenomics, from drug development to drug use. Part II defines pharmacogenomics in further detail and explains the use of pharmacogenomics in drug development. Part III identifies potential legal questions raised by this approach to drug development and delivery. Parts IV to VIII offer possible solutions to these potential problems, analyzing the law in both the United States and the European Union (EU).
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2,337,642 |
Chronic pancreatitis with pancreaticolithiasis and pseudocyst in a 5-year-old boy with homozygous SPINK1 mutation.
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We report a 5-year-old boy with a 5-month history of symptoms owing to chronic pancreatitis. Abdominal imaging revealed a large pseudocyst in the pancreatic tail and concretions in the main pancreatic duct. Successful endoscopic papillotomy and stent implantation were performed. Genetic testing showed homozygous SPINK1-N34S mutation, which is an established risk factor for chronic pancreatitis.
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2,337,643 |
Pitfalls in the diagnosis of cervical intraepithelial neoplasia 1.
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This review article outlines the issues involved in (1) the cytologic diagnosis of low-grade squamous intra-epithelial lesion (cervical intraepithelial neoplasia [CIN] 1), (2) histologic diagnosis of CIN 1, (3) the advantages and disadvantages of various management strategies for CIN 1 confirmed by biopsy, and (4) the evolving technology that may be useful for predicting the course of the disease.</AbstractText>A MEDLINE search was conducted using the search terms cervical intraepithelial neoplasia, low-grade dysplasia, mild dysplasia, low-risk squamous intraepithelial lesion, mild dyskaryosis, HPV, colposcopy, histology, and cytology. RESULTS.: Using a loop electrosurgical excision procedure or cone biopsy assessment of the cervix as the gold standard, a cytologic assessment of CIN 1 alone results in a high false-positive rate (51.5%) and a false-negative rate (24%) for CIN 3. The appropriate second test after low-grade squamous intraepithelial lesion (CIN 1) cytologic results includes repeat cervical cytologic analysis. Subsequent human papillomavirus testing provides no advantage and increases the cost of care. Immediate referral to colposcopy is costly but minimizes the percent of women lost to follow-up. Using a loop electrosurgical excision procedure or cone biopsy assessment of the cervix as the gold standard, the colposcopically directed biopsy may give a false-positive result (11.7%) or false-negative result (up to 31%) for CIN 3. One contributing issue is the moderate interobserver reliability of histologic analysis (kappa= 0.46). There are advantages and disadvantages to both the immediate and expectant management strategies. The most crucial concern for immediate treatment is overtreatment, and that for expectant management the high rate of patients lost to follow-up. Novel technologies, including MIB-1, p16(INK)4a, and genetic assessments, may be helpful in predicting those CIN 1 lesions destined to progress or to persist.</AbstractText>The cytologic and histologic diagnosis of CIN 1 is fraught with problems related to the subjectivity of the diagnosis. Both management options are also fraught with concerns. Any technique that can better predict disease course would be an advantage to the care of women with this abnormality.</AbstractText>
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2,337,644 |
Isothermal RNA sequence amplification method for rapid antituberculosis drug susceptibility testing of Mycobacterium tuberculosis.
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RNA transcript quantification by an isothermal sequence amplification reaction was evaluated for susceptibility testing of 15 Mycobacterium tuberculosis strains. Agreement with the proportion method on Ogawa egg medium and the BACTEC MGIT 960 system was 100 and 87% for rifampin, 93 and 100% for isoniazid, 60 and 53% for ethambutol, and 80 and 80% for streptomycin, respectively.
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2,337,645 |
Comparison of a real-time reverse transcriptase PCR assay and a culture technique for quantitative assessment of viral load in children naturally infected with respiratory syncytial virus.
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Respiratory syncytial virus (RSV) is the most common cause of lower respiratory infection of children. Understanding RSV pathogenesis and evaluating interventions requires quantitative RSV testing. Previous studies have used the plaque assay technique. Real-time reverse transcriptase PCR (RTrtPCR) offers possible greater sensitivity, stability after freeze/thaw, and lower cost, thus facilitating multicenter studies. We developed RTrtPCR assays based upon the RSV N and F genes. The N-gene assay detected greater RSV quantity and was further evaluated. Standard curves utilized both extractions from RSV culture supernatants of known quantity and cloned purified copies of the target DNA. In vitro, the ratio of RSV subgroup A (RSV-A) genome copies to PFU was 153:1. A total of 462 samples collected quantitatively from 259 children were analyzed in duplicate by RTrtPCR. Results were compared with those of RSV plaque assays performed on fresh aliquots from the same children. Duplicate RTrtPCR results were highly correlated (r2 = 0.9964). The mean viral load from nasal washes obtained on the first study day was 5.75 +/- standard error of the mean 0.09 log PFU equivalents (PFUe)/ml. Viral load by RTrtPCR correlated with plaque assay results (r2 = 0.158; P < 0.0001). Within individuals, upper and lower respiratory tract secretions contained similar viral concentrations. RSV-A-infected children had 1.17 log PFUe higher viral loads than did those with RSV-B (P < 0.0001). RSV quantification by RTrtPCR of the N gene is precise and has significant, though limited, correlation with quantitative culture. The utility of the RTrtPCR quantification technique for clinical studies would be solidified after its correlation with RSV disease severity is established.
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2,337,646 |
Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer).
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Germ-line mutations in the mismatch-repair genes MLH1, MSH2, MSH6, and PMS2 lead to the development of the Lynch syndrome (hereditary nonpolyposis colorectal cancer), conferring a strong susceptibility to cancer. We assessed the frequency of such mutations in patients with colorectal cancer and examined strategies for molecular screening to identify patients with the syndrome.</AbstractText>Patients with a new diagnosis of colorectal adenocarcinoma at the major hospitals in metropolitan Columbus, Ohio, were eligible for the study. Genotyping of the tumor for microsatellite instability was the primary screening method. Among patients whose screening results were positive for microsatellite instability, we searched for germ-line mutations in the MLH1, MSH2, MSH6, and PMS2 genes with the use of immunohistochemical staining for mismatch-repair proteins, genomic sequencing, and deletion studies. Family members of carriers of the mutations were counseled, and those found to be at risk were offered mutation testing.</AbstractText>Of 1066 patients enrolled in the study, 208 (19.5 percent) had microsatellite instability, and 23 of these patients had a mutation causing the Lynch syndrome (2.2 percent). Among the 23 probands with the Lynch syndrome, 10 were more than 50 years of age and 5 did not meet the Amsterdam criteria or the Bethesda guidelines for the diagnosis of hereditary nonpolyposis colorectal cancer (including the use of age and family history to identify patients at high risk for the Lynch syndrome). Genotyping for microsatellite instability alone and immunohistochemical analysis alone each failed to identify two probands. In the families of 21 of the probands, 117 persons at risk were tested, and of these, 52 had Lynch syndrome mutations and 65 did not.</AbstractText>Routine molecular screening of patients with colorectal adenocarcinoma for the Lynch syndrome identified mutations in patients and their family members that otherwise would not have been detected. These data suggest that the effectiveness of screening with immunohistochemical analysis of the mismatch-repair proteins would be similar to that of the more complex strategy of genotyping for microsatellite instability.</AbstractText>Copyright 2005 Massachusetts Medical Society.</CopyrightInformation>
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2,337,647 |
Polymorphisms in the IL-12B gene and outcome of HCV infection.
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Most people with hepatitis C virus (HCV) develop chronic infection with persistent viremia. Resolution of infection is associated with antiviral cellular immune responses of T helper 1 (Th1) type. Interleukin-12 (IL-12) is a key cytokine in the generation of Th1 responses, and functionally relevant polymorphisms of the IL12B gene and its promoter have been described recently. We sought an association between three IL12B polymorphisms and outcome of HCV infection in 195 HCV antibody-positive patients; 123 were chronically infected with detectable HCV RNA, and 72 had spontaneously resolved infection testing repeatedly negative for HCV RNA. Genotyping was performed for a single nucleotide polymorphism (SNP) in the 3'-UTR (1188A/C) of the IL12B gene and for 4-bp insertion/deletion polymorphisms in the IL12B promoter region and in the intron 4 region of the IL12B gene. We found chronically infected patients were significantly more likely than those with resolved HCV infection to be homozygous for the 3'-UTR A allele (66% vs. 50%; chi-square = 4.12, p = 0.04 with Yates correction), which has been associated with lower IL-12 production. No other significant association was found. Our findings support the concept that an individual's genetically determined ability to produce IL-12 is another factor that can influence the outcome of HCV infection.
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2,337,648 |
The difference between observed and expected prevalence of MCAD deficiency in The Netherlands: a genetic epidemiological study.
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Medium chain acyl coenzyme A dehydrogenase (MCAD) deficiency is assumed to be the most common inherited disorder of mitochondrial fatty acid oxidation. Few reports mention the difference between the expected and observed prevalence of MCAD deficiency on the basis of the carrier frequency in the population. We performed a population-wide retrospective analysis of all known MCAD-deficient patients in The Netherlands. In this study, the observed prevalence of MCAD deficiency in The Netherlands was 1/27 400 (95% confidence interval (CI) 1/23 000-1/33 900), significantly different from the expected prevalence of 1/12 100 (95% CI 1/8450-1/18 500). The observed prevalence of MCAD deficiency showed a remarkable north-south trend within the country. From the patients in this cohort, it can be observed that underdiagnosis contributes to a larger extent to the difference between the expected and observed prevalences of MCAD deficiency in our country, than reduced penetrance. We determined estimates of the segregation proportion in a cohort of 73 families under the assumption of complete ascertainment (p(LM) = 0.41, 95% CI 0.31-0.51) and single ascertainment (p(D) = 0.28, 95% CI 0.19-0.37). With the expectation-maximization algorithm, a third estimate was obtained (p(EM) = 0.28, 95% CI 0.20-0.37). The agreement between the latter two estimates supports incomplete selection and the segregation proportions were in agreement with normal mendelian autosomal recessive inheritance.
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2,337,649 |
Screening of mutations in the CFTR gene in 1195 couples entering assisted reproduction technique programs.
