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2,337,000 |
Recent developments in genomewide association scans: a workshop summary and review.
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With the imminent availability of ultra-high-volume genotyping platforms (on the order of 100,000-1,000,000 genotypes per sample) at a manageable cost, there is growing interest in the possibility of conducting genomewide association studies for a variety of diseases but, so far, little consensus on methods to design and analyze them. In April 2005, an international group of >100 investigators convened at the University of Southern California over the course of 2 days to compare notes on planned or ongoing studies and to debate alternative technologies, study designs, and statistical methods. This report summarizes these discussions in the context of the relevant literature. A broad consensus emerged that the time was now ripe for launching such studies, and several common themes were identified--most notably the considerable efficiency gains of multistage sampling design, specifically those made by testing only a portion of the subjects with a high-density genomewide technology, followed by testing additional subjects and/or additional SNPs at regions identified by this initial scan.
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2,337,001 |
ERBB2 in pediatric cancer: innocent until proven guilty.
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Adult oncologists and their research colleagues have "led the charge" in the war on cancer. Their efforts have generated effective new chemotherapies that target cancer causing molecular alterations. It is hoped that these successes will be repeated within the pediatric oncology community. Testing whether molecular targeted therapies of adult cancers are also effective against childhood cancers might allow the rapid introduction of these exciting new agents into the pediatric clinic. However, it is imperative that we do not introduce blindly these agents into the pediatric population. We must ensure that molecular targets in adult cancers also fulfill a number of important criteria within the pediatric disease. This review addresses the issues surrounding the identification of molecular targets in pediatric cancers by focusing on studies of the ERBB2 oncogene.
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2,337,002 |
Association mapping of kernel size and milling quality in wheat (Triticum aestivum L.) cultivars.
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Association mapping is a method for detection of gene effects based on linkage disequilibrium (LD) that complements QTL analysis in the development of tools for molecular plant breeding. In this study, association mapping was performed on a selected sample of 95 cultivars of soft winter wheat. Population structure was estimated on the basis of 36 unlinked simple-sequence repeat (SSR) markers. The extent of LD was estimated on chromosomes 2D and part of 5A, relative to the LD observed among unlinked markers. Consistent LD on chromosome 2D was <1 cM, whereas in the centromeric region of 5A, LD extended for approximately 5 cM. Association of 62 SSR loci on chromosomes 2D, 5A, and 5B with kernel morphology and milling quality was analyzed through a mixed-effects model, where subpopulation was considered as a random factor and the marker tested was considered as a fixed factor. Permutations were used to adjust the threshold of significance for multiple testing within chromosomes. In agreement with previous QTL analysis, significant markers for kernel size were detected on the three chromosomes tested, and alleles potentially useful for selection were identified. Our results demonstrated that association mapping could complement and enhance previous QTL information for marker-assisted selection.
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2,337,003 |
A genetic screen targeting the tumor necrosis factor/Eiger signaling pathway: identification of Drosophila TAB2 as a functionally conserved component.
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Signaling by tumor necrosis factors (TNFs) plays a prominent role in mammalian development and disease. To fully understand this complex signaling pathway it is important to identify all regulators and transduction components. A single TNF family member, Eiger, is encoded in the Drosophila genome, offering the possibility of applying genetic approaches for pursuing this goal. Here we present a screen for the isolation of novel genes involved in the TNF/Eiger pathway. On the basis of Eiger's ability to potently activate Jun-N-terminal kinase (JNK) and trigger apoptosis, we used the Drosophila eye to establish an assay for dominant suppressors of this activity. In a large-scale screen the Drosophila homolog of TAB2/3 (dTAB2) was identified as an essential component of the Eiger-JNK pathway. Genetic epistasis and biochemical protein-protein interaction assays assign an adaptor role to dTAB2, linking dTRAF1 to the JNKKK dTAK1, demonstrating a conserved mechanism of TNF signal transduction in mammals and Drosophila. Thus, in contrast to morphogenetic processes, such as dorsal closure of the embryo, in which the JNK pathway is activated by the JNKKK Slipper, Eiger uses the dTAB2-dTAK1 module to induce JNK signaling activity.
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2,337,004 |
Information, understanding and the benign order of everyday life in genetic counselling.
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Genetic counselling as a medical encounter is characterised by the centrality of the provision of information. Much of the counselling session is filled by information delivery about the symptoms, the prognosis and the transmission of the disease, the risks involved and the possibilities for genetic testing. The present paper is a study of how information is delivered in actual genetic counselling sessions. The data consist of 10 video-recorded sessions from a genetics clinic in Finland, and the methodology is based on conversation analysis. The paper focuses on the doctor's talk in a specific interactional context, the slot after a candidate understanding by a client. The analysis shows that the doctors have two basic orientations: they work towards securing correct understanding and they display being attuned to what the information means to the clients, particularly to whether it is positive or negative to them. The latter orientation is related to what has been called 'the benign order of everyday life' (Maynard 2003). The findings in the paper offer a possibility for a discussion about the principles and practices of genetic counselling.
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2,337,005 |
Promoter-dependent disruption of genes: simple, rapid, and specific PCR-based method with application to three different yeast.
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PCR product-based gene disruption has greatly accelerated molecular analysis of Saccharomyces cerevisiae. This approach involves amplification of a marker gene (e.g., URA3) including its flanking regulatory (promoter and polyadenylation) regions using primers that include at their 5' ends about 50 bases of homology to the targeted gene. Unfortunately, this approach has proved less useful in organisms with higher rates of non-homologous recombination; e.g., in the yeast Candida glabrata, desired recombinants represent < or =2% of transformants. We modified the PCR-based approach by eliminating marker-flanking regions and precisely targeting recombination such that marker expression depends on the regulatory sequences of the disrupted gene. Application of this promoter-dependent disruption of genes (PRODIGE) method to three C. glabrata genes (SLT2, LEM3, and PDR1) yielded desired recombinants at frequencies of 20, 31, and 11%, the latter representing a weakly expressed gene. For Candida albicans LEM3 and RHO1, specificity was 79-95% for one or both alleles, >sixfold higher than the published results with conventional PCR-based gene disruption. All 5 C. glabrata and C. albicans mutants had predicted phenotypes of calcofluor hypersensitivity (slt2Delta and RHO1/rho1Delta), cycloheximide hypersensitivity (pdr1Delta), or miltefosine resistance (lem3Delta and lem3Delta/lem3Delta). PRODIGE application to the S. cerevisiae PDR5 gene in strains with and without the Pdr1-Pdr3 transcriptional activators of this gene confirmed that transformant yield and growth rate depend on promoter strength. Using this PDR5 promoter-URA3 recombinant, we further demonstrate a simple extension of the method that yields regulatory mutants via 5-fluoroorotic acid selection. PRODIGE warrants testing in other yeast, molds, and beyond.
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2,337,006 |
Reexploring the possible roles of some genes associated with nasopharyngeal carcinoma using microarray-based detection.
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In gene expression profiling, nasopharyngeal carcinoma (NPC) 5-8F cells differ from 6-10B cells in terms of their high tumorigenicity and metastatic ability. Differentially expressed genes from the two cell types were analyzed by combining with MILANO (the automatic custom annotation of microarray results which is based on all the available published work in PubMed). The results showed that five genes, including CTSD, P63, CSE1L, BPAG1 and EGR1, have been studied or mentioned in published work on NPC. Subsequently, we reevaluated the roles of these genes in the pathogenesis of NPC by combining the data of gene chips from NPCs versus NPs and pooled cells from 5-8F, 6-10B and CNE2 versus NPs. The results suggested that the roles of BPAG1 and EGR1 are possibly different from those reported in previous NPC studies. These five genes are likely to be involved in the proliferation, apoptosis, invasion and metastasis of NPC. A reexploration of the genes will further define their roles in the pathogenesis of NPC.
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2,337,007 |
Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix.
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Correlated multiple testing is widely performed in genetic research, particularly in multilocus analyses of complex diseases. Failure to control appropriately for the effect of multiple testing will either result in a flood of false-positive claims or in true hits being overlooked. Cheverud proposed the idea of adjusting correlated tests as if they were independent, according to an 'effective number' (M(eff)) of independent tests. However, our experience has indicated that Cheverud's estimate of the Meff is overly large and will lead to excessively conservative results. We propose a more accurate estimate of the M(eff), and design M(eff)-based procedures to control the experiment-wise significant level and the false discovery rate. In an evaluation, based on both real and simulated data, the M(eff)-based procedures were able to control the error rate accurately and consequently resulted in a power increase, especially in multilocus analyses. The results confirm that the M(eff) is a useful concept in the error-rate control of correlated tests. With its efficiency and accuracy, the M(eff) method provides an alternative to computationally intensive methods such as the permutation test.
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2,337,008 |
Forty-two supernumerary marker chromosomes (SMCs) in 43,273 prenatal samples: chromosomal distribution, clinical findings, and UPD studies.