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Genetic testing of the cystic fibrosis transmembrane conductance (CFTR) gene is currently performed in couples undergoing assisted reproduction techniques (ART), because of the high prevalence of healthy carriers in the population and the pathogenic relationship with congenital bilateral absence of vas deferens (CBAVD). However, discordant data have been reported concerning the usefulness of this genetic test in couples with no family history of cystic fibrosis (CF). In this study, we report the results of CFTR molecular screening in 1195 couples entering ART. Genetic testing was initially carried out in a single partner of each couple. CFTR mutations were detected in 55 subjects (4.6%), a percentage that overlaps with the one reported in the general population. However, significantly higher frequencies of were found in CBAVD individuals (37.5%) and in males with nonobstructive azoospermia (6.6%). The 5T allele was found in 78 patients (6.5%). This figure was again significantly different in males with nonobstructive-azoospermia (9.9%) and in those with CBAVD (100%). All together, 139 subjects (11.6%) had either a CFTR mutation or the 5T allele. Subsequent molecular analysis of their partners disclosed a CFTR mutation or 5T allele in nine cases (6.5%). However, none of these couples had CFTR alterations in both members, a CFTR mutation being invariably present in one partner and the 5T allele in the other. In order to improve genetic counselling of these couples, the TG-M470V-5T association was analyzed, and a statistically significant relationship between 12TG-V470 and CBAVD was detected.
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2,337,650 |
Genetic modifiers interact with Cpe(fat) to affect body weight, adiposity, and hyperglycemia.
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Obesity and Type II diabetes are complex diseases in the human population. The existence of a large number of contributing loci and gene-gene as well as gene-environment interactions make it difficult to identify the disease genes underlying these complex traits. In mouse models of obesity and Type II diabetes such as the murine fat mutation, genetic crosses can be used to dissect the genetic complexity influencing the observed phenotypes. The underlying defect in the fat mutant is a Ser202Pro change in carboxypeptidase E (CPE), an enzyme responsible for the final proteolytic processing step of prohormone intermediates. On the HRS/J (HRS) inbred strain background, mice homozygous for the fat mutation exhibit early onset hyperinsulinemia followed by postpubertal moderate obesity without hyperglycemia. In contrast, on the C57BLKS/J (BKS) genetic background, fat/fat mice become severely obese, hyperinsulinemic, and hyperglycemic. Therefore, in the Cpe(fat) genetic model, the fat mutation is necessary but not sufficient for the development of obesity, Type II diabetes, and related metabolic disorders. To dissect the susceptibility loci responsible for modifying obesity- and diabetes-associated traits, we characterized, both genetically and phenotypically, fat/fat male progeny from a large intercross between BKS. HRS-fat/fat and HRS-+/+ mice. Four major loci were mapped, including a locus for body weight (body weight 1) on chromosome 14; a locus for hyperglycemia (fat-induced diabetes 1) on chromosome 19; a locus for hyperglycemia, hyperinsulinemia, and hypercholesterolemia (fat-induced diabetes 2) on chromosome 5; and a locus for adiposity and body weight (fat-induced adiposity 1) on chromosome 11. The identification of these interacting genetic determinants for obesity and Type II diabetes may allow better definition of the obesity/diabetes-related hormone signaling pathways and ultimately may provide new insights into the pathogenesis of these complex diseases.
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2,337,651 |
How many clones need to be sequenced from a single forensic or ancient DNA sample in order to determine a reliable consensus sequence?
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Forensic and ancient DNA (aDNA) extracts are mixtures of endogenous aDNA, existing in more or less damaged state, and contaminant DNA. To obtain the true aDNA sequence, it is not sufficient to generate a single direct sequence of the mixture, even where the authentic aDNA is the most abundant (e.g. 25% or more) in the component mixture. Only bacterial cloning can elucidate the components of this mixture. We calculate the number of clones that need to be sampled (for various mixture ratios) in order to be confident (at various levels of confidence) to have identified the major component. We demonstrate that to be >95% confident of identifying the most abundant sequence present at 70% in the ancient sample, 20 clones must be sampled. We make recommendations and offer a free-access web-based program, which constructs the most reliable consensus sequence from the user's input clone sequences and analyses the confidence limits for each nucleotide position and for the whole consensus sequence. Accepted authentication methods must be employed in order to assess the authenticity and endogeneity of the resulting consensus sequences (e.g. quantification and replication by another laboratory, blind testing, amelogenin sex versus morphological sex, the effective use of controls, etc.) and determine whether they are indeed aDNA.
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2,337,652 |
Enhanced blood coagulation and fibrinolysis in mice lacking histidine-rich glycoprotein (HRG).
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Histidine-rich glycoprotein (HRG) is a serum protein belonging to the cystatin superfamily. HRG may play a regulatory role in hemostasis and innate immunity. However, this role is uncertain because of a lack of rigorous testing in an animal model. We generated mice lacking the translation start point of exon 1 of the Hrg gene, effectively resulting in a null mutation (Hrg-/-). The mice were viable and fertile but had no HRG in their blood. Antithrombin activity in the plasma of Hrg-/- mice was higher than in the plasma of heterozygous Hrg+/- or wild-type Hrg+/+ mice. The prothrombin time was shorter in Hrg-/- mice than in Hrg+/- and Hrg+/+ mice. Bleeding time after tail tip amputation in Hrg-/- mice was shorter than in Hrg+/+ mice. The spontaneous fibrinolytic activity in clotted blood of Hrg-/- mice was higher than in Hrg+/+ mice. These findings suggest that HRG plays a role as both an anticoagulant and an antifibrinolytic modifier, and may regulate platelet function in vivo.
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2,337,653 |
Activity and therapeutic potential of ORI-1001 antisense oligonucleotide on human papillomavirus replication utilizing a model of dysplastic human epithelium.
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Human Papillomaviruses (HPVs) are small double-stranded DNA viruses that infect the cutaneous or mucosal epithelium. The high-risk genital HPVs are associated with squamous intraepithelial lesions of the anogenital region that can progress to cancer. Cervical cancer is the third leading cause of cancer death in women worldwide, yet there are no specific therapeutic treatments for HPV-associated malignancies. Development of specific antisense oligonucleotides as antiviral agents is an alternative therapeutic strategy. We utilized the organotypic raft culture system which recapitulates the entire HPV life cycle, including the production of infectious virions. We studied the effect of the ORI-1001 antisense phosphorothioate oligonucleotide designed against the E1 mRNA translation start site of low-risk HPV6 and HPV11, and tested it against high-risk HPV31b and HPV16 vegetative replication and oncogene promoter activity. ORI-1001 significantly inhibited HPV31b genome amplification. In contrast, HPV16 genome amplification was unaffected. In addition, ORI-1001 significantly downregulated transcriptional activity from a HPV31b p99 early promoter luciferase reporter construct, and inhibited E1 and E6E7 transcript expression from the wild-type genome. Our results support the idea that the antisense activity of OR-1001 can target HPV31b functional activities in the differentiation dependent life cycle of this virus. Our results predict that binding stability between antisense oligonucleotides with partial homology to HPV genes may mediate targeting of multiple HPV types. Our studies also highlight the utility of the raft culture system in defining the parameters for testing antisense oligonucleotides against HPV.
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2,337,654 |
A breast cancer patient from Italy with germline mutations in both the BRCA1 and BRCA2 genes.
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We report the first case in Italy of a non-Ashkenazi double heterozygote for BRCA1 and BRCA2 genes. This finding is predictably rare, with a maximum frequency of 1/250,000. The proband and her mother were diagnosed with early-onset breast cancer. No other relatives with breast and/or ovarian cancer were observed. The implications of this case in regard to genetic testing and counseling are substantial.
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2,337,655 |
Cystic fibrosis lung disease: genetic influences, microbial interactions, and radiological assessment.
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Cystic fibrosis (CF) is a multiorgan disease caused by mutation of the CF transmembrane conductance regulator (CFTR) gene. Obstructive lung disease is the predominant cause of morbidity and mortality; thus, most efforts to improve outcomes are directed toward slowing or halting lung-disease progression. Current therapies, such as mucolytics, airway clearance techniques, bronchodilators, and antibiotics, aim to suppress airway inflammation and the processes that stimulate it, namely, retention and infection of mucus plaques at the airway surface. New approaches to therapy that aim to ameliorate specific CFTR mutations or mutational classes by restoring normal expression or function are being investigated. Because of its sensitivity in detecting changes associated with early airway obstruction and regional lung disease, high-resolution CT (HRCT) complements pulmonary function testing in defining disease natural history and measuring response to both conventional and experimental therapies. In this review, perspectives on the genetics and microbiology of CF provide a context for understanding the increasing importance of HRCT and other imaging techniques in assessing CF therapies.
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2,337,656 |
[Confidentiality, genetic counseling, and public health: a case study on sickle cell trait].
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Sickle cell anemia is the most prevalent genetic disease in Brazil. Screening for sickle cell trait in blood donation centers has been recommended by the Brazilian government since 1976. This screening mechanism is one of most common forms of genetic screening for sickle cell disease in the country. This article is based on an ethnographic survey of individuals undergoing genetic counseling in a large blood donation center. The article contends that confidentiality should be a prerequisite for the broad dissemination of genetic information in public health. The ethical principle of confidentiality needs to be seen as a human right and public health issue.
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2,337,657 |
Association of serotonin transporter gene polymorphism with obstructive sleep apnea syndrome.
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Obstructive sleep apnea syndrome (OSAS) is a common condition characterized by repetitive pharyngeal collapse during sleep and daytime sleepiness. There is genetic predisposition to sleep disorders. Serotonin is involved in the regulation of sleep. The synaptic 5-hydroxytryptamine (HT) is inactivated by presynaptic reuptake, which is mediated by the serotonin transporter. Blockage of the serotonin transporter leads to increased extracellular 5-HT. Polymorphism of the serotonin transporter gene (STG) leads to alterations in serotonin level and may be important in OSAS. In this study, we aimed to assess the role of STG polymorphism in OSAS.</AbstractText>Twenty-seven OSAS patients and 162 healthy volunteers were involved in the study. STG polymorphism was investigated using leukocytes obtained from peripheral blood.</AbstractText>There was no difference between the genotypes and allele frequencies of the patients and controls regarding VNTR and HTTLPR polymorphisms (P > .05). The VNTR and HTTLPR variants and the frequencies of 12/12, 12/10, L, and S alleles were not significantly different between male and female control subjects (P > .05). The 12/12 and SS genotypes were over-represented in the female patients, whereas 12/10 and LL genotypes were over-represented in the male patients (P < .05). The genotypes 12 to 12 were over-represented in the male controls, whereas the genotypes 12 to 10 and L/S were over-represented in the male patients (P < .05). The alleles 10 and L were more frequent in the male patients than male controls (P < .05). The genotypes of female patients and female controls were not significantly different (P > .05). The allele 10 and L were less frequent in the female patients than female controls with Fisher's exact testing (P < .05). There was no relation between genotypes and clinical data of the patients (P > .05).</AbstractText>STG polymorphism appears to be associated with the occurrence of OSAS, especially in male patients. Absence of association of between genetic variants and polysomnography findings may suggest that some mechanisms other than STG polymorphism are involved in OSAS pathophysiology. Our results need confirmation in a larger group of patients with OSAS.</AbstractText>
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2,337,658 |
What is new related to Helicobacter pylori infection in children and teenagers?
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Helicobacter pylori infection is a common bacterial infection for humans, and the organism is the most prevalent gastric microbial pathogen. However, the major route of transmission remains poorly understood. The outcome of chronic H pylori infection varies from asymptomatic gastritis to peptic ulceration and gastric malignancies. Recently, H pylori has been associated with the development of extradigestive disorders, including refractory iron-deficiency (sideropenic) anemia and chronic autoimmune thrombocytopenic purpura. Virulence factors of H pylori and host genetic factors are both considered important determinants of disease outcome. Multiple tests, including novel noninvasive approaches, are available for establishing the presence of H pylori infection, but there is still little consensus about which study should be performed and in what clinical setting. Eradicating H pylori uses combination therapy, including a proton pump inhibitor and 2 antibiotics taken twice daily for 7 to 14 days. Antibiotic resistance is a growing and serious problem that interferes with the success of eradication therapy. Testing and eradication therapy for H pylori are currently recommended only for the subset of infected persons in whom the disease sequelae are proven or highly suspected.
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2,337,659 |
Preimplantation genetic diagnosis: technological promise and ethical perils.
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To describe the ethical issues inherent to the current and foreseeable uses of preimplantation genetic diagnosis (PGD).</AbstractText>Review of ethical principles and their application to PGD.</AbstractText>Academic medical center.</AbstractText><AbstractText Label="PATIENT(S)" NlmCategory="METHODS">None.</AbstractText><AbstractText Label="INTERVENTION(S)" NlmCategory="METHODS">None.</AbstractText><AbstractText Label="MAIN OUTCOME MEASURE(S)" NlmCategory="METHODS">A discussion of the current ethical perils surrounding the use of PGD, and a prediction of future ethical quandaries that will arise from the use of this technology.</AbstractText><AbstractText Label="RESULT(S)" NlmCategory="RESULTS">Although PGD may be used to predict and prevent disease, it may also be used to determine nondisease traits. The ever-expanding ability of genetics to determine qualities of the preimplantation embryo continues to open up new ethical questions relating to the use of PGD for preimplantation diagnosis.</AbstractText><AbstractText Label="CONCLUSION(S)" NlmCategory="CONCLUSIONS">Preimplantation genetic diagnosis is a powerful technique with many positive applications. As with all such new technologies, care should be taken to ponder the ethical implications of its use before routinely accepting PGD as a tool in the reproductive armamentarium.</AbstractText>
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2,337,660 |
Identification of genes needed for regeneration, stem cell function, and tissue homeostasis by systematic gene perturbation in planaria.
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Planarians have been a classic model system for the study of regeneration, tissue homeostasis, and stem cell biology for over a century, but they have not historically been accessible to extensive genetic manipulation. Here we utilize RNA-mediated genetic interference (RNAi) to introduce large-scale gene inhibition studies to the classic planarian system. 1065 genes were screened. Phenotypes associated with the RNAi of 240 genes identify many specific defects in the process of regeneration and define the major categories of defects planarians display following gene perturbations. We assessed the effects of inhibiting genes with RNAi on tissue homeostasis in intact animals and stem cell (neoblast) proliferation in amputated animals identifying candidate stem cell, regeneration, and homeostasis regulators. Our study demonstrates the great potential of RNAi for the systematic exploration of gene function in understudied organisms and establishes planarians as a powerful model for the molecular genetic study of stem cells, regeneration, and tissue homeostasis.
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2,337,661 |
Opening a new can of worms: a large-scale RNAi screen in planarians.
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In this issue of Developmental Cell, Reddien et al. describe the first large-scale RNAi screen in freshwater planarians, classic models for regeneration studies. Their work paves the way for a detailed understanding of regeneration and tissue maintenance in these fascinating animals.
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2,337,662 |
Isolation of genes from plant Y chromosomes.
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Few plant species are dioecious and only a small fraction of these species are known to have sex chromosomes. Considerable efforts to isolate sex-linked genes from dioecious Silene latifolia (Caryophillaceae) have resulted in the isolation of surprisingly few sex-linked genes, suggesting that the methods used previously were not efficient in plants. This chapter analyzes the methods that have been and can be used for isolation of genes from plant sex chromosomes. The most successful method used for the isolation of Y-linked genes included the screening of a male complementary DNA (cDNA) library with the probe obtained by degenerate oligonucleotide-primed polymerase chain reaction (PCR) of the microdissected Y chromosomes. However, chromosome microdissection requires sophisticated equipment and is difficult to apply to species with cytologically indistinguishable sex chromosomes. Genome and cDNA library subtraction methods were surprisingly unsuccessful, probably because of low divergence between the homologous X- and Y-linked genes in plants. Segregation testing and genomics-based methods are increasingly popular and are the most promising approaches for isolation of multiple genes from plant sex chromosomes.
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2,337,663 |
Family studies in insomnia.
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Several predisposing factors to insomnia have been hypothesized, including a familial component; however, few studies have focused on this topic. The aim of this study is to evaluate the prevalence of insomnia among first-degree relatives of chronic insomniacs and to compare the symptoms between sporadic and familial insomnia.</AbstractText>Two hundred fifty-six consecutive chronic insomniacs completed a clinical interview, psychometric questionnaires, a questionnaire on the family history of insomnia and, when indicated, a polysomnography. A control group was performed to estimate a base-rate incidence of insomnia in their families.</AbstractText>Patients with primary (n=77) and psychiatric (n=104) insomnia were definitely included. Of those with primary insomnia, 72.7% reported familial insomnia compared with 24.1% in the noninsomnia control group. Among the psychiatric insomniacs, 43.3% reported familial insomnia. The mother was the relative most frequently affected. Comparisons between the family prevalence rates of insomnia assessed by the probands and by first-degree relatives show high concordance. A tendency to a younger age at onset was observed in familial and primary insomnia.</AbstractText>This study reports a significant increase of familial aggregation of insomnia, warranting further genetic studies in primary insomnia with early age at onset.</AbstractText>
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2,337,664 |
Classification of human population based on HLA gene polymorphism and the concept of Prakriti in Ayurveda.
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Correlating phenotypes with genotypes remains the major postgenomic challenge. Attempts to correlate phenotype characteristics associated with ethnicity, geographical divisions, or diseases to genotypes have had limited success. This means that current approaches for identifying phenotypes associated with haplotypes may be inadequate.</AbstractText>We hypothesize that a human phenome based on Ayurveda could provide an appropriate approach. Specifically, there could be a genetic basis for the three major constitutions (Prakriti) described in Ayurveda. The Prakriti classification is based on differences in physical, physiological, and psychologics characteristics and is independent of racial, ethnic, or geographical considerations. It may provide an appropriate means of classifying phenotypes to be considered collectively for genotyping.</AbstractText>As a pilot study to test the hypothesis, we evaluated 76 subjects both for their Prakriti and human leucocyte antigen (HLA) DRB1 types. The genomic DNA was extracted using a standard protocol. Subsequently, HLA DRB1 typing was done by low-resolution polymerase chain reaction sequence specific primers and oligonucleotide probes.</AbstractText>We observed a reasonable correlation between HLA type and Prakriti type. The complete absence of the HLA DRB1*02 allele in the Vata type and of HLA DRB1*13 in the Kapha type are significant, with X2 = 4.715 and p < 0.05. HLA DRB1*10 had higher allele frequency in the Kapha type than in the Pitta and Vata types.</AbstractText>Ayurveda classifies the whole human population in three major constitutions as Vata, Pitta, Kapha and their possible combinations. Their homologous relation to human genetic structure needs to be studied for validation. If validated, our hypothesis would have far reaching implications for pharmacogenomics, modern genetics, human health, and Ayurveda.</AbstractText>
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2,337,665 |
Complementary medicine and genetic medicine: polar disciplines or dynamic partners?
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For more than a decade, a powerful movement promoting the integration of complementary and alternative medicine (CAM) and conventional medicine has evolved. Throughout the same period, there has been a monumental shift in the biologic sciences, and in perspectives on disease, resulting from advances in genetics. It is noteworthy, and perhaps not coincidental, that these "movements" have been occurring in parallel. The simultaneous growth of complementary medicine and genetic medicine may be fueled by a deep interest in the development of "personalized" medicine. There is a prevailing view that the metaphysical visions of these two fields are in conflict. To advance discussion of this question, we describe what we believe are the common philosophies and goals of these apparently disparate fields, and why it would be advantageous for them to work together in the service of the public's health.
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2,337,666 |
Diagnostic value of mitochondrial DNA mutation analysis in juvenile unilateral ptosis.
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To highlight the diagnostic relevance of mitochondrial DNA (mtDNA) mutation analysis in acquired juvenile unilateral upper eyelid ptosis.</AbstractText>A 13-year-old boy presented with acquired, slowly progressive unilateral ptosis. We performed ophthalmological and neurological examinations, laboratory testing, skeletal muscle biopsy including histological and histochemical investigations, biochemical analysis of respiratory chain enzymes in skeletal muscle homogenate and molecular genetic testing of skeletal muscle DNA.</AbstractText>Though clinical, laboratory, histological and biochemical analyses did not reveal any hints suggesting a mitochondrial cytopathy, molecular genetic testing by Southern blot analysis of total DNA from skeletal muscle tissue showed a 5.8 kb mtDNA deletion thus proving the diagnosis of mitochondrial chronic progressive external ophthalmoplegia (CPEO).</AbstractText>In patients with unexplained acquired juvenile unilateral ptosis, an underlying mitochondrial cytopathy should be considered even in cases of inconspicuous ancillary examinations comprising skeletal muscle histology and biochemistry. To establish the diagnosis, molecular genetic testing of DNA derived from skeletal muscle tissue is essential in those patients.</AbstractText>
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2,337,667 |
[The value of pharmacogenetic tests in antidepressive medication therapy].
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The pharmacokinetics and effect of antidepressants are influenced by genetic factors. Modern methods of genotyping allow fast and inexpensive identification of genetic variants and thus can be used in clinical diagnostics to improve the tolerance to drug therapy. Numerous studies have investigated the significance of genetic variants in drug-metabolizing enzymes, drug and natural substrate transporters, neurotransmitter receptors, and molecules involved in signal transduction. While the interindividual differences in oral clearance, half-life, and bioavailability caused by genetic variants in the cytochrome P450 liver enzymes can be overcome by individual adjustment of dosage according to certain genotypes, the effects of genetic variants in antidepressive target structures are more difficult to translate into clinical recommendations. This article gives an overview of the currently available literature and points to situations in which the determination of pharmacogenetic variants might change drug therapy or therapeutic strategies for the individual patient. Dose adjustments for common antidepressant drugs based upon differences in pharmacokinetic parameters caused by genetic variability will be given.