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Fluorescence in situ hybridization (FISH) analyses were performed on supernumerary marker chromosomes (SMCs) detected in 43,273 prenatal diagnoses over a period of 11 years, 1993-2003. A total of 42 pregnancies with SMC were identified, indicating a prevalence of one in 1032. A total of 15 SMCs were endowed with detectable euchromatin (prevalence, 1/2884), including six SMCs containing the cat eye critical region (CECR) on chromosome 22q11.21 (1/7212). De novo SMCs were found in 29 pregnancies (1/1492), including 14 euchromatic SMCs (48.2%). Follow-up studies were available for 24 cases. Nine pregnancies (37.5%) were terminated; two children (8.3%) were born with Pallister-Killian syndrome and cat eye syndrome (CES), respectively; 13 children (54.1%) showed apparently normal development. Familial SMCs were identified in 13 pregnancies (1/3328) from 11 unrelated women. They were all acrocentric. In all, 10 were heterochromatic and one was an extra der(22)t(11;22) chromosome. A total of 12 cases were available for follow-up. One pregnancy was terminated due to anhydramnios, spina bifida, and cystic-dysplastic kidneys; one child suffered from a der(22) syndrome; 10 children (83.3%) appeared unaffected. Studies for uniparental disomy were performed on seven pregnancies and revealed a case of maternal heterodisomy for chromosome 22. So far this is the largest FISH study of prenatally ascertained SMCs and the first study with detailed data on the prevalence. Findings illustrate the spectrum and clinical outcomes of prenatally diagnosed SMCs, and indicate a higher frequency of SMCs than generally assumed.
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2,337,009 |
Methanol-dependent gene expression demonstrates that methyl-coenzyme M reductase is essential in Methanosarcina acetivorans C2A and allows isolation of mutants with defects in regulation of the methanol utilization pathway.
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Methanosarcina acetivorans C2A is able to convert several substrates to methane via at least four distinct methanogenic pathways. A common step in each of these pathways is the reduction of methyl-coenzyme M (CoM) to methane catalyzed by methyl-CoM reductase (MCR). Because this enzyme is used in each of the known pathways, the mcrBDCGA operon, which encodes MCR, is expected to be essential. To validate this prediction, a system for conditional gene inactivation was developed. A heterologous copy of the mcrBDCGA operon was placed under the control of the highly regulated mtaC1 promoter, which directs the expression of genes involved in methanol utilization, and recombined onto the M. acetivorans chromosome. This allowed for disruption of the endogenous mcr operon in the presence of methanol. Because the PmtaC1 promoter is transcribed only during growth on methanol, mcrBDCGA was rendered methanol dependent and the strain was unable to grow in trimethylamine media, strongly suggesting that mcrBDCGA is essential. Upon prolonged incubation, suppressed mutants which expressed mcrBDCGA constitutively could be selected. Expression analysis of PmtaC1::uidA gene fusions in several isolated suppressed mutants suggests that they carry trans-active mutations leading to deregulation of all genes under control of this promoter. Subsequently, proteome analysis of one such suppressed mutant revealed that all known proteins derived from mtaC1 promoter-dependent expression were constitutively expressed in this mutant. This genetic system can therefore be employed for the testing of essential genes and for the identification of genes under a common regulatory mechanism by making regulatory mutations phenotypically selectable.
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2,337,010 |
Failure to find association between TRAR4 and schizophrenia in the Chinese Han population.
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The TRAR4 gene locates in SCZD5 (MIM 603175), which a number of studies have linked with schizophrenia. One recent study suggested that three TRAR4 variants (M1: rs4305745, P=0.0014; M2: rs6903874, P=0.0026; M3: rs6937506, P=0.0052) in the 3'-UTR were associated with schizophrenia. To replicate these findings, we conducted a family-based association study within a sample of 235 Chinese Han trios. However, we didn't find significant evidence of preferential transmission of the three variants across all the trios (all P values>0.2). Thus, we conclude that TRAR4 is not a major or independent determinant in the occurrence of schizophrenia in the Chinese Han population.
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2,337,011 |
Linkage analyses of chromosomal region 18p11-q12 in dyslexia.
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Dyslexia is characterized as a significant impairment in reading and spelling ability that cannot be explained by low intelligence, low school attendance or deficits in sensory acuity. It is known to be a hereditary disorder that affects about 5% of school aged children, making it the most common of childhood learning disorders. Several susceptibility loci have been reported on chromosomes 1, 2, 3, 6, 15, and 18. The locus on chromosome 18 has been described as having the strongest influence on single word reading, phoneme awareness, and orthographic coding in the largest genome wide linkage study published to date (Fisher et al., 2002). Here we present data from 82 German families in order to investigate linkage of various dyslexia-related traits to the previously described region on chromosome 18p11-q12. Using two- and multipoint analyses, we did not find support for linkage of spelling, single word reading, phoneme awareness, orthographic coding and rapid naming to any of the 14 genotyped STR markers. Possible explanations for our non-replication include differences in study design, limited power of our study and overestimation of the effect of the chromosome 18 locus in the original study.
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2,337,012 |
[Indirect cystic fibrosis carrier detection in two Chilean families by analysis of DNA polymorphisms closely linked to the CFTR gene].
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Molecular genetic analysis is the only method that allows accurate detection of Cystic Fibrosis (CF) carriers. Nevertheless, its application is restricted to those families in which the affected child holds known mutations. Since most Chilean CF patients already studied are heterozygous and carry a mutation not yet characterized, direct identification of carriers is limited. Linkage analysis of Restriction Fragment Length Polymorphisms (RFLP), using DNA markers closely linked to the CFTR gene, is a useful tool for the detection of carriers in families in which the patient carries an unknown mutation.</AbstractText>To emphasize the usefulness of KM19 and MetH markers for RFLP analysis in extended genealogies in order to identify carriers of unknown mutations.</AbstractText>Selection of three families, in which a sibling of an index case, identified as EthF-508/unknown mutation, could not be identified as heterozygous carrier or a normal homozygous. Haplotypic characterization for KM19 and MetH markers was performed by PCR amplification of genomic DNA followed by allele specific restriction enzymatic digestion.</AbstractText>The siblings of two families were identified as carriers and the sibling of the third family was identified as normal.</AbstractText>KM19 and MetH haplotypic analysis provided a rapid method for carrier detection in the families under study. The analysis may be used as a supplement to direct genetic diagnosis and be helpful in genetic counseling.</AbstractText>
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2,337,013 |
Genomewide cDNA microarray screening of genes related to benefits and toxicities of platinum-based chemotherapy in patients with advanced lung cancer.
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The authors conducted a study using cDNA microarray analysis to determine whether expression levels of genes in tumors were correlated with the outcome of chemotherapy. Forty-seven patients were studied, and all except 3 received platinum-based chemotherapy. The expression levels of 1176 genes in transbronchial biopsy specimens of tumors that were obtained before chemotherapy were analyzed using the Atlas Human Cancer 1.2 Array. Multivariate regression analysis revealed that 3 genes were each independent factors related to tumor resistance to chemotherapy and patient survival (P < 0.01). Among various chemotherapy-related toxicities, 1, 3, 3, 1, and 1 genes were also revealed to be independent factors that were correlated with neutropenia, anemia, diarrhea, infection, and increased serum creatinine respectively (P < 0.01). It is concluded that not only the benefits but also the toxicities of chemotherapy can be predicted by cDNA microarray using tumor specimens obtained before chemotherapy.
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2,337,014 |
Narrative review: screening for colorectal cancer in patients with a first-degree relative with colonic neoplasia.
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Many patients and providers are aware that colorectal cancer (CRC) "runs in families." A patient with 1 first-degree relative with CRC has approximately twice the personal risk for CRC as a similar person without this family history. Colorectal cancer is the third most common type of cancer in the United States. When providers neglect to collect information on family history, they may fail to appropriately tailor recommendations for screening for CRC for many patients. This review considers the existing data and summarizes an evidence-based approach to the common clinical problem of how and when to implement screening for CRC in a patient with a family history of colonic neoplasia. The authors discuss the varying risks for CRC given the patient's age, health habits, and personal and family histories. In the context of a clinical case that focuses on the effect of a single affected first-degree relative, the authors weigh the risks and benefits of various screening alternatives and briefly address chemoprevention, genetic testing, and future directions in screening for CRC.
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2,337,015 |
Characterization of a recurrent germ line mutation of the E-cadherin gene: implications for genetic testing and clinical management.
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To identify germ line CDH1 mutations in hereditary diffuse gastric cancer (HDGC) families and develop guidelines for management of at risk individuals.</AbstractText>We ascertained 31 HDGC previously unreported families, including 10 isolated early-onset diffuse gastric cancer (DGC) cases. Screening for CDH1 germ line mutations was done by denaturing high-performance liquid chromatography and automated DNA sequencing.</AbstractText>We identified eight inactivating and one missense CDH1 germ line mutation. The missense mutation conferred in vitro loss of protein function. Two families had the previously described 1003C>T nonsense mutation. Haplotype analysis revealed this to be a recurrent and not a founder mutation. Thirty-six percent (5 of 14) of the families with a documented DGC diagnosed before the age of 50 and other cases of gastric cancer carried CDH1 germ line mutations. Two of 10 isolated cases of DGC in individuals ages <35 years harbored CDH1 germ line mutations. One mutation positive family was ascertained through a family history of lobular breast cancer (LBC) and another through an individual with both DGC and LBC. Occult DGC was identified in five of six prophylactic gastrectomies done on asymptomatic, endoscopically negative 1003C>T mutation carriers.</AbstractText>In addition to families with a strong history of early-onset DGC, CDH1 mutation screening should be offered to isolated cases of DGC in individuals ages <35 years and for families with multiple cases of LBC, with any history of DGC or unspecified GI malignancies. Prophylactic gastrectomy is potentially a lifesaving procedure and clinical breast screening is recommended for asymptomatic mutation carriers.</AbstractText>
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2,337,016 |
Machine learning approaches for phenotype-genotype mapping: predicting heterozygous mutations in the CYP21B gene from steroid profiles.
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Non-linear relations between multiple biochemical parameters are the basis for the diagnosis of many diseases. Traditional linear analytical methods are not reliable predictors. Novel nonlinear techniques are increasingly used to improve the diagnostic accuracy of automated data interpretation. This has been exemplified in particular for the classification and diagnostic prediction of cancers based on expression profiling data. Our objective was to predict the genotype from complex biochemical data by comparing the performance of experienced clinicians to traditional linear analysis, and to novel non-linear analytical methods.</AbstractText>As a model, we used a well-defined set of interconnected data consisting of unstimulated serum levels of steroid intermediates assessed in 54 subjects heterozygous for a mutation of the 21-hydroxylase gene (CYP21B) and in 43 healthy controls.</AbstractText>The genetic alteration was predicted from the pattern of steroid levels with an accuracy of 39% by clinicians and of 64% by linear analysis. In contrast, non-linear analysis, such as self-organizing artificial neural networks, support vector machines, and nearest neighbour classifiers, allowed for higher accuracy up to 83%.</AbstractText>The successful application of these non-linear adaptive methods to capture specific biochemical problems may have generalized implications for biochemical testing in many areas. Nonlinear analytical techniques such as neural networks, support vector machines, and nearest neighbour classifiers may serve as an important adjunct to the decision process of a human investigator not 'trained' in a specific complex clinical or laboratory setting and may aid them to classify the problem more directly.</AbstractText>
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2,337,017 |
The new look of behavioral genetics in developmental psychopathology: gene-environment interplay in antisocial behaviors.
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This article reviews behavioral-genetic research to show how it can help address questions of causation in developmental psychopathology. The article focuses on studies of antisocial behavior, because these have been leading the way in investigating environmental as well as genetic influences on psychopathology. First, the article illustrates how behavioral-genetic methods are being newly applied to detect the best candidates for genuine environmental causes among the many risk factors for antisocial behavior. Second, the article examines findings of interaction between genes and environments (G x E) associated with antisocial behavior, outlining steps for testing hypotheses of measured G x E. Third, the article envisages future work on gene-environment interplay, arguing that it is an interesting and profitable way forward for psychopathology research.
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2,337,018 |
Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency.
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Deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier (AGC), encoded by the SLC25A13 gene on chromosome 7q21.3, causes autosomal recessive disorders: adult-onset type II citrullinemia (CTLN2) and neonatal hepatitis associated with intrahepatic cholestasis (NICCD). So far, we have described 12 SLC25A13 mutations: 11 were from Japan and one from Israel. Three mutations found in Chinese and Vietnamese patients were the same as those in Japanese patients. In the present study, we identified a novel mutation IVS6+1G>C in a Japanese CTLN2 patient and widely screened 12 SLC25A13 mutations found in Japanese patients in control individuals from East Asia to confirm our preliminary results that the carrier frequency was high in Asian populations. Mutations 851-854del and 1638-1660dup were found in all Asian countries tested, and 851-854del associated with 290-haplotype in microsatellite marker D7S1812 was especially frequent. Other mutations frequently detected were IVS11+1G>A in Japanese and Korean, S225X in Japanese, and IVS6+5G>A in Chinese populations. We found a remarkable difference in carrier rates in China (including Taiwan) between north (1/940) and south (1/48) of the Yangtze River. We detected many carriers in Chinese (64/4169 = 1/65), Japanese (20/1372 = 1/69) and Korean (22/2455 = 1/112) populations, suggesting that over 80,000 East Asians are homozygotes with two mutated SLC25A13 alleles.
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2,337,019 |
The effect of genotyping error in sib-pair genomewide linkage scans depends crucially upon the method of analysis.
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In genomewide linkage scans for complex diseases involving many loci with small genetic effects, it may be the case that no loci reach conventional statistical significance. A complementary method of evaluating linkage results, locus counting, may provide evidence for the existence of a number of genetic loci in these cases. Sib-pair study designs are often used in genomewide linkage scans, but because all genotype configurations are consistent with Mendelian inheritance, genotyping error will go largely undetected. Previous work on the effect of genotyping error has focused on a single disease locus. We considered the effect of two levels of genotyping error on genomewide evidence for linkage by using the simulated GAW 13 data. For affected sib-pair and non-parametric quantitative trait study designs, a 0.5% genotyping error rate reduced the number of independent linkage regions towards that expected under the null hypothesis of no linkage. A 2% genotyping error rate yielded less independent linkage regions than expected under the null hypothesis of no linkage. For a quantitative trait analysed using a parametric regression-based method, there was very little erosion of the linkage signal, even for error rates as high as 2%.
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2,337,020 |
Glucose-6-phosphate dehydrogenase deficiency and Southeast Asian ovalocytosis in asymptomatic Plasmodium carriers in Sumba island, Indonesia.
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Glucose-6-phosphate dehydrogenase (G6PD) deficiency and Southeast Asian ovalocytosis (SAO) caused by a 27-bp deletion in the band 3 gene (Band3Delta 27) are well-documented genetic traits resistant to malarial diseases; however, relationships between these traits and asymptomatic malaria infection hitherto had not been investigated. Filter-blotted blood samples were collected from a total of 210 healthy individuals, 100 males and 110 females, aged 6-17 years, in Sumba island, Indonesia, to survey for the presence of Plasmodium parasites, G6PD activity and the Band3Delta 27 mutation. Presence of P. falciparum and/or P. vivax was identified in 25 subjects (11.9%). In all, 24 subjects (11.4%) showed Band3Delta 27 heterozygously. In males and females, eight and nine subjects, respectively, showed G6PD deficiency. There was no significant difference in the prevalence of asymptomatic malaria infection between individuals with or without these traits (P>0.05). No alterations in the prevalence of asymptomatic malaria infection suggest that parasite invasion into erythrocytes is unlikely to be a target phase in which the two polymorphisms demonstrate possible protective effects against malaria.
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2,337,021 |
Avoiding versus seeking: the relationship of information seeking to avoidance, blunting, coping, dissonance, and related concepts.
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How have theorists and empirical researchers treated the human tendency to avoid discomforting information?</AbstractText>A historical review (1890-2004) of theory literature in communication and information studies, coupled with searches of recent studies on uptake of genetic testing and on coping strategies of cancer patients, was performed.</AbstractText>The authors' review of the recent literature included searches of the MEDLINE, PsychInfo, and CINAHL databases between 1992 and summer of 2004 and selective, manual searches of earlier literature. Search strategies included the following subject headings and key words: MeSH headings: Genetic Screening/psychology, Decision Making, Neoplasms/diagnosis/genetics/psychology; CINAHL headings: Genetic Screening, Genetic Counseling, Anxiety, Decision Making, Decision Making/Patient; additional key words: avoidance, worry, monitoring, blunting, cancer. The "Related Articles" function in MEDLINE was used to perform additional "citation pearl" searching.</AbstractText>The assumption that individuals actively seek information underlies much of psychological theory and communication practice, as well as most models of the information-seeking process. However, much research has also noted that sometimes people avoid information, if paying attention to it will cause mental discomfort or dissonance. Cancer information in general and genetic screening for cancer in particular are discussed as examples to illustrate this pattern.</AbstractText>That some patients avoid knowledge of imminent disease makes avoidance behavior an important area for social and psychological research, particularly with regard to genetic testing.</AbstractText>
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2,337,022 |
Neurexophilin 3 is highly localized in cortical and cerebellar regions and is functionally important for sensorimotor gating and motor coordination.
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Neurexophilin 3 (Nxph3) is a specific ligand of synaptic alpha-neurexins that are essential for efficient neurotransmitter release. Previous biochemical work demonstrated that Nxph3 interacts with an extracellular domain of alpha-neurexins in a tight complex; however, no information is available on the localization or functional role of Nxph3 in the brain. Here, we generated lacZ reporter gene knock-in mice to investigate the distribution of Nxph3 at the single-cell level and Nxph3 knockout mice to examine its functional importance. Nxph3 expression was restricted mostly to subplate-derived neurons in cortical layer 6b, granule cells in the vestibulocerebellum, and Cajal-Retzius cells during development. Colabeling experiments demonstrated that neurons expressing Nxph3 do not belong to a uniform cell type. Morphological analyses and systematic behavioral testing of knockout mice revealed no anatomical defects but uncovered remarkable functional abnormalities in sensory information processing and motor coordination, evident by increased startle response, reduced prepulse inhibition, and poor rotarod performance. Since Nxph3-deficient mice behaved normally while performing a number of other tasks, our data suggest an important role for Nxph3 as a locally and temporally regulated neuropeptide-like molecule, presumably acting in a complex with alpha-neurexins in select neuronal circuits.
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2,337,023 |
Unique genetic profile of hereditary hemochromatosis in Russians: high frequency of C282Y mutation in population, but not in patients.
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Hereditary hemochromatosis (HH) is a common cause of primary iron overload induced by genetic impairment of iron metabolism. More than 80% of HH patients in populations of European origin are homozygotes for a single mutation C282Y, or compound heterozygotes for C282Y and H63D mutations in the HFE gene. However, in the majority of Asian, African, Australasian, and Amerindian populations, frequencies of C282Y are close to zero. Data on the prevalence of HFE mutations in Russian population and in Russian patients with HH are very limited. In this work, we determined frequencies of C282Y and H63D in ethnical Russians living in the Central European region of Russia. Furthermore, we tested whether homozygocity for C282Y is the major cause of HH in Russians. We found that, in the Russian population, the frequency of C282Y mutation in the HFE gene is relatively high and corresponds to mean European levels. However, in contrast to the majority of European populations, homozygocity for C282Y is found only in a small proportion (5%) of patients with biochemical and clinical signs of HH. These data suggest that either the penetrance of C282Y in Russia is lower than in Western countries, or that a more frequent non-HFE dependent mechanism of primary iron overload dominates in Russian population.