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2,337,668 |
Testosterone and alcohol use among adolescent male twins: testing between-family associations in within-family comparisons.
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We examined associations of testosterone (T) and alcohol use in adolescent twin brothers, conducting both between- and within-family analyses. The twins completed semi-structured interviews, provided two saliva samples to assay T, and reported their drinking patterns and pubertal development. We adjusted T levels for diurnal/seasonal effects and association with pubertal maturation. In analyses of twins as individuals, higher T levels characterized boys reporting ever drinking, more frequent intoxication, high density drinking, more alcohol symptoms, and diagnosed alcohol dependency on interview. Adjusting for pubertal development, only associations with symptom count and diagnosis remained significant. The association with frequent intoxication replicated among drinking-discordant twin brothers, effectively ruling out between-family confounds, but that association was not significant after adjustment for pubertal development. The phenotypic correlation between T and pubertal maturation is largely genetic, inviting study of the magnitude and meaning of linkages between testosterone and symptoms of alcoholism on follow-up in early adulthood.
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2,337,669 |
Use of repeated measures to interpret genetic and environmental correlations in animal research.
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A method for partitioning environmental correlations into two distinct sources of covariation--lifetime rearing effects and idiosyncratic stimulus events occurring during testing ("noise")--is presented. The method, which is based on structural equation modeling of repeated tests, is demonstrated using correlations obtained from pairs of sessions in an Open Field Test and in a Light-Dark Test. Heritabilities of most behaviors are low, but genetic correlations between- and within-test sessions are high and thus substantively influence phenotypic correlations, including test-retest reliability. Testing "noise" is usually the primary source of environmental covariance among pairs of measures, although some instances of rearing environment being the sole source of E correlations were observed. Effects of Session 1 testing and/or the additional experience between S1 and S2 test sessions produce some significant differences between S1 and S2 within-session correlations, but these are usually not large. Although varying in size, the genetic, the rearing environment and the test environment correlations between a pair of variables were always consistent in sign. The analysis demonstrates the value of incorporating some of the contemporary research and analytic strategies used in the human individual differences field into animal studies.
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2,337,670 |
Optimal conditions and specific characteristics of Vent exo- DNA polymerase in ligation-mediated polymerase chain reaction protocols.
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An optimized procedure for the ligation-mediated polymerase chain reaction (PCR) technique using Thermococcus litoralis exo- DNA polymerase (Vent exo-) was developed. The optimal dosage of Vent exo- at the primer extension and PCR amplification steps as well as the optimal DNA quantity to use were established. We showed that Vent exo- can efficiently create the blunt-ended termini required for subsequent linker ligation. Vent exo- proves to be more efficient than Pyrococcus furiosus exo- (Pfu exo-) for this task. Vent exo- resolves highly GC-rich sequence substantially better than Thermus aquaticus DNA polymerase (Taq) and with a similar efficiency as Pfu exo-. The DNA/DNA polymerase activity ratio is significantly higher for Vent exo- than for Pfu exo-, which is reflected by the sensibility of Vent exo- in efficiently amplifying genomic DNA. Furthermore, the range of efficiency of Vent exo- demonstrates the importance of conducting evaluative testing to identify the optimal dosage of use of this polymerase to obtain successful PCR amplification. Optimal MgSO4 concentrations to use with Vent exo- were established. Our results show that Vent exo- DNA polymerase produces bands of uniform and strong intensity and can efficiently be used for the analysis of DNA in living cells by ligation-mediated PCR.
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2,337,671 |
Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance.
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Evasion from apoptosis is a hallmark of cancer, and recent success using targeted therapeutics underscores the importance of identifying anti-apoptotic survival pathways. Here we utilize RNA interference (RNAi) to systematically screen the kinase and phosphatase component of the human genome. In addition to known kinases, we identified several new survival kinases. Interestingly, numerous phosphatases and associated regulatory subunits contribute to cell survival, revealing a previously unrecognized general role for phosphatases as negative regulators of apoptosis. We also identified a subset of phosphatases with tumour-suppressor-like activity. Finally, RNAi targeting of specific protein kinases sensitizes resistant cells to chemotherapeutic agents. The development of inhibitors that target these kinases or phosphatases may lead to new anti-cancer strategies.
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2,337,672 |
Pharmacogenetic testing for drug metabolizing enzymes: is it happening in practice?
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It is widely claimed that pharmacogenetics may form the basis of 'personalized medicine'. We sought to determine the current utilization of pharmacogenetic testing for drug metabolizing enzymes (DMEs). The hypothesis was that these tests were rarely performed clinically. Questionnaires were sent to 629 individuals representing laboratories, hospitals and universities throughout Australia and New Zealand. The questionnaires asked which facilities performed pharmacogenetic tests for selected DMEs, and details about the tests, if performed. The overall response rate was 81.1% (510/629); three respondents declined to participate. Clinical genotyping and phenotyping tests for DMEs could be performed by 10 (2.0% of 507) and 18 (3.6%) facilities, respectively. The most frequently performed genetic tests were for thiopurine methyltransferase (approximately 400 times in 2003) and pseudocholinesterase (approximately 250 times). The frequency of phenotyping exceeded genotyping by five- and eight-fold, respectively. One centre performed CYP2D6 phenotyping frequently (approximately 4200 times in 2003) for perhexiline. Genotyping and phenotyping tests for other cytochrome P450 enzymes, N-acetyltransferase-2 and dihydropyrimidine dehydrogenase were effectively never undertaken for clinical purposes. Pharmacogenetic tests for DMEs are currently performed rarely in clinical practice, despite repeated claims that they may benefit patient care. The only tests performed with any regularity in Australasia are for thiopurine methyltransferase and pseudocholinesterase, and CYP2D6 phenotyping in one centre for patients on perhexiline. The low clinical utilization reflects a poor evidence base, unestablished clinical relevance and, in the few cases with the strongest rationale, a slow translation to the clinical setting.
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2,337,673 |
A mutation in the drug transporter gene ABCC2 associated with impaired methotrexate elimination.
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Human multidrug resistance protein 2 (MRP2, encoded by ABCC2) is involved in active efflux of anionic drugs such as methotrexate. MRP2 is expressed on the luminal side of hepatocytes and renal proximal tubular cells, indicating an important role in drug elimination. We postulated that loss-of-function mutations in ABCC2, which are involved in the Dubin-Johnson syndrome, may be associated with impaired methotrexate elimination and an increased risk of toxicity. We studied the biological phenotype and ABCC2 coding sequence in a patient receiving a high-dose methotrexate infusion for large B-cell lymphoma and who had an unusual pharmacokinetic profile, mainly characterized by a three-fold reduction in the methotrexate elimination rate. This resulted in severe methotrexate over-dosing and reversible nephrotoxicity. An inversion of the urinary coproporphyrin isomer I/III ratio (a specific biological marker of the Dubin-Johnson syndrome) was observed in this patient. Genetic analysis of ABCC2 identified a heterozygous mutation replacing a highly conserved arginine by glycine in the cytoplasmic part of the second membrane-spanning domain (position 412 of MRP2), a region associated with substrate affinity. This genetic variant was not found in a control population. Functional analysis in transiently transfected Chinese hamster ovary cells revealed a loss of transport activity of the G412 MRP2 mutant protein. An ABCC2 mutation altering MRP2-mediated methotrexate transport and resulting in impaired drug elimination and subsequent renal toxicity was identified. Candidates for methotrexate therapy should be considered for MRP2 functional testing.
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2,337,674 |
Genetic factors related to unconjugated hyperbilirubinemia amongst adults.<Pagination><StartPage>43</StartPage><EndPage>50</EndPage><MedlinePgn>43-50</MedlinePgn></Pagination><Abstract><AbstractText>Some variations in the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene are involved in the development of unconjugated hyperbilirubinemia. We hypothesize that other genetic factors may also be associated with this disease. A total of 227 adults with normal routine haematology and liver function (apart from bilirubin testing for which they revealed bilirubin > or = 25.7 micromol/l and unconjugated bilirubin/total bilirubin > or = 80%), and 235 sex- and age-matched controls, were recruited. All subjects were analysed for UGT1A1, glucose-6-phosphate dehydrogenase (G6PD) and organic anion transporter polypeptide 2 (OATP2) genotypes using polymerase chain reaction-restriction fragment length polymorphism. The results indicated that G6PD deficiency, variant UGT1A1 gene and variant OATP2 gene were risk factors for hyperbilirubinemia. The odds ratios (OR) (with 95% confidence interval) were 220.83 (34.68-1406.30), 73.61 (17.01-318.63), 45.15 (11.19-182.22), 15.46 (4.35-54.99) and 6.51 (1.83-23.09), respectively, for individuals featuring the common UGT1A1/OATP2 haplotypes homozygous/heterozygous, compound heterozygous/heterozygous, compound heterozygous/wild-type, heterozygous/heterozygous and heterozygous/wild-type variations amongst subjects with normal G6PD activity. Amongst the subjects with G6PD deficiency, the OR was 159.00 (24.57-1028.94) for individuals carrying variations in both UGT1A1 and OATP2 genes. The UGT1A1/OATP2 haplotypes homozygous/wild-type, homozygous/compound heterozygous and homozygous/homozygous for G6PD normal and variant/wild-type for G6PD deficient individuals were only observed in the case group, and not in the control group. Amongst hyperbilirubinemic adults, bilirubin values tended to parallel variation status of their haplotypes. Adults featuring certain haplotypes in UGT1A1, OATP2 and G6PD genes face a high risk of developing unconjugated hyperbilirubinemia.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Huang</LastName><ForeName>Ching-Shan</ForeName><Initials>CS</Initials><AffiliationInfo><Affiliation>Department of Medical Technology, Fooyin University, Kaohsiung, Taiwan. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Huang</LastName><ForeName>May-Jen</ForeName><Initials>MJ</Initials></Author><Author ValidYN="Y"><LastName>Lin</LastName><ForeName>Min-Shung</ForeName><Initials>MS</Initials></Author><Author ValidYN="Y"><LastName>Yang</LastName><ForeName>Sien-Sing</ForeName><Initials>SS</Initials></Author><Author ValidYN="Y"><LastName>Teng</LastName><ForeName>Hsiu-Chen</ForeName><Initials>HC</Initials></Author><Author ValidYN="Y"><LastName>Tang</LastName><ForeName>Kung-Sheng</ForeName><Initials>KS</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Pharmacogenet Genomics</MedlineTA><NlmUniqueID>101231005</NlmUniqueID><ISSNLinking>1744-6872</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D027381">Liver-Specific Organic Anion Transporter 1</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 1.1.1.49</RegistryNumber><NameOfSubstance UI="D005954">Glucosephosphate Dehydrogenase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.4.1.-</RegistryNumber><NameOfSubstance UI="C418331">UGT1A1 enzyme</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.4.1.17</RegistryNumber><NameOfSubstance UI="D014453">Glucuronosyltransferase</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000328" MajorTopicYN="N">Adult</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016022" MajorTopicYN="N">Case-Control Studies</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005838" MajorTopicYN="N">Genotype</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005954" MajorTopicYN="N">Glucosephosphate Dehydrogenase</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014453" MajorTopicYN="N">Glucuronosyltransferase</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006239" MajorTopicYN="N">Haplotypes</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006579" MajorTopicYN="N">Heterozygote</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006720" MajorTopicYN="N">Homozygote</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006932" MajorTopicYN="N">Hyperbilirubinemia</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008099" MajorTopicYN="N">Liver</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D027381" MajorTopicYN="N">Liver-Specific Organic Anion Transporter 1</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008875" MajorTopicYN="N">Middle Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009154" MajorTopicYN="N">Mutation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016017" MajorTopicYN="N">Odds Ratio</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016133" MajorTopicYN="N">Polymerase Chain Reaction</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012150" MajorTopicYN="N">Polymorphism, Restriction Fragment Length</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012307" MajorTopicYN="N">Risk Factors</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>5</Month><Day>3</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>7</Month><Day>19</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>5</Month><Day>3</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15864125</ArticleId><ArticleId IdType="doi">10.1097/01213011-200501000-00007</ArticleId><ArticleId IdType="pii">01213011-200501000-00007</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15864026</PMID><DateCompleted><Year>2005</Year><Month>06</Month><Day>30</Day></DateCompleted><DateRevised><Year>2019</Year><Month>06</Month><Day>06</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0009-921X</ISSN><JournalIssue CitedMedium="Print"><Issue>434</Issue><PubDate><Year>2005</Year><Month>May</Month></PubDate></JournalIssue><Title>Clinical orthopaedics and related research</Title><ISOAbbreviation>Clin Orthop Relat Res</ISOAbbreviation></Journal>Prenatal diagnosis of musculoskeletal anomalies.