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2,337,024 |
In pursuit (and discovery) of a genetic basis for congenital central hypoventilation syndrome.
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Congenital central hypoventilation syndrome (CCHS) typically presents in the newborn period with a phenotype including alveolar hypoventilation, symptoms of autonomic nervous system dysregulation, and in a subset of cases Hirschsprung disease and later tumors of neural crest origin. Study of genes related to the autonomic dysregulation and the embryologic origin of the neural crest has led to identification of the genetic basis for CCHS, the mode of inheritance, and the presence of mosaicism in a subset of parents. Polyalanine expansion mutations in PHOX2B have been identified to be the disease-defining mutation in CCHS, with a small subset of patients having other mutations in PHOX2B. Further, the size of the polyalanine repeat mutation in PHOX2B is correlated with the severity of the phenotype in CCHS, and non-polyalanine repeat mutations appear to, in general, result in CCHS phenotypes at the severe end of the spectrum. These studies highlight the utility of PHOX2B genetic testing for confirmation of the CCHS diagnosis, for prenatal diagnosis, and for identification of previously undiagnosed adults with unexplained hypercarbia or control of breathing deficits. This diagnostic approach may be a consideration for other complex, seemingly undecipherable diseases that affect infants and children. The purpose of this article is to provide a comprehensive review of current research into the genetic basis for CCHS, an explanation for how these studies evolved, recent studies that begin to explain the mechanisms through which mutations in PHOX2B exert their effects, and clinical application of the genetic testing.
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2,337,025 |
Association analysis of brain-derived neurotrophic factor (BDNF) gene 196 A/G polymorphism with Alzheimer's disease (AD) in mainland Chinese.
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A functional polymorphism in the coding region of brain-derived neurotrophic factor (BDNF) gene (196 A/G, Met66Val) has recently been reported to be associated with Alzheimer's disease (AD) and with an overrepresentation of G allele in AD patients, but different results have also been presented. We conducted a case-control study to analyze the association between the BDNF A/G polymorphism and sporadic AD in a sample composed of 203 AD patients and 239 controls from Mainland Chinese Han population. No association between the polymorphism and AD, no association between the polymorphism and age at onset in AD, and no significant interaction between BDNF and apolipoprotein E (APOE) genotype were detected in either the total or the male samples. However, a significantly high frequency of the GG genotype in the female controls compared with the female patients was detected. A postponed age at onset in the female patients with the GG genotype was also observed. These results suggest that the GG genotype has a protection effect from AD development in females. A significant low frequency of AD patients with the BDNF GG genotype in the AD APOEepsilon4 carriers compared with the frequency of the controls with the BDNF GG genotype in the control APOEepsilon4 carriers was also detected in the female individuals, suggesting that the BDNF GG genotype may reduce the effect of APOEepsilon4 on AD risk in females. Additionally, low frequencies of BDNF G allele and GG genotype were revealed in Chinese when compared with that in the other race populations so far reported.
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2,337,026 |
Base composition analysis of human mitochondrial DNA using electrospray ionization mass spectrometry: a novel tool for the identification and differentiation of humans.
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In traditional approaches, mitochondrial DNA (mtDNA) variation is exploited for forensic identity testing by sequencing the two hypervariable regions of the human mtDNA control region. To reduce time and labor, single nucleotide polymorphism (SNP) assays are being sought to possibly replace sequencing. However, most SNP assays capture only a portion of the total variation within the desired regions, require a priori knowledge of the position of the SNP in the genome, and are generally not quantitative. Furthermore, with mtDNA, the clustering of SNPs complicates the design of SNP extension primers or hybridization probes. This article describes an automated electrospray ionization mass spectrometry method that can detect a number of clustered SNPs within an amplicon without a priori knowledge of specific SNP positions and can do so quantitatively. With this technique, the base composition of a PCR amplicon, less than 140 nucleotides in length, can be calculated. The difference in base composition between two samples indicates the presence of an SNP. Therefore, no post-PCR analytical construct needs to be developed to assess variation within a fragment. Of the 2754 different mtDNA sequences in the public forensic mtDNA database, nearly 90% could be resolved by the assay. The mass spectrometer is well suited to characterize and quantitate heteroplasmic samples or those containing mixtures. This makes possible the interpretation of mtDNA mixtures (as well as mixtures when assaying other SNPs). This assay can be expanded to assess genetic variation in the coding region of the mtDNA genome and can be automated to facilitate analysis of a large number of samples such as those encountered after a mass disaster.
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2,337,027 |
Association of HLA DQB1 0602 in sarcoidosis patients with small fiber neuropathy.
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Sarcoidosis has been reported to be associated with the HLA genes, in particular DQB1.</AbstractText>High resolution DQB 1 of 103 sarcoidosis patients was obtained by sequence-based typing; low resolution HLA-A/B/DRB 1 typing was performed by serological and molecular methods. Small fiber neuropathy (SFN) was established by thermal threshold testing.</AbstractText>Sixty-seven patients suffered from SFN (SFN+), in 36 patients SFN was absent (SFN-). Comparing HLA DQB 1 typings of SFN+ patients, SFN- patients and control individuals revealed a significant increase of the allele DQB 1 0602 in SFN+ patients compared to controls.</AbstractText>This association might be correlated with a severe course of the disease.</AbstractText>
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2,337,028 |
The implications of electronic health records for personalized medicine.
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The emerging concept of an electronic health record (EHR) targeted at a patient centric, cross-institutional and longitudinal information entity (possibly spanning the individuals lifetime) has great promise for personalized medicine. In fact, it is probably the only vehicle through which we may truly realize the personalization of medicine beyond population-based genetic profiles that are expected to become part of medication and treatment indications in the near future. The new EHR standards include mechanisms that integrate clinical data with genomic testing results obtained through applying research-type procedures, such as full DNA sequencing, to an individual patient. Although the most optimal process for the utilization of integrated clinical-genomic data in the EHR framework is still unclear, the new Health Level Seven (HL7) Clinical Genomics Draft Standard for Trial Use suggests using the 'encapsulate & bubble-up' approach, which includes two main phases: the encapsulation of raw genomic data and bubbling-up the most clinically significant portions of that data, while associating it with clinical phenotypes residing in the individual's EHR.
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2,337,029 |
Human immunodeficiency virus type 1 env clones from acute and early subtype B infections for standardized assessments of vaccine-elicited neutralizing antibodies.
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Induction of broadly cross-reactive neutralizing antibodies is a high priority for AIDS vaccine development but one that has proven difficult to be achieved. While most immunogens generate antibodies that neutralize a subset of T-cell-line-adapted strains of human immunodeficiency virus type 1 (HIV-1), none so far have generated a potent, broadly cross-reactive response against primary isolates of the virus. Even small increments in immunogen improvement leading to increases in neutralizing antibody titers and cross-neutralizing activity would accelerate vaccine development; however, a lack of uniformity in target strains used by different investigators to assess cross-neutralization has made the comparison of vaccine-induced antibody responses difficult. Thus, there is an urgent need to establish standard panels of HIV-1 reference strains for wide distribution. To facilitate this, full-length gp160 genes were cloned from acute and early subtype B infections and characterized for use as reference reagents to assess neutralizing antibodies against clade B HIV-1. Individual gp160 clones were screened for infectivity as Env-pseudotyped viruses in a luciferase reporter gene assay in JC53-BL (TZM-bl) cells. Functional env clones were sequenced and their neutralization phenotypes characterized by using soluble CD4, monoclonal antibodies, and serum samples from infected individuals and noninfected recipients of a recombinant gp120 vaccine. Env clones from 12 R5 primary HIV-1 isolates were selected that were not unusually sensitive or resistant to neutralization and comprised a wide spectrum of genetic, antigenic, and geographic diversity. These reference reagents will facilitate proficiency testing and other validation efforts aimed at improving assay performance across laboratories and can be used for standardized assessments of vaccine-elicited neutralizing antibodies.
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2,337,030 |
Genotoxicity testing of four textile dyes in two crosses of Drosophila using wing somatic mutation and recombination test.
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In this study, four textile dyes, namely Astrazon Yellow, Red, Blue, and Black, were tested for their genotoxic effects in the wing cells of Drosophila melanogaster. Two crosses were used, the standard cross (ST) and the improved high-bioactivation cross (HB), the latter being characterized by increased sensitivity to the genotoxic effects of promutagens and procarcinogens. Three-day-old larvae were exposed to different concentrations of dyes. Commonly known mutagens were applied as positive controls. All concentrations of textile dyes, ethyl methanesulfonate (EMS), and urethane caused a decrease in survival proportional to concentration used. EMS and urethane caused an increase in the number of all types of spots in both standard and high-bioactivation crosses. Compared to ST crosses, the number of induced spots in the HB cross treated with urethane was considerably high. Treatment of the standard and the high-bioactivation crosses with textile dyes gave positive results, apparent from increase in the frequency of the small single spots. Yellow and red dyes also increased the number of large single spots in both crosses, whereas the twin spots were positive only at the highest dose of yellow dye. All these results indicate that D. melanogaster wing spot test can be recommended as a suitable in vivo test for the determination of genotoxicity of textile dyes.
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2,337,031 |
The canine telomerase catalytic subunit (dogTERT): characterisation of the gene promoter and identification of proximal core sequences necessary for specific transcriptional activity in canine telomerase positive cell lines.
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Telomerase biology is complicated by studies that show that telomere expression and telomere biology differs between species, and that existing animal models do not closely resemble the human situation. We have previously reported a description of telomere/telomerase biology in the dog and have suggested this as an alternative model system. To further elucidate telomerase biology in this species we have cloned and characterised the canine reverse transcriptase (dogTERT) promoter. We demonstrate that core promoter activity is contained within a region extending approximately 300 bp upstream of the ATG codon. Transient transfections in telomerase-positive canine cell lines and telomerase negative fibroblasts showed that the promoter is only active in telomerase positive cell lines. Sequence analysis demonstrated that the 5' regulatory region is GC-rich and contains no TATA or CAAT box, similar to the human TERT promoter. Motif searches revealed the presence of multiple transcription factor binding sites common to both the human and canine TERT promoters, including a single E-box, Sp1, AP1, MZF-2 and ER/Sp1 binding sites. These findings suggest that the dogTERT gene shares similar transcriptional control to hTERT. Identification of the core promoter necessary for activity may allow the use of naturally occurring cancers in dogs as a preclinical testing ground for telomerase targeted therapies in human cancer patients.
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2,337,032 |
Investigating the specificity of real-time PCR assays using synthetic oligonucleotides.
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Potato spindle tuber viroid (PSTVd) causes damaging diseases of solanaceous crops and is a quarantine pathogen in the European Union. Previously a one-tube real-time RT-PCR assay based on TaqMan chemistry was developed and shown to be ideally suited to PSTVd detection. However, since it was impossible to trace infected plant material for every published PSTVd sequence reported, in silico predictions were made about assay specificity based on the positions of nucleotide polymorphisms within the published viroid sequences and the regions of the primers and probe. The predictions could not be verified due to the absence of viroid material. This paper describes work investigating the detection of these sequence variants by designing synthetic oligonucleotides to sequences from the database and testing them with a real-time PCR assay. The results show that all PSTVd sequence variants are detected, and that the closely related Mexican papita viroid is also detected, although with a lower efficiency. The paper gives indications as to what effect nucleotide changes at different positions within primers and probes might do and should aid in the testing of future assays, although it is difficult to draw fixed rules about the possible effect changes may have.
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2,337,033 |
Monophyly of primary photosynthetic eukaryotes: green plants, red algae, and glaucophytes.
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Between 1 and 1.5 billion years ago, eukaryotic organisms acquired the ability to convert light into chemical energy through endosymbiosis with a Cyanobacterium (e.g.,). This event gave rise to "primary" plastids, which are present in green plants, red algae, and glaucophytes ("Plantae" sensu Cavalier-Smith). The widely accepted view that primary plastids arose only once implies two predictions: (1) all plastids form a monophyletic group, as do (2) primary photosynthetic eukaryotes. Nonetheless, unequivocal support for both predictions is lacking (e.g.,). In this report, we present two phylogenomic analyses, with 50 genes from 16 plastid and 15 cyanobacterial genomes and with 143 nuclear genes from 34 eukaryotic species, respectively. The nuclear dataset includes new sequences from glaucophytes, the less-studied group of primary photosynthetic eukaryotes. We find significant support for both predictions. Taken together, our analyses provide the first strong support for a single endosymbiotic event that gave rise to primary photosynthetic eukaryotes, the Plantae. Because our dataset does not cover the entire eukaryotic diversity (but only four of six major groups in), further testing of the monophyly of Plantae should include representatives from eukaryotic lineages for which currently insufficient sequence information is available.
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2,337,034 |
Coral gardens: paternity and drug testing on the reef.
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An international team has used molecular genetics and chemical tagging to trace how baby clownfish travel from their mother's nest through the ocean to the anemone they will live on. More than one out of five juveniles came from nests that were only meters away, despite spending over a week drifting in ocean currents. Such surprising fidelity to a small area of the coral reef bodes well for efforts to preserve coral reef diversity with reserves.
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2,337,035 |
Strong selection against hybrids at a hybrid zone in the Ensatina ring species complex and its evolutionary implications.
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The analysis of interactions between lineages at varying levels of genetic divergence can provide insights into the process of speciation through the accumulation of incompatible mutations. Ring species, and especially the Ensatina eschscholtzii system exemplify this approach. The plethodontid salamanders E. eschscholtzii xanthoptica and E. eschscholtzii platensis hybridize in the central Sierran foothills of California. We compared the genetic structure across two transects (southern and northern Calaveras Co.), one of which was resampled over 20 years, and examined diagnostic molecular markers (eight allozyme loci and mitochondrial DNA) and a diagnostic quantitative trait (color pattern). Key results across all studies were: (1) cline centers for all markers were coincident and the zones were narrow, with width estimates of 730 m to 2000 m; (2) cline centers at the northern Calaveras transect were coincident between 1981 and 2001, demonstrating repeatability over five generations; (3) there were very few if any putative F1s, but a relatively high number of backcrossed individuals in the central portion of transects; and (4) we found substantial linkage disequilibrium in all three studies and strong heterozygote deficit both in northern Calaveras, in 2001, and southern Calaveras. Both linkage disequilibrium and heterozygote deficit showed maximum values near the center of the zones. Using estimates of cline width and dispersal, we infer strong selection against hybrids. This is sufficient to promote accumulation of differences at loci that are neutral or under divergent selection, but would still allow for introgression of adaptive alleles. The evidence for strong but incomplete isolation across this centrally located contact is consistent with theory suggesting a gradual increase in postzygotic incompatibility between allopatric populations subject to divergent selection and reinforces the value of Ensatina as a system for the study of divergence and speciation at multiple stages.
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2,337,036 |
Genealogical footprints of speciation processes in wild tomatoes: demography and evidence for historical gene flow.
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Multilocus studies assessing patterns of nucleotide polymorphism within and among closely related species provide access to genealogical information bearing on demographic and geographic aspects of their speciation history. However, the technical difficulties in obtaining sufficient sequence data have severely limited this approach thus far, especially in outbred plant taxa. We employ the analytical framework of divergence population genetics in testing the isolation model of speciation in three self-incompatible species of wild tomatoes (clade Lycopersicon), in particular the assumption of divergence without gene flow. Based on DNA sequence data for 13 nuclear loci, average levels of silent polymorphism vary more than three-fold among species. We estimate a large effective population size for the ancestral species, quite similar to that of the highly polymorphic L. peruvianum. The other two species, however, exhibit concordant signatures of population-size reduction. These demographic inferences are biologically plausible and consistent with results obtained from standard neutrality tests. While the isolation model cannot be rejected by goodness-of-fit criteria, patterns of intragenic linkage disequilibrium in L. peruvianum are indicative of historical introgression at least in some regions of the genome. Considered jointly with the geographic pattern of postzygotic reproductive isolation, our results suggest that speciation occurred under residual gene flow, implying natural selection as one of the evolutionary forces driving the diversification of tomato lineages.
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2,337,037 |
Prenatal diagnosis of spinal muscular atrophy: Indian scenario.
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To study the psychosocial issues associated with prenatal diagnosis of SMA in India and the use of SMN1 copy number analysis for carrier detection prior to offering prenatal diagnosis.</AbstractText>Homozygous deletion of SMN1 gene was done by PCR-RFLP. Copy number analysis of SMN1 gene was performed by quantitative PCR.</AbstractText>We report our experience of eight cases of prenatal diagnosis for SMA and the use of carrier detection prior to offering prenatal diagnosis. Quantitative PCR results show that SMN1 copy number analysis is useful to identify couples at risk.</AbstractText>Case analyses depict unique psychosocial issues associated with prenatal diagnosis of SMA from India.</AbstractText>Copyright 2005 John Wiley & Sons, Ltd.</CopyrightInformation>
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2,337,038 |
ATM polymorphism and hereditary nonpolyposis colorectal cancer (HNPCC) age of onset (United States).
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We examined a G-to-A single nucleotide polymorphism of the ATM gene, to determine if it influences hereditary non-polyposis colorectal cancer (HNPCC) age of onset. HNPCC is caused by mutations in mismatch repair genes, especially hMLH1 and hMSH2. ATM germline mutations have been associated with breast and digestive cancers. In a smaller European study, the G-to-A polymorphism was associated with an increased risk of developing an HNPCC-related cancer within HNPCC families.</AbstractText>We genotyped 109 mismatch repair gene (MMR) mutation carriers from 53 HNPCC families for the ATM polymorphism using PCR and single strand conformational polymorphism (SSCP) analysis. We tested the association between the ATM genotypes and HNPCC age of onset by survival analysis.</AbstractText>The ATM polymorphism did not significantly modify HNPCC age of onset, nor overall risk, in our population.</AbstractText>Although a modifier effect was not seen in our study, future studies that examine the polymorphism in combination with other genetic and environmental factors may elucidate an association. Revealing such associations in MMR mutation carriers may improve risk estimates and help to identify individuals who are genetically susceptible to developing HNPCC at an earlier age.</AbstractText>
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2,337,039 |
Age at menarche and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.
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Age at menarche is a strong and consistent predictor of breast cancer risk in the general population, but has not been well studied in women with a family history of breast cancer. We conducted this study to examine whether the presence of a deleterious BRCA1 or BRCA2 mutation influences age at menarche and to investigate whether or not there is an association between age at menarche and the risk of breast cancer in BRCA1 or BRCA2 mutation carriers. The presence of a deleterious BRCA1 or BRCA2 mutation did not appear to influence a woman's age at menarche. A matched case-control study was conducted on 1311 pairs of women who have been identified to be carriers of a deleterious mutation in either the BRCA1 (n = 945 pairs) or the BRCA2 gene (n = 366 pairs). Information about age at menarche was derived from a questionnaire routinely administered to carriers of a mutation in either gene. Among women who carried a deleterious BRCA1 mutation, age at menarche was inversely associated with the risk of breast cancer (p trend = 0.0002). This association was not observed among BRCA2 mutation carriers (p trend = 0.49). Compared with BRCA1 carriers whose age at menarche was < or =11 years, women with a menarcheal age between 14 and 15 years old had a 54% reduction in risk (OR = 0.46; 95% CI 0.30-0.69). This study implicates early age at menarche as a determinant of breast cancer among women with a BRCA1 mutation.