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Some variations in the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene are involved in the development of unconjugated hyperbilirubinemia. We hypothesize that other genetic factors may also be associated with this disease. A total of 227 adults with normal routine haematology and liver function (apart from bilirubin testing for which they revealed bilirubin > or = 25.7 micromol/l and unconjugated bilirubin/total bilirubin > or = 80%), and 235 sex- and age-matched controls, were recruited. All subjects were analysed for UGT1A1, glucose-6-phosphate dehydrogenase (G6PD) and organic anion transporter polypeptide 2 (OATP2) genotypes using polymerase chain reaction-restriction fragment length polymorphism. The results indicated that G6PD deficiency, variant UGT1A1 gene and variant OATP2 gene were risk factors for hyperbilirubinemia. The odds ratios (OR) (with 95% confidence interval) were 220.83 (34.68-1406.30), 73.61 (17.01-318.63), 45.15 (11.19-182.22), 15.46 (4.35-54.99) and 6.51 (1.83-23.09), respectively, for individuals featuring the common UGT1A1/OATP2 haplotypes homozygous/heterozygous, compound heterozygous/heterozygous, compound heterozygous/wild-type, heterozygous/heterozygous and heterozygous/wild-type variations amongst subjects with normal G6PD activity. Amongst the subjects with G6PD deficiency, the OR was 159.00 (24.57-1028.94) for individuals carrying variations in both UGT1A1 and OATP2 genes. The UGT1A1/OATP2 haplotypes homozygous/wild-type, homozygous/compound heterozygous and homozygous/homozygous for G6PD normal and variant/wild-type for G6PD deficient individuals were only observed in the case group, and not in the control group. Amongst hyperbilirubinemic adults, bilirubin values tended to parallel variation status of their haplotypes. Adults featuring certain haplotypes in UGT1A1, OATP2 and G6PD genes face a high risk of developing unconjugated hyperbilirubinemia.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Huang</LastName><ForeName>Ching-Shan</ForeName><Initials>CS</Initials><AffiliationInfo><Affiliation>Department of Medical Technology, Fooyin University, Kaohsiung, Taiwan. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Huang</LastName><ForeName>May-Jen</ForeName><Initials>MJ</Initials></Author><Author ValidYN="Y"><LastName>Lin</LastName><ForeName>Min-Shung</ForeName><Initials>MS</Initials></Author><Author ValidYN="Y"><LastName>Yang</LastName><ForeName>Sien-Sing</ForeName><Initials>SS</Initials></Author><Author ValidYN="Y"><LastName>Teng</LastName><ForeName>Hsiu-Chen</ForeName><Initials>HC</Initials></Author><Author ValidYN="Y"><LastName>Tang</LastName><ForeName>Kung-Sheng</ForeName><Initials>KS</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Pharmacogenet Genomics</MedlineTA><NlmUniqueID>101231005</NlmUniqueID><ISSNLinking>1744-6872</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D027381">Liver-Specific Organic Anion Transporter 1</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 1.1.1.49</RegistryNumber><NameOfSubstance UI="D005954">Glucosephosphate Dehydrogenase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.4.1.-</RegistryNumber><NameOfSubstance UI="C418331">UGT1A1 enzyme</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.4.1.17</RegistryNumber><NameOfSubstance UI="D014453">Glucuronosyltransferase</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000328" MajorTopicYN="N">Adult</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016022" MajorTopicYN="N">Case-Control Studies</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005838" MajorTopicYN="N">Genotype</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005954" MajorTopicYN="N">Glucosephosphate Dehydrogenase</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014453" MajorTopicYN="N">Glucuronosyltransferase</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006239" MajorTopicYN="N">Haplotypes</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006579" MajorTopicYN="N">Heterozygote</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006720" MajorTopicYN="N">Homozygote</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006932" MajorTopicYN="N">Hyperbilirubinemia</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008099" MajorTopicYN="N">Liver</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D027381" MajorTopicYN="N">Liver-Specific Organic Anion Transporter 1</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008875" MajorTopicYN="N">Middle Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009154" MajorTopicYN="N">Mutation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016017" MajorTopicYN="N">Odds Ratio</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016133" MajorTopicYN="N">Polymerase Chain Reaction</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012150" MajorTopicYN="N">Polymorphism, Restriction Fragment Length</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012307" MajorTopicYN="N">Risk Factors</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>5</Month><Day>3</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>7</Month><Day>19</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>5</Month><Day>3</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15864125</ArticleId><ArticleId IdType="doi">10.1097/01213011-200501000-00007</ArticleId><ArticleId IdType="pii">01213011-200501000-00007</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">15864026</PMID><DateCompleted><Year>2005</Year><Month>06</Month><Day>30</Day></DateCompleted><DateRevised><Year>2019</Year><Month>06</Month><Day>06</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0009-921X</ISSN><JournalIssue CitedMedium="Print"><Issue>434</Issue><PubDate><Year>2005</Year><Month>May</Month></PubDate></JournalIssue><Title>Clinical orthopaedics and related research</Title><ISOAbbreviation>Clin Orthop Relat Res</ISOAbbreviation></Journal><ArticleTitle>Prenatal diagnosis of musculoskeletal anomalies.</ArticleTitle><Pagination><StartPage>8</StartPage><EndPage>15</EndPage><MedlinePgn>8-15</MedlinePgn></Pagination><Abstract>Musculoskeletal anomalies are not uncommon in prenatal life. They can be either sporadic or part of chromosomal syndromes causing prenatal morbidity and mortality. The prenatal diagnosis of musculoskeletal anomalies is based on information assembled from various imaging modalities and from biochemical and genetic workups. The prenatal diagnosis can serve as a prognostic tool and in counseling the parents. Among the imaging methods, ultrasonography is the most popular and cost effective in observing and following fetal development from the very early stages of gestation. Transvaginal sonography can detect and identify most of the normal and the specific pathologic changes very close to the stage of their embryogenic development. From a practical point of view, early detailed transvaginal sonography screening at 14 to 15 weeks of gestation is very useful while late detection at 20 to 23 weeks of gestation may provide some additional information in low-risk pregnancies. Very early screening, even during the ninth week, may be indicated in high-risk pregnancies. Additional genetic counseling is recommended when abnormal findings are suspected. We summarize the diagnostic approach and the information available for the most common musculoskeletal anomalies.
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2,337,675 |
[Multiple endocrine neoplasia syndromes. Type 2].
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The second type of multiple endocrine neoplasia syndromes can be described as rare syndromes, heritable in autosomal dominant manner and linking medullary thyroid carcinoma to different tumors of endocrine organ system and endocrinopathies. This syndrome is divided into multiple endocrine neoplasia syndrome type 2A (MEN 2A), characterized with combination of medullary thyroid carcinoma, pheochromocytoma and primary hyperparathyroidism; type 2B (MEN 2B), characterized with combination of medullary thyroid carcinoma, pheochromocytoma, marfanoid habitus and ganglioneuromatosis, and familial medullary thyroid carcinoma syndrome, characterized with the only indication, which is hereditary medullary thyroid carcinoma. Though type 2 multiple endocrine neoplasia syndrome has been known since 1961, yet, the cause of the syndrome, which is germline mutations of c-ret protooncogene, was detected just a decade ago and syndrome pathogenesis with its characterized endocrine neoplasia carcinogenesis machinery were detected. Implementation of progressive genetic researches in clinical practice enabled precise diagnosis of multiple endocrine neoplasia syndrome and its subtypes not only for ill patients but also for healthy syndrome inheritors, e.g. relatives of the sick. Stated genotype link to phenotype helps to prognosticate possible combinations of endocrine neoplasia and endocrinopathies, and to choose purposeful patient observation. Genetic screening of the inheritors of multiple endocrine neoplasia type 2 syndrome enabled purposeful researches and observations of patients with a huge risk of uprising endocrine neoplasia, it also enabled application of effective prophylaxis methods, avoidance or early diagnostic of malignant tumors and life prognosis improvement for patients with malignant tumors while practicing well-timed treatment adaptation. This literature review contains the newest data on multiple endocrine neoplasia syndrome type 2 and its pathogenesis, diagnostics, patient observation, endocrine cancer prophylaxis and methods of treatment, which are characteristic for syndrome and which are being chosen according to biochemical endocrine neoplasia symptoms and genetic diagnosis.
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2,337,676 |
Evidence of an association between genetic variation of the coactivator PGC-1beta and obesity.