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2,337,040 |
Genotyping microarray for the detection of more than 200 CFTR mutations in ethnically diverse populations.
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Cystic fibrosis (CF), which is due to mutations in the cystic fibrosis transmembrane conductance regulator gene, is a common life-shortening disease. Although CF occurs with the highest incidence in Caucasians, it also occurs in other ethnicities with variable frequency. Recent national guidelines suggest that all couples contemplating pregnancy should be informed of molecular screening for CF carrier status for purposes of genetic counseling. Commercially available CF carrier screening panels offer a limited panel of mutations, however, making them insufficiently sensitive for certain groups within an ethnically diverse population. This discrepancy is even more pronounced when such carrier screening panels are used for diagnostic purposes. By means of arrayed primer extension technology, we have designed a genotyping microarray with 204 probe sites for CF transmembrane conductance regulator gene mutation detection. The arrayed primer extension array, based on a platform technology for disease detection with multiple applications, is a robust, cost-effective, and easily modifiable assay suitable for CF carrier screening and disease detection.
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2,337,041 |
Experience and strategy for the molecular testing of Duchenne muscular dystrophy.
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Mutations in the dystrophin gene result in both Duchenne and Becker muscular dystrophies (DMD and BMD). Approximately two-thirds of the affected patients have large deletions or duplications. Using the multiplex polymerase chain reaction and Southern blotting techniques, the detection of these larger mutations is relatively straightforward. Detection of the point mutations in the remaining one-third of the patients has been challenging, mainly due to the large gene size and lack of hotspots or prevalent mutations. However, with the addition of some of the newer molecular screening methods, it is becoming more feasible for clinical laboratories to test for point mutations in the larger genes like dystrophin. Here we review the clinical features, describe the mutation distributions, evaluate current molecular strategies, and illustrate how the genetic findings have impacted the current clinical diagnostics of Duchenne and Becker muscular dystrophies.
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2,337,042 |
Association of chronic fatigue syndrome with human leucocyte antigen class II alleles.
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A genetic component to the development of chronic fatigue syndrome (CFS) has been proposed, and a possible association between human leucocyte antigen (HLA) class II antigens and chronic fatigue immune dysfunction has been shown in some, but not all, studies.</AbstractText>To investigate the role of HLA class II antigens in CFS.</AbstractText>Forty nine patients with CFS were genotyped for the HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles and the frequency of these alleles was compared with a control group comprising 102 normal individuals from the UK. All patients and controls were from the same region of England and, apart from two patients, were white.</AbstractText>Analysis by 2 x 2 contingency tables revealed an increased frequency of HLA-DQA1*01 alleles in patients with CFS (51.0% v 35%; odds ratio (OR), 1.93; p = 0.008). HLA-DQB1*06 was also increased in the patients with CFS (30.2% v 20.0%; OR, 1.73, p = 0.052). Only the association between HLA-DQA1*01 and CFS was significant in logistic regression models containing HLA-DQA1*01 and HLA-DRQB1*06, and this was independent of HLA-DRB1 alleles. There was a decreased expression of HLA-DRB1*11 in CFS, although this association disappeared after correction for multiple comparisons.</AbstractText>CFS may be associated with HLA-DQA1*01, although a role for other genes in linkage disequilibrium cannot be ruled out.</AbstractText>
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2,337,043 |
The involvement of the aspartate triad of the active center in all catalytic activities of multisubunit RNA polymerase.
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Three conserved aspartate residues in the largest subunit of multisubunit RNA polymerases (RNAPs) coordinate two Mg2+ ions involved in the catalysis of phosphodiester bond synthesis. A structural model based on the stereochemistry of nucleotidyl transfer reaction as well as recent crystallographic data predict that these Mg2+ ions should also be involved in the reverse reaction of pyrophosphorolysis as well as in the endo- and exonucleolytic cleavage of the nascent RNA. Here, we check these predictions by constructing point substitutions of each of the three Asp residues in the beta' subunit of Escherichia coli RNAP and testing the mutant enzymes' functions. Using artificially assembled elongation complexes, we demonstrate that substitutions of any of the three aspartates dramatically reduce all known RNAP catalytic activities, supporting the model's predictions that same amino acids participate in all RNAP catalytic reactions. We demonstrate that though substitutions in the DFDGD motif decrease Mg2+ binding to free RNAP below detection limits, the apparent affinity to Mg2+ in transcription complexes formed by the mutant and wild-type RNAPs is similar, suggesting that NTP substrates and/or nucleic acids actively contribute to the retention of active center Mg2+.
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2,337,044 |
Quantifying mixed populations of drug-resistant human immunodeficiency virus type 1.
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In order to survive prolonged treatment with antiretroviral nucleoside analogs, the human immunodeficiency virus type 1 (HIV-1) is selectively forced to acquire mutations in the reverse transcriptase (RT) gene. Some of these mutations are more common than others and have become markers for antiretroviral resistance. For the early detection of these markers, a novel MultiCode-RTx one-step testing system to rapidly and simultaneously characterize mixtures of HIV-1 targets was designed. For cDNA, nucleotide polymorphisms for codon M184V (ATG to GTG) and K65R (AAA to AGA) could be differentiated and quantified even when the population mixture varied as much as 1 to 10,000. Standard mixed-population curves using 1 to 100% of the mutant or wild type generated over 4 logs of total viral particle input did not affect the overall curves, making the method robust. The system was also applied to a small set of samples extracted from infected individuals on nucleoside reverse transcriptase inhibitor therapy. Of 13 samples tested, all were positive for HIV and 10 of the 13 genotypes determined were concordant with the line probe assay. MultiCode-RTx could be applied to other drug-selected mutations in the viral genome or for applications where single-base changes in DNA or RNA occur at frequencies reaching 0.01% to 1%, respectively.
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2,337,045 |
Animal breeding and disease.
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Single-locus disorders in domesticated animals were among the first Mendelian traits to be documented after the rediscovery of Mendelism, and to be included in early linkage maps. The use of linkage maps and (increasingly) comparative genomics has been central to the identification of the causative gene for single-locus disorders of considerable practical importance. The 'score-card' in domestic animals is now more than 100 disorders for which the molecular lesion has been identified and hence for which a DNA test is available. Because of the limited lifespan of any such test, a cost-effective and hence popular means of protecting the intellectual property inherent in a DNA test is not to publish the discovery. While understandable, this practice creates a disconcerting precedent. For multifactorial disorders that are scored on an all-or-none basis or into many classes, the effectiveness of control schemes could be greatly enhanced by selection on estimated breeding values for liability. Genetic variation for resistance to pathogens and parasites is ubiquitous. Selection for resistance can therefore be successful. Because of the technical and welfare challenges inherent in the requirement to expose animals to pathogens or parasites in order to be able to select for resistance, there is a very active search for DNA markers for resistance. The first practical fruits of this research were seen in 2002, with the launch of a national scrapie control programme in the UK.
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2,337,046 |
Estimation of effective population sizes from data on genetic markers.
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The effective population size (Ne) is an important parameter in ecology, evolutionary biology and conservation biology. It is, however, notoriously difficult to estimate, mainly because of the highly stochastic nature of the processes of inbreeding and genetic drift for which Ne is usually defined and measured, and because of the many factors (such as time and spatial scales, systematic forces) confounding such processes. Many methods have been developed in the past three decades to estimate the current, past and ancient effective population sizes using different information extracted from some genetic markers in a sample of individuals. This paper reviews the methodologies proposed for estimating Ne from genetic data using information on heterozygosity excess, linkage disequilibrium, temporal changes in allele frequency, and pattern and amount of genetic variation within and between populations. For each methodology, I describe mainly the logic and genetic model on which it is based, the data required and information used, the interpretation of the estimate obtained, some results from applications to simulated or empirical datasets and future developments that are needed.
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2,337,047 |
Differential expression of genes at stages when regeneration can and cannot occur after injury to immature mammalian spinal cord.
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Comprehensive screens were made for genes that change their expression during a brief critical period in development when neonatal mammalian central nervous system (CNS) loses its capacity to regenerate. In newly born opossums older than 12 days regeneration ceases to occur in the cervical spinal cord. It continues for 5 more days in lumbar regions. The mRNA's expressed in cords that do and do not regenerate were analyzed by polymerase chain reaction-based subtractive hybridization. The mRNAs extracted from cervical cords of animals aged 9 and 12 days were subtracted reciprocally, old from young and young from old. Additional subtractions were made between lumbar regions of 12 day-old cords (which can regenerate) and cervical regions (which cannot). Mini libraries of approximately 2000 opossum cDNA clones resulted from each subtraction. Many sequences were novel. Others that were expressed differentially were related to cell growth, proliferation, differentiation, motility, adhesion, cytoskeleton and extracellular matrix. A major task was to narrow the search and to eliminate genes that were not associated with regeneration. Clones from different subtractions were cross-hybridized. After those common to regenerating and nonregenerating cords were rejected, approximately 284 sequences of interest remained. Our results revealed novel sequences, as well as genes involved in transcription, cell signaling, myelin formation, growth cone motility, liver regeneration, and nucleic acid and protein management as the candidates important for neuroregeneration. For selected genes of potential interest for regeneration (for example cadherin, catenin, myelin basic protein), their temporal and spatial distributions and levels of expression in the CNS were measured by Northern blots, semiquantitative and real-time RT-PCR, and in situ hybridization. Our experiments set the stage for testing the efficacy of candidate genes in turning on or off the capacity for spinal cord regeneration. Opossum spinal cords in vitro provide a reliable and rapid assay for axon outgrowth and synapse formation.