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Peroxisome proliferator activated receptor-gamma coactivator-1beta (PGC-1beta) is a recently identified homologue of the tissue specific coactivator PGC-1alpha, a coactivator of transcription factors such as the peroxisome proliferators activated receptors and nuclear respiratory factors. PGC-1alpha is involved in adipogenesis, mitochondrial biogenesis, fatty acid beta oxidation, and hepatic gluconeogenesis.</AbstractText>We studied variation in the coding region of human PPARGC1B in Danish whites and related these variations to the prevalence of obesity and type 2 diabetes in population based samples.</AbstractText>Twenty nucleotide variants were identified. In a study of 525 glucose tolerant subjects, the Ala203Pro and Val279Ile variants were in almost complete linkage disequilibrium (R2 = 0.958). In a case-control study of obesity involving a total of 7790 subjects, the 203Pro allele was significantly less frequent among obese participants (p = 0.004; minor allele frequencies: normal weight subjects 8.1% (95% confidence interval: 7.5 to 8.8), overweight subjects 7.6% (7.0 to 8.3), obese subjects 6.5% (5.6 to 7.3)). In a case-control study involving 1433 patients with type 2 diabetes and 4935 glucose tolerant control subjects, none of the examined variants were associated with type 2 diabetes.</AbstractText>Variation of PGC-1beta may contribute to the pathogenesis of obesity, with a widespread Ala203 allele being a risk factor for the development of this common disorder.</AbstractText>
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2,337,677 |
Reverse cascade screening of newborns for hereditary haemochromatosis: a model for other late onset diseases?
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Genetic testing can determine those at risk for hereditary haemochromatosis (HH) caused by HFE mutations before the onset of symptoms. However, there is no optimum screening strategy, mainly owing to the variable penetrance in those who are homozygous for the HFE Cys282Tyr (C282Y) mutation. The objective of this study was to identify the majority of individuals at serious risk of developing HFE haemochromatosis before they developed life threatening complications.</AbstractText>We first estimated the therapeutic penetrance of the C282Y mutation in people living in la Somme, France, using genetic, demographic, biochemical, and follow up data. We examined the benefits of neonatal screening on the basis of increased risk to relatives of newborns carrying one or two copies of the C282Y mutation. Between 1999 and 2002, we screened 7038 newborns from two maternity hospitals in the north of France for the C282Y and His63Asp (H63D) mutations in the HFE gene, using bloodspots collected on Guthrie cards. Family studies and genetic counselling were undertaken, based on the results of the baby's genotype.</AbstractText>In la Somme, we found that 24% of the adults homozygous for the C282Y mutation required at least 5 g iron to be removed to restore normal iron parameters (that is, the therapeutic penetrance). In the reverse cascade screening study, we identified 19 C282Y homozygotes (1/370), 491 heterozygotes (1/14) and 166 compound heterozygotes (1/42) in 7038 newborns tested. The reverse cascade screening strategy resulted in 80 adults being screened for both mutations. We identified 10 previously unknown C282Y homozygotes of whom six (four men and two women) required venesection. Acceptance of neonatal screening was high; parents understood the risks of having HH and the benefits of early detection, but a number of parents were reluctant to take the test themselves. Neonatal screening for HH is straightforward. Reverse cascade screening increased the efficiency of detecting affected adults with undiagnosed haemochromatosis. This strategy allows almost complete coverage for HH and could be a model for efficient screening for other late onset genetic diseases.</AbstractText>
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2,337,678 |
Large genomic rearrangements of both BRCA2 and BRCA1 are a feature of the inherited breast/ovarian cancer phenotype in selected families.
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A strong family history of breast and/or ovarian cancer can often be explained by small insertions, deletions, or substitutions in BRCA1 or BRCA2 and large genomic rearrangements in BRCA1. However, there is little evidence that genomic rearrangements are a major factor in BRCA2 associated breast cancer and the frequencies of rearrangements in BRCA1 in large clinic based populations are unknown.</AbstractText>To investigate the frequency of large genomic rearrangements in BRCA1 and BRCA2 in a large clinic based population at high risk of developing breast and/or ovarian cancer.</AbstractText>Multiplex ligation dependent probe amplification was used to comprehensively screen BRCA1 and/or BRCA2 in 312 index cases.</AbstractText>Three novel deletions detected in BRCA2 were found exclusively in families with at least one case of male breast cancer. Novel rearrangements in BRCA1 were detected mostly in families with both breast and ovarian cancer. Families with these mutations were significantly younger at average age of cancer diagnosis.</AbstractText>Screening for large genomic rearrangements in both BRCA1 and BRCA2 is strongly supported by this study, in particular in multiple case breast/ovarian families with a young age of onset (BRCA1) and families containing at least one case of male breast cancer (BRCA2).</AbstractText>
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2,337,679 |
Is maternal duplication of 11p15 associated with Silver-Russell syndrome?
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Silver-Russell syndrome (SRS) is a heterogeneous malformation syndrome characterised by intrauterine and postnatal growth retardation (IUGR, PGR) and dysmorphisms. The basic causes are unknown, however in approximately 10% of patients a maternal uniparental disomy (UPD) of chromosome 7 or chromosomal aberrations can be detected. Four growth retarded children, two with SRS-like features, associated with maternal duplications of 11p15 have been described. Considering the involvement of this genomic region in Beckwith-Wiedemann overgrowth syndrome (BWS), we postulated that some cases of SRS--with an opposite phenotype to BWS--might also be caused by genomic disturbances in 11p15.</AbstractText>A total of 46 SRS patients were screened for genomic rearrangements in 11p15 by STR typing and FISH analysis.</AbstractText>Two SRS patients with duplications of maternal 11p material in our study population (n = 46) were detected. In patient SR46, the duplicated region covered at least 9 Mb; FISH analysis revealed a translocation of 11p15 onto 10q. In patient SR90, additional 11p15 material (approximately 5 Mb) was translocated to the short arm of chromosome 15.</AbstractText>We suggest that diagnostic testing for duplication in 11p15 should be offered to patients with severe IUGR and PGR with clinical signs reminiscent of SRS. SRS is a genetically heterogeneous condition and patients with a maternal duplication of 11p15.5 may form an important subgroup.</AbstractText>
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2,337,680 |
Nuchal translucency thickness in fetuses with chromosomal translocation at 11-12 weeks of gestation.
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To investigate differences in nuchal translucency thickness among fetuses in which either parent is a balanced chromosome translocation carrier.</AbstractText>A prospective observational study was conducted with 98 pregnant women in the first trimester. Each had been advised to undergo chorionic villous sampling for fetal karyotyping for the indication of parental balanced chromosomal translocation. Fetal nuchal translucency measurement was performed before chorionic villous sampling. Nuchal translucency thickness was compared among fetuses with 3 kinds of karyotypes: normal, balanced translocation, and unbalanced translocation.</AbstractText>There were no differences in maternal age, gestational age, parity, and number of previous miscarriages among pregnancies with normal karyotype, balanced chromosomal translocation, and unbalanced chromosomal translocation. A significantly greater nuchal translucency thickness was shown in the unbalanced chromosomal translocation group (2.9 +/- 1.2 mm) compared with both the balanced chromosomal translocation group (1.0 +/- 0.6 mm; P < .001) and the normal karyotype group (1.0 +/- 0.8 mm; P < .001). No statistically significant difference in nuchal translucency thickness was found between the balanced chromosomal translocation group and normal karyotype group (P = .991). Nuchal translucency thickness did not differ significantly between unbalanced chromosomal translocation dependent on paternal origin and that dependent on maternal origin (P = .611).</AbstractText>In fetuses with unbalanced chromosomal translocation, nuchal translucency thickness tends to be greater, and thus nuchal translucency measurement might be considered part of the investigation for pregnancies marked by a parental balanced chromosomal translocation.</AbstractText>
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2,337,681 |
Controversies and ethical issues in cancer-genetics clinics.
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Genetic testing is a powerful technology that enables prediction of future health status. Testing for cancer-predisposition genes provides information for both the individual and his or her family. The use of this information reaches beyond the medical sphere to the psychological, social, legal, and ethical. The important issues include informed consent, autonomy, confidentiality, justice, disclosure and non-disclosure, duty to warn, genetic discrimination, predictive genetic testing of children, preimplantation genetic diagnosis, and patenting of cancer-predisposition genes.
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2,337,682 |
Intra-abdominal carcinomatosis after prophylactic oophorectomy in women of hereditary breast ovarian cancer syndrome kindreds associated with BRCA1 and BRCA2 mutations.
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Prophylactic surgical removal of the ovaries has been offered for many years as a potential preventative of ovarian cancer in women deemed to be at increased hereditary risk for this disease. Now, it is possible to test for specific mutations of the BRCA1 and BRCA2 genes that render members of hereditary breast ovarian cancer (HBOC) syndrome families susceptible to cancer. Widespread intra-abdominal carcinomatosis, which mimics metastatic ovarian serous carcinoma, has been reported following oophorectomy in individuals at increased hereditary risk. This study was undertaken to examine and report particularly the occurrence of intra-abdominal carcinomatosis, as well as other cancers, following prophylactic oophorectomy in patients who carry cancer susceptibility mutations of BRCA1 and BRCA2 and to assess the cumulative risks for this disease in order to assist in developing appropriate surgical interventions, based on currently available information, and to counsel patients who choose prophylactic surgery, concerning the potential prognosis, thereafter.</AbstractText>The Creighton University Hereditary Cancer Institute registry was searched for members of HBOC syndrome families who had undergone prophylactic oophorectomy. The histories and results of DNA testing for the BRCA1 and BRCA2 mutations carried in their families were recorded, tabulated and examined, and the aggregate data are reported along with pertinent details of those individuals who developed neoplastic diseases after prophylactic oophorectomy. All available histologic and cytologic materials of patients who were diagnosed with intra-abdominal carcinomatosis were reviewed, and life-table calculations were performed to assess cumulative risks for this disease following prophylactic oophorectomy.</AbstractText>From 72 HBOC syndrome families that carried either BRCA1 or BRCA2 cancer-associated mutations, 238 individuals who had undergone prophylactic oophorectomy were recorded in our registry between January 1985 and December 2002. During a mean follow-up of 9.3 years, cancers were diagnosed in 27 subjects, including 16 individuals with breast cancer and five patients with intra-abdominal carcinomatosis. Breast cancers were stage I in 10 of 12 proven carriers of cancer-associated mutations. All five cases of intra-abdominal carcinomatosis were serous carcinomas, and all occurred in BRCA1 mutation carriers. Histologic review of the prophylactically removed ovaries found borderline lesions in two cases, one with possible early stromal invasion. Two of the five patients who developed intra-abdominal carcinomatosis were among 78 patients in this series who were diagnosed and treated for breast cancer before prophylactic oophorectomy. A 3.5% cumulative risk for all mutation carriers and a 3.9% cumulative risk for BRCA1 mutation carriers were calculated through 20 years of follow-up after prophylactic oophorectomy.</AbstractText>Intra-abdominal carcinomatosis in our series was diagnosed only in BRCA1 mutation carriers. The calculated cumulative risks of developing intra-abdominal carcinomatosis after prophylactic oophorectomy in members of HBOC syndrome families, specifically those who carry deleterious mutations, are well below the estimated risks of ovarian cancer published in the literature for similar patients. Breast cancers, which tended to be small and localized, were the most common malignancy in BRCA1 and BRCA2 mutation carriers after prophylactic oophorectomy.</AbstractText>
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2,337,683 |
Homozygous partial genomic triplication of the parkin gene in early-onset parkinsonism.
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Autosomal recessive mutations in the parkin gene are the predominant cause of familial, early-onset parkinsonism; missense mutations involving one or a few nucleotides, exonic deletions and duplications have been described. Here we report a family with two affected brothers. Direct sequencing of parkin did not detect mutations, but semi-quantitative analysis identified a novel exonic rearrangement of exons 2-4. Both patients were homozygous for unique genomic triplications of the parkin gene.
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2,337,684 |
The APOC3 SstI polymorphism is weakly associated with sporadic Alzheimer's disease in a Chinese population.
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In order to clarify the relationship of apolipoprotein CIII (APOC3) polymorphism and sporadic Alzheimer's disease (AD) in Chinese, 165 sporadic AD patients and 174 age-matched elderly individuals were genotyped for the APOC3 SstI and apolipoprotein E (APOE) HhaI polymorphisms. As the result, the APOC3 3017G allele was found to be associated with AD in APOE epsilon4 allele noncarriers (chi2=4.433, P=0.035), and the risk estimate of allele C versus G resulted in an OR of 1.56 (95% CI: 1.03-2.37), although in total no significant differences of allelic or genotypic frequencies between patients and controls were found. Assessment of interaction between APOE epsilon4 and APOC3 3017G status presented an adjusted odds ratio of 0.62 (95% CI: 0.37-1.03) with a borderline significant P-value (P=0.066). Therefore, we conclude that the rare APOC3 G allele may offer some protection against the development of sporadic AD in APOE epsilon4 noncarriers in Chinese.
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2,337,685 |
Evaluation of Lipin 2 as a candidate gene for autosomal dominant 1 high-grade myopia.
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The first autosomal dominant high-grade myopia locus has been mapped to chromosome 18p11.31 between markers D18S59 and D18S1138 by haplotype analysis. Refinement of the region by transmission disequilibrium testing suggests that a candidate gene (or genes) for this locus named myopia 2 (MYP2) is likely in an interval between markers D18S63 and D18S52. Lipin 2 (LPIN2), a candidate gene for lipodystrophy, maps in proximity to this locus. Our purpose in this study was to identify mutations and polymorphisms in the LPIN2 gene in myopic patients and control subjects. Expression studies of this gene by reverse transcription-polymerase chain reaction (RT-PCR) showed that LPIN2 was ubiquitously expressed in various tissues, such as brain, kidney, lung, heart, and skeletal muscles. It was also expressed in cornea, lens, retina, optic nerve, and sclera. Direct sequencing of the LPIN2 gene revealed 11 single nucleotide polymorphisms (SNPs) in myopia and unaffected individuals. Eight of them were novel. Among the 11 SNPs detected in this study, 2 exonic variants (G2950692A and C2924436T) were synonymous and do not lead to changes in amino acid of the translated protein product. Two transversions in intron 1 (T2951033A homozygote and heterozygote, C2951049A) and one transversions in intron 7 (G2924536C homozygote and heterozygote), 5 nucleotide variants (A 2909606T, del2909343T, G2907798C, T2907425G, T2907152C) in the 3'-untranslated region (3'-UTR), and TATTAA nucleotide deletions (homozygote and heterozygote) at 2950970-5 in intron 1 were also detected. Although LPIN2 gene was excluded as a candidate for MYP2, the SNPs detected in this study will aid in future mapping and association studies involving this gene.
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2,337,686 |
Identification of predictive factors for the occurrence of predisposing MLH1 and MSH2 germline mutations among Sardinian patients with colorectal carcinoma.
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Factors predictive of carrying MLH1 and MSH2 germline mutations in patients with colorectal cancer (CRC) are as yet unknown. The aim of this population-based study, was to further define the role of MLH1/MSH2 mutations through an evaluation clinic program with 362 consecutive Sardinian CRC patients. Eight MLH1/MSH2 germline mutations were detected in 21 (6%) patients. Examining family cancer history, MLH1/MSH2 mutations were found in 14/48 (29.2%) probands from CRC families and, among them, in 10/13 (76.9%) families fulfilling the Amsterdam criteria. The patients with low familial recurrence (two CRCs in the family) presented a much lower frequency of MLH1/MSH2 mutations (2/55; 3.6%). Significantly higher rates of MLH1/MSH2 mutations were found in patients with age of onset 45 years (P=0.012) or with 3 affected family members (P=0.009). While no significant predictive value was found for the presence of endometrial cancer within the family, earlier age of diagnosis and/or familial CRC recurrence should be considered as strong predictors for the occurrence of MLH1/MSH2 mutations, and therefore useful in recommending CRC patients for genetic testing.
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2,337,687 |
Synergistic heterozygosity in mice with inherited enzyme deficiencies of mitochondrial fatty acid beta-oxidation.
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We have used mice with inborn errors of mitochondrial fatty acid beta-oxidation to test the concept of synergistic heterozygosity. We postulated that clinical disease can result from heterozygous mutations in more than one gene in single or related metabolic pathways. Mice with combinations of mutations in mitochondrial fatty acid beta-oxidation genes were cold challenged to test their ability to maintain normal body temperature, a sensitive indicator of overall beta-oxidation function. This included mice of the following genotypes: triple heterozygosity for mutations in very-long-chain acyl CoA dehydrogenase, long-chain acyl CoA dehydrogenase, and short-chain acyl CoA dehydrogenase genes (VLCAD+/-//LCAD+/-//SCAD+/-); double heterozygosity for mutations in VLCAD and LCAD genes (VLCAD+/-//LCAD+/-); double heterozygosity for mutations in LCAD and SCAD genes (LCAD+/-//SCAD+/-); single heterozygous mice (VLCAD+/-, LCAD+/-, SCAD+/-) and wild-type. We found that approximately 33% of mice with any of the combined mutant genotypes tested became hypothermic during a cold challenge. All wild-type and single heterozygous mice maintained normal body temperature throughout a cold challenge. Despite development of hypothermia in some double heterozygous mice, blood glucose concentrations remained normal. Biochemical screening by acylcarnitine and fatty acid analyses demonstrated results that varied by genotype. Thus, physiologic reduction of the beta-oxidation pathway, characterized as cold intolerance, occurred in mice with double or triple heterozygosity; however, the derangement was milder than in mice homozygous for any of these mutations. These results substantiate the concept of synergistic heterozygosity and illustrate the potential complexity involved in diagnosis and characterization of inborn errors of fatty acid metabolism in humans.
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2,337,688 |
Coeliac disease.
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Coeliac disease (CD) probably affects one in 100 Australians, but is greatly underdiagnosed. Heightened media interest in the negative effects of dietary gluten has led many patients to request testing for CD or follow inappropriate diets. Doctors have had little education in CD because of its perceived rarity.</AbstractText>This article summarises current knowledge of clinical presentations, optimal screening and diagnostic tests, and how the general practitioner can best assist patients in adopting a successful gluten free diet.</AbstractText>Coeliac disease is associated with a range of conditions including type 1 diabetes, thyroid disease, osteoporosis, and iron deficiency with or without anaemia. Gastrointestinal symptoms may not be present. The GP therefore has an important role in considering CD in the differential diagnosis in a variety of clinical presentations. Antitransglutaminase IgA and total serum IgA are the preferred screening tests but may miss occasional patients with CD. Endoscopic duodenal biopsy while eating gluten is needed for definitive diagnosis. A gluten free diet is complex, and may fail without the involvement of a skilled dietician.</AbstractText>
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2,337,689 |
Innogenetics NV.
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Innogenetics NV is a Belgium-based international biopharmaceutical company that has applied its know-how and synergies in molecular biology, immunology and virology to build two distinct businesses: a specialty diagnostics business grounded in personalized medicine, and a pharmaceutical business that is developing therapeutic vaccines. The advantage of this dual model is that the growing revenues from the profitable specialty diagnostics business partially support the development of its biopharmaceutical pipeline. The company employs some 600 persons, with affiliates in Germany, Spain, Italy, France, and the USA.
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2,337,690 |
A point mutation in the iron-responsive element of the L-ferritin in a family with hereditary hyperferritinemia cataract syndrome.
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Hereditary hyperferritinemia cataract syndrome is an autosomal dominant condition that is characterized by a high serum ferritin level and bilateral early-onset cataracts in the absence of iron overload. The genetic abnormality is identified as a mutation in the 5' regulatory region of the L-ferritin messenger RNA known as the iron-responsive element (IRE). The IRE controls ferritin synthesis in response to cytoplasmic iron pools by interacting with regulatory proteins called iron responsive proteins. Mutations in the IRE decrease its affinity for iron responsive proteins, leading to the constitutive synthesis of L-ferritin which results in hyperferritinemia and the intracellular accumulation of ferritin in the lens and eventual cataract formation.</AbstractText>A 22-year-old woman who was being investigated for hyperferritinemia was diagnosed with hereditary hyperferritinemia cataract syndrome after an extensive workup, including genetic testing for hemochromatosis and a liver biopsy to rule out iron overload. She developed anemia with phlebotomy treatments and subsequently developed symptomatic cataracts. The pedigree of her family affected with cataracts was consistent with an autosomal dominant transmission pattern. DNA was extracted from peripheral leukocytes of eight family members, four of whom were affected by cataracts. Polymerase chain reaction amplification of the 5' region of the L-ferritin gene was performed and a heterozygous point mutation (G32T) was identified in the bulge region of the IRE.</AbstractText>The combination of early-onset cataracts and an elevated ferritin level should suggest this genetic syndrome.</AbstractText>
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2,337,691 |
TGFBR1*6A may contribute to hereditary colorectal cancer.