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2,337,048 |
Spectrum and prevalence of BRCA1 and BRCA2 germline mutations in Sardinian patients with breast carcinoma through hospital-based screening.
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Factors that are predictive of carrying BRCA1 and BRCA2 germline mutations in patients with breast carcinoma are awaited widely. The genetically homogeneous Sardinian population may be useful for defining the role of such genetic alterations further through a clinical evaluation program.</AbstractText>One hundred two of 659 patients with breast carcinoma (15.5%) who were collected consecutively had a family history of breast carcinoma and were screened for BRCA1/2 mutations by denaturing high-performance liquid chromatography and DNA sequencing.</AbstractText>Three deleterious germline BRCA1/2 mutations were detected in 15 of 102 families (14.7%), including 13 families (86.7%) with BRCA2 mutations and 2 families (13.3%) with BRCA1 mutations. A single variant, BRCA2-8765delAG, was the most recurrent mutation in the series and was found in 12 of 102 families (11.8%) and in 18 of 657 patients (2.7%). The average age at diagnosis was significantly younger in families with BRCA1/2 mutations (48.6 yrs) compared with the age of patients who had no detectable mutation (52.9 yrs; P = 0.039). Moreover, BRCA1/2 mutations were found at a significantly higher rate in families who had at least 1 member with ovarian carcinoma or male breast carcinoma (5 of 12 families; 41.7%) than in families without such an association (10 of 90 families; 11.1%; P = 0.003).</AbstractText>BRCA2 mutations were approximately 6 times more prevalent than BRCA1 mutations. A diagnosis of breast carcinoma before age 50 years, ovarian carcinoma, male breast carcinoma, and 3 affected generations all were associated significantly with BRCA1/2 mutations. Although the current findings provided further support for the hypothesis that additional breast carcinoma susceptibility genes remain to be identified, such indicators of the presence of BRCA1/2 mutations may be useful in counseling patients about undergoing genetic testing.</AbstractText>Copyright 2005 American Cancer Society.</CopyrightInformation>
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2,337,049 |
Novel and established markers of cobalamin deficiency: complementary or exclusive diagnostic strategies.
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New developments in diagnostic markers and a better understanding of the limitations of traditional diagnostic strategies have allowed diagnosis of earlier stages and atypical forms of cobalamin deficiency. Still, there are no generally accepted guidelines for the definition, diagnosis, treatment, and follow-up of cobalamin deficiency. The new trend toward defining cobalamin deficiency purely on the basis of biochemical test outcomes in the absence of overt clinical signs and symptoms could, however, be problematic and may result in overdiagnosis and overtreatment. Use of metabolic markers for the assessment of cobalamin deficiency allows the demonstration of tissue deficiency, but the establishment of the cause of deficiency should also be part of the diagnostic approach. Four groups of diagnostic tests are currently available and these include total cobalamin and cobalamin fractions (such as holo-transcobalamin), tests of gastrointestinal dysfunction, tests of metabolic function, and different gene tests. Among the available tests, only homocysteine, methylmalonic acid, holo-transcobalamin, and possibly methylcitric acid are considered to be useful in clinical practice to add to cobalamin. Gastrointestinal function tests may identify the cause of cobalamin deficiency, whereas the diagnostic usefulness of genetic testing needs to be evaluated. This article provides an overview of recent developments and a reappraisal of novel and established diagnostic markers for cobalamin deficiency.
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2,337,050 |
Women's attitudes toward testing for fragile X carrier status: a qualitative analysis.
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Fragile X syndrome (FXS) is primarily due to a repeat expansion mutation found in the FMR1 X-linked gene. We have conducted a qualitative analysis of responses from women concerning their attitudes toward testing for carrier status of the fragile X mutation among reproductive-age women. We obtained responses from focus groups including women with and without FXS in their families. We found the following themes: (1) mothers of children with FXS have difficulty formulating their opinions on population screening because of their unique experiences surrounding their own carrier diagnosis and their relationship with their children with FXS, (2) the motivation for carrier testing and need for information differ by family history of FXS and parental status, and (3) the timing of carrier testing with respect to a woman's life stage dictates whether carrier information will be viewed as beneficial or detrimental. There was evidence that non-carrier women from the general population would be wholly unprepared for positive carrier results. These findings have significant implications for genetic counseling as well as for population screening.
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2,337,051 |
Policy recommendations for carrier testing and predictive testing in childhood: a distinction that makes a real difference.
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The genetic testing of children raises many ethical concerns. This paper examines how five position statements from Canada, UK and USA, which present guidelines for good practice in this area produce different recommendations for carrier testing and predictive testing. We find that the genetic information generated through carrier testing is routinely presented as less serious than that generated from predictive testing. Additionally, the reproductive implications of predictive testing are also routinely erased. Consequently, the papers argue strongly against predictive testing but advise caution against carrier testing in somewhat weaker terms. We argue that these differences rest on assumptions about the status of reproduction in people's lives and on an ethical stance that foregrounds the self over others. We propose that questioning the crude and sharp distinction between carrier and predictive testing in principle may enable practitioners and parents/families to make more nuanced decisions in practice.
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2,337,052 |
Genetic counseling for fragile x syndrome: updated recommendations of the national society of genetic counselors.
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These recommendations describe the minimum standard criteria for genetic counseling and testing of individuals and families with fragile X syndrome, as well as carriers and potential carriers of a fragile X mutation. The original guidelines (published in 2000) have been revised, replacing a stratified pre- and full mutation model of fragile X syndrome with one based on a continuum of gene effects across the full spectrum of FMR1 CGG trinucleotide repeat expansion. This document reviews the molecular genetics of fragile X syndrome, clinical phenotype (including the spectrum of premature ovarian failure and fragile X-associated tremor-ataxia syndrome), indications for genetic testing and interpretation of results, risks of transmission, family planning options, psychosocial issues, and references for professional and patient resources. These recommendations are the opinions of a multicenter working group of genetic counselors with expertise in fragile X syndrome genetic counseling, and they are based on clinical experience, review of pertinent English language articles, and reports of expert committees. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. The professional judgment of a health care provider, familiar with the facts and circumstances of a specific case, will always supersede these recommendations.
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2,337,053 |
Hangover susceptibility in relation to aldehyde dehydrogenase-2 genotype, alcohol flushing, and mean corpuscular volume in Japanese workers.
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A study of Asian-American students suggested a positive association between inactive ALDH2*2 and susceptibility to hangover. A biomarker for moderate-to-heavy drinking in persons with inactive aldehyde dehydrogenase-2 (ALDH2) is increased mean corpuscular volume (MCV).</AbstractText>Associations between hangover and ALDH2 genotype, alcohol flushing, and MCV were examined for 251 Japanese workers (139 men, 112 women).</AbstractText>Inactive ALDH2*1/2*2 heterozygotes drank less alcohol than active ALDH2*1/2*1 homozygotes (p < 0.0001), but the frequency of hangover did not significantly differ between the two groups for either gender. The amount of drinking reported to lead to hangover was significantly less for male and female ALDH2*1/2*2 heterozygotes than for their ALDH2*1/2*1 homozygous counterparts (p < 0.005). The proportion of men who had hangover three times or more during the past year increased significantly with increased daily alcohol consumption in men with the ALDH2*1/2*2 genotype (p = 0.0002) but not in those with the ALDH2*1/2*1 genotype. For men who usually consumed <44 g of ethanol/day, the median amount of drinking before hangover was significantly lower for ALDH2*1/2*2 men than for ALDH2*1/2*1 men reporting the same level of consumption. Hangover occurred with consistently high frequency among ALDH2*1/2*1 men, regardless of their daily consumption. Similar findings were observed in a comparison of men who never flushed and those who reported current or former flushing, a surrogate marker of inactive ALDH2. Assessment of hangover risk by quartiles of MCV showed that men with MCV of > or =96 had a significantly higher risk of hangover than did men with MCV of <91 (odds ratio = 5.56; 95% confidence interval = 1.69-18.25).</AbstractText>Inactive heterozygous ALDH2, alcohol flushing, and increased MCV were positively associated with hangover susceptibility in Japanese workers, suggesting that acetaldehyde is etiologically linked to the development of hangover.</AbstractText>
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2,337,054 |
A statistical model for HIV-1 sequence classification using the subtype analyser (STAR).
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HIV-1 antiretroviral drug resistance testing produces large amounts of HIV-1 protease and reverse transcriptase sequences. These provide an excellent resource to study the incidence, spread and clinical significance of HIV-1 subtypes. We have produced a program, Subtype Analyser (STAR) that rapidly and accurately subtypes HIV-1. Here we have determined a robust and statistically validated model for subtype assignment.</AbstractText>We have significantly extended our HIV-1 subtyping tool (STAR), such that each query sequence when evaluated against subtype profile alignments, returns a discriminating score based on the ratio of subtype positive to negative amino acid positions. These scores were transformed into a Z-score distribution and evaluated. Of the 141 sequences used to define the subtype alignments, 98% were correctly reclassified. Inclusion of additional recombination detection within STAR increased the detection of known recombinant sequences to 95%.</AbstractText>STAR is available as compiled (Linux Fedora 3) or source code from http://pgv19.virol.ucl.ac.uk/download/star_linux.tar</AbstractText>[email protected]</AbstractText>http://pgv19.virol.ucl.ac.uk/download/star_supplement</AbstractText>
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2,337,055 |
MBL2 polymorphisms screening in a regional Italian CF Center.