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TGFBR16A is a tumor susceptibility gene that increases breast, colon, and ovarian cancer risk. Fourteen percent of the general population carries TGFBR16A, and TGFBR16A homozygotes have a greater than 100% increased colon cancer risk compared with noncarriers. Low-penetrance genes such as TGFBR16A may account for a sizable proportion of familial colorectal cancer occurrences. To test this hypothesis, we determined whether TGFBR16A contributes to a proportion of mismatch repair (MMR) gene mutation-negative hereditary nonpolyposis colorectal cancer (HNPCC) patients.</AbstractText>A case-case study was performed of 208 index patients with HNPCC meeting the Amsterdam criteria. Patients were examined for mutations and genomic rearrangements in the MLH1, MSH2, and MSH6 genes and genotyped for TGFBR16A. Tumor microsatellite instability status was available for 95 patients.</AbstractText>A total of 144 patients (69.2%) carried a deleterious mutation and were classified as positive for MMR gene mutation; 64 patients (30.8%) had no evidence of mutations and were classified as MMR negative. TGFBR16A allelic frequency was significantly higher among MMR-negative patients (0.195) than among MMR-positive patients (0.104; P = .011). The proportion of TGFBR16A homozygotes was nine-fold higher among MMR-negative (6.3%) than among MMR-positive patients (0.7%; P = .032). The highest TGFBR16A allelic frequency was found among MMR-negative patients with tumors exhibiting no microsatellite instability (0.211), and the lowest frequency was found among MMR-positive patients with tumors exhibiting microsatellite instability (0.121); the difference was not statistically significant (P = .17).</AbstractText>TGFBR16A may be causally responsible for a proportion of HNPCC occurrences.</AbstractText>
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2,337,692 |
The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and myelodysplastic syndromes.
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A somatic mutation in the JH2 autoinhibitory domain of the Janus kinase 2 (JAK2) tyrosine kinase was recently described in polycythemia vera, essential thrombocythemia, and myelofibrosis with myeloid metaplasia. The prevalence of this mutation in either "atypical" myeloproliferative disorders (MPDs) or the myelodysplastic syndromes (MDSs) is unknown. Bone marrow-derived genomic DNA from 245 patients--119 with chronic myelomonocytic leukemia (CMML), 101 with MDS, 11 with hypereosinophilic syndrome (HES), 8 with systemic mastocytosis (SM), and 6 with chronic neutrophilic leukemia (CNL)--was screened for the JAK2 V617F mutation. A mutant allele was detected in 11 patients: 3 with CMML (3%), 5 with MDS (5%), 2 with SM, and 1 with CNL. Interestingly, one of the patients with SM and the patient with CNL with JAK2 V617F had a history of lymphoma, and this patient with SM also had associated myelofibrosis and CMML. The current observation strengthens the specific association between JAK2 V617F and classic MPD, but also suggests an infrequent occurrence in other myeloid disorders.
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2,337,693 |
Mutation screening and association study of the neprilysin gene in sporadic Alzheimer's disease in Chinese persons.
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Neprilysin has been reported to be a major beta-amyloid peptide (Abeta)-degrading enzyme. The decreased expression and activity of it may contribute to the development of Alzheimer's disease by promoting the accumulation of Abeta. We used denaturing high-performance liquid chromatography to screen the neprilysin gene (NEP) for single nucleotide polymorphisms (SNPs) in 257 Chinese sporadic Alzheimer's disease patients and 242 cognitive normal controls. As a result, eight novel and one known SNP were identified. Three of them, -204G-->C in the promoter region, IVS17-294C-->T, and IVS22+36C-->A showed a significant association with Alzheimer's disease (p = .006,.017, and.003, respectively). Subsequent haplotype analysis provided further evidence of the association (global p < .0001 for the three SNPs mentioned above, and global p < .01 for the eight SNPs with rare allele frequency > 1%). These findings indicate that genetic variations within or extremely close to NEP might influence the susceptibility to Alzheimer's disease in Chinese persons.
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2,337,694 |
The dopamine D4 receptor gene 48-base-pair-repeat polymorphism and mood disorders: a meta-analysis.
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We conducted a meta-analysis to re-evaluate the role of the dopamine D4 receptor gene 48-base-pair- repeat (DRD4) polymorphism in mood disorders.</AbstractText>DRD4 allele frequencies were compared between 917 patients with unipolar (UP) or bipolar affective disorder (BP) and 1164 control subjects from 12 samples, using the Cochrane Review Manager.</AbstractText>An association was found between all mood disorder groups and DRD4.2. After correcting for multiple testing, the association between DRD4.2 and BP dropped to insignificance; however, the evidence of an association between the DRD4.2 allele and UP (p < .001) and the combined group (p < .001) remained. There was no evidence for heterogeneity or publication bias.</AbstractText>These findings suggest that the DRD4.2 allele is a risk allele for depression symptomatology. Meta-analysis may be a valuable objective tool for a quantitative summary of evidence for association studies in psychiatric genetics.</AbstractText>
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2,337,695 |
Screening for mutations in CYP4V2 gene in Japanese patients with Bietti's crystalline corneoretinal dystrophy.
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To describe the clinical and genetic characteristics of six Japanese families with Bietti's crystalline corneoretinal dystrophy (BCD).</AbstractText>Case reports and results of DNA analysis.</AbstractText>Mutation screening was performed on six unrelated patients with BCD by direct sequencing. The clinical features were characterized by the visual acuity, slit-lamp biomicroscopy, electroretinography, fluorescein angiography, and kinetic visual field testing.</AbstractText>An identical IVS6 to 8delTCATACAGGTCATCGCG/insGC mutation in the CYP4V2 gene was identified in five of the patients with BCD; the sixth patient had a novel Trp340X mutation in the CYP4V2 gene. Three patients showed crystalline-like deposits at the limbus by specular microscopy. Ophthalmic findings of all patients had a rapid progression after age 50 years.</AbstractText>Our findings suggest that the IVS6 to 8delTCATACAGGTCATCGCG/insGC mutation is a common mutation in Japanese patients with BCD. Although phenotypic variability was found, the natural course was almost the same in all of our patients.</AbstractText>
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2,337,696 |
Variants of calpain-10 gene and its association with type 2 diabetes mellitus in a Chinese population.
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Variants of calpain-10 gene (CAPN 10) have recently been reported to be associated with type 2 diabetes (T2DM). Haplotype combination 112/121 defined by three single nucleotide polymorphisms (SNPs) (UCSNP-43, -19 and -63) of CAPN 10 conferred the highest risk for T2DM in Mexican-Americans. In this study, we aim to examine whether these genetic variants contribute to the susceptibility for T2DM in a Chinese population. The frequencies of these three SNPs were determined in 168 patients with T2DM and 104 controls. Distribution of alleles, genotypes and haplotypes at three loci were not significantly different between the two groups. No difference was observed in the 112/121 haplotype combination distribution. However, haplotype combination 112/221 was more prevalent in the control group than in T2DM group (16.35% versus 7.14%, p = 0.025). Control subjects with haplotype combination 112/121 had higher serum cholesterol level than others without haplotype combination 112/121 (5.7 +/- 1.4 versus 5.2 +/- 0.7, p = 0.011). Our results suggest that haplotype combination 112/221 associated with reduced risk for T2DM and haplotype combination 112/121 might be a risk factor for increased serum cholesterol in Chinese population.
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2,337,697 |
Comparative genomic analysis reveals a distant liver enhancer upstream of the COUP-TFII gene.
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COUP-TFII is a central nuclear hormone receptor that tightly regulates the expression of numerous target lipid metabolism genes in vertebrates. However, it remains unclear how COUP-TFII itself is transcriptionally controlled since studies with its promoter and upstream region fail to recapitulate the gene's liver expression. In an attempt to identify liver enhancers in the vicinity of COUP-TFII, we employed a comparative genomic approach. Initial comparisons between humans and mice of the 3470-kb gene-poor region surrounding COUP-TFII revealed 2023 conserved noncoding elements. To prioritize a subset of these elements for functional studies, we performed further genomic comparisons with the orthologous pufferfish (Fugu rubripes) locus and uncovered two anciently conserved noncoding sequences (CNS) upstream of COUP-TFII (CNS-62kb and CNS-66kb). Testing these two elements using reporter constructs in liver cells (HepG2) revealed that CNS-66kb, but not CNS-62kb, yielded robust in vitro enhancer activity. In addition, an in vivo reporter assay using naked DNA transfer with CNS-66kb linked to luciferase displayed strong reproducible liver expression in adult mice, further supporting its role as a liver enhancer. Together, these studies further support the utility of comparative genomics to uncover gene regulatory sequences based on evolutionary conservation and provide the substrates to better understand the regulation and expression of COUP-TFII.
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2,337,698 |
[Prospects for genetic hearing loss screening: 35delG mutation tracking in a newborn population].
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To investigate the prevalence of the 35delG mutation in a newborn population, with specific molecular testing, and to evaluate the prospects for genetic neonatal screening for hearing impairment.</AbstractText>233 newborn were evaluated at the Hospital de Base de São José do Rio Preto, SP, for molecular analysis of the 35delG mutation in the connexin 26 gene, with the reaction technique in allele-specific polymerase chain reaction, after genomic DNA extraction from umbilical cord blood.</AbstractText>Five heterozygotes were identified, obtaining a prevalence of 2.24% of 35delG mutation carriers in the study population.</AbstractText>Using the molecular test allowed for the identification of the 35delG mutation in the study population with the possibility of being used as a complement to neonatal audiometric screening as being simple, fast, and easily to perform with low costs.</AbstractText>
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2,337,699 |
[Molecular-genetic aspects of congenital hypothyroidism].
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Congenital hypothyroidism manifests a complex of symptoms caused by a total lack or significant deficiency of thyroxine (T4) and triiodothyronine (T3) in foetal life and in the first years of child's life. The incidence of congenital hypothyroidism is 1 per 3000-4000 newborns in the world and l per 4800 in Poland. There are two main causes of congenital hypothyroidism: defects of thyroid development (about 90%), defects of thyroid hormones biosynthesis (~10%), and the more seldom occurring defects of the TBG proteins (thyroxine binding globulin) or resistance. syndrome to thyroid hormones. Defects of thyroid gland development include ectopia, hypoplasia or complete lack of the thyroid (athyreosis). These defects are caused by immunological, factors, drugs as well as genetic factors such as: TSH receptor gene or thyroid transcription factors: PAX 8. TTF l, TTF 2, Pit 1, Prop 1. Defects of thyroid hormones biosynthesis are inherited as autosomal recessive. There are 5 main defects of thyroid hormones biosynthesis: iodide transport (mutation of hNIS gene), iodine oxygenation (mutation of TPO, THOX, PDS genes), the iodination of the tyrosine of thyroglobulin and their conjunction (the mutation of TPO TG, PDS genes), the hydrolysis of the T3 and T4 as well as deiodination. Searching molecular-genetic basis of congenital hypothyroidism may improve its diagnostics, make possible to introduce genetic examination among patients with congenital hypothyroidism and their family members and may make gene therapy possible in the future.
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