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We performed MBL2 genotyping in 47 CF patients-cared of at the regional CF Centre of Trieste-trying to establish a correlation within allelic variants of MBL2 and modification of patients' clinical outcome. FEV1 values were significantly lowered and a significantly earlier age at onset of Pseudomonas aeruginosa colonisation was found in CF patients with at least one MBL2 variant.
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2,337,056 |
Incontinentia pigmenti case series: clinical spectrum of incontinentia pigmenti in 53 female patients and their relatives.
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A retrospective case series of 53 female patients with incontinentia pigmenti (IP) including 28 secondary cases (female relatives of probands) was reviewed and compared with other series in an attempt to estimate more accurately the true disease burden of patients with IP. We found that, while the frequency of the first three cutaneous stages of IP was comparable with previous studies, none of the secondary cases manifested any serious neurological complications but all displayed stage IV pale anhidrotic reticulate lines on their posterior calves. This important clinical feature of IP in secondary cases has previously been under-represented in studies that often involved only paediatric probands. Hence, mildly affected cases of IP are often undiagnosed and under-represented in case series to date, possibly leading to inappropriately high estimates of neurological and eye involvement. With the availability of genetic testing, it is now feasible to confirm the variability of the phenotype and the risk of complications in IP.
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2,337,057 |
Decision making and decision support for hereditary breast-ovarian cancer susceptibility.
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Genetic testing for disease susceptibility has the potential to revolutionize health care by allowing for individually tailored disease prevention strategies. To achieve this promise, patients and physicians must use the information obtained through genetic testing to make medical decisions that are consistent with patient preferences and that lead to reduced disease morbidity and mortality. However, decisions associated with genetic testing can be complex. In this article, the authors review decision making associated with genetic testing and the medical management of hereditary breast-ovarian cancer susceptibility. They focus on decisions regarding BRCA1/2 testing and prophylactic surgery among BRCA1 and BRCA2 mutation carriers. They highlight the role of patient preferences and decision support in this population. The studies reviewed indicate that although patients' preferences do predict genetic testing and management decisions, other factors also influence their decision making. In particular, the authors discuss the role of anxiety and worry in relation to testing and surgery decisions.
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2,337,058 |
[Genetic counseling].
|
The emergence of molecular genetics into a routine medical service is demanding a paradigm shift in medical practice. An adequate reformation of its discipline and technology is required in every field of medical service including nursing. In 2000, the JFCR hospital founded a Familial Cancer Center to provide genetic counseling and genetic testing for cancer patents. Based upon our experiences with 250 families having various cancers, we have attempted to extract issues to be addressed in further detail.
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2,337,059 |
[The state of the art of hereditary cancer studies].
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During the last two decades, many genes responsible for hereditary cancer syndromes have been isolated. Based on the accumulating genetic information, genetic testing for both patients and the relatives is carried out in hospitals and clinics, and the clinical significance has been investigated. In addition to the genetic analyses of known genes and the functional analyses of the gene products, the recent research trends in hereditary cancer studies tend to move into the second era of research strategies including the isolation of novel genes responsible for remaining hereditary cancers, associated studies for finding cancer-susceptibility variants and the comprehensive analyses of expression profiles in tumors. Such new strategies are not only important to elucidate the pathophysiological mechanism of each hereditary cancer but may provide a potential application of tailor-made cancer therapy depending on the mutation status because many of the gene products seem to participate in the chemosensitivity of cancer cells. Furthermore, the research efforts have been expected to develop novel strategies for cancer prevention, diagnostics and therapeutics. In this paper, we have outlined the state of the art of studies on hereditary cancer syndrome, focusing on familial breast cancer and hereditary non-polyposis colorectal cancer.
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2,337,060 |
[Gene testing of hereditary cancer on comprehensive gene medical examination support system].
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It has been estimated that genetic factors or a combination of genetic and environmental factors play a role in the development of 10-15% of all cancers. A genetic cause of hereditary cancer has been identified in more than 40 diseases till now. For preventing this cancer, gene testing is essential because it has no definite clinical marker as in hereditary non-polyposis colorectal cancer: HNPCC. Much more experience must be accumulated in this testing at the clinical base in order to increase specificity and sensitivity while safeguarding ethical, legal and social issues (ELSI). Recently, the Personal Information Protection Law was enforced. Gene inspection involving hereditary cancer should be carried out under a comprehensive gene medical examination organization. It is important for the family doctor, medical specialist, and gene inspection person in charge to cooperate closely with one another, and this will be a subject of future study.
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2,337,061 |
[Clinical genetics for hereditary cancers: from the viewpoint of physicians working at a hospital specialized in cancer].
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In our daily practice, we provide clinical genetic consultation for patients at risk for hereditary cancers. The clinical characteristics of hereditary cancer syndromes in adults differ from those of hereditary diseases in children, although both involve genetic disease. One major difference is the difficulty in diagnosing hereditary cancers. Genetic testing has enabled us to diagnose HNPCC and familial breast and ovarian cancers. Another difference is the possibility to improve the outcomes of hereditary cancer syndromes by medical intervention. Intentional surveillance thus plays a key role in the management of hereditary cancer syndromes. These features make genetic counseling essential for hereditary cancer syndromes, including genetic testing and lifelong disease management. Networking among genetic disease specialists is particularly necessary. Clinical geneticists should be responsible for not only genetic disease but also for genomic information about cancer, with the ultimate goal of providing "order-made" medical consultation and services. Another important goal is the establishment of systems for the comprehensive care of patients and for the career development of specialists to provide regional-based care for persons who have or are at risk for hereditary cancers, including future generations.
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2,337,062 |
[Genetic medicine in the university hospital].
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The importance of genetic medicine is growing along with the development of genome science. Especially for hereditary cancer syndromes, genetic counseling and genetic tests are becoming an essential part of the medical service for those diseases. However, in Japan, there is a shortage of clinical geneticists who are familiar with hereditary tumor syndromes. There are also many other problems such as the cost of genetic tests that should be solved.
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2,337,063 |
[Knowledge, attitude and behavior about the inherited predisposition to cancer. A survery of a population without any history of cancer in central Tunisia].
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The genetic bases of inherited predisposition to cancer are now established. The aim of our study is to value the knowledge, attitude and behavior of the general population about the inherited predisposition to cancer. Our study involved a population of 200 individuals. Without any history of cancer. The mean age of our population was 37.5 years (18 to 74 years). The education level was low in 62.5% of cases (illiterate or primary education). About knowledge: heredity was considered a predisposing factor to cancer by 42.5% of the respondents. About attitude: we noted a cancerophobia in 82% of cases. 86.5% of our respondents trought that an early diagnosis increased the chance of recovery. About behavior: 72.5% of the studied population wishd to know if they were predisposed to develop cancer. In case of pregnancy, 79% wished to know if the foetus wasa cancer gene predisposition carrier. 28% would keep this foetus in case of positive genetic testing. These results are encouraging to develop oncogenetic counselling in Tunisia.
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2,337,064 |
Couples at risk: HIV-1 concordance and discordance among sexual partners receiving voluntary counseling and testing in Uganda.
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To determine correlates of HIV-1 concordance for couples receiving voluntary HIV counseling and testing.</AbstractText>Cross-sectional study of couples receiving voluntary HIV counseling and testing in Kampala, Uganda.</AbstractText>An interview and physical examination were conducted for 49 HIV-1-concordant (both partners infected with HIV) and 126 HIV-1-discordant (1 partner infected with HIV and 1 partner HIV negative) couples. Blood samples from all participants were tested for HIV-1 and syphilis serology. CD4 cell count and HIV load were characterized for all HIV-infected persons. Urine samples were tested for Neisseria gonorrhoeae and Chlamydia trachomatis using ligase chain reaction. Associations between couples' HIV status and key sociodemographic, behavioral, and biomedical factors were analyzed.</AbstractText>Men in HIV-concordant couples were more likely than men in HIV-discordant couples to be living together with their sexual partner (odds ratio [OR], 11.3; 95% confidence interval [CI], 2.8-53.7; P=0.004), to be uncircumcised (OR, 4.5; 95% CI, 1.1-18.8; P=0.042), and to have higher HIV loads (OR for each log increase, 3.0; 95% CI, 2.0-4.7; P<0.001). Women in HIV-concordant couples were more likely than women in HIV-discordant couples to be living together with their sexual partner (OR, 19.0; 95% CI, 3.8-84.8), to have an uncircumcised male partner (OR, 6.5; 95% CI, 1.6-26.4), to have had a sexually transmitted disease in the 6 months before enrollment (OR, 1.9; 95% CI, 0.9-4.5), and to have higher HIV loads (OR for each log increase, 2.2; 95% CI, 1.5-3.2).</AbstractText>Several behavioral and biologic risk factors were associated with HIV concordance for couples. Providing early sexually transmitted disease diagnosis and treatment, antiretroviral therapy, and specially designed counseling to HIV-discordant couples may help prevent HIV transmission in couples where being in a stable sexual relationship is a major risk factor for HIV infection.</AbstractText>
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2,337,065 |
Familial Alzheimer disease: decreases in CSF Abeta42 levels precede cognitive decline.
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CSF amyloid beta-peptide 42 (Abeta42) levels in presymptomatic subjects with pathogenic mutations in the PS1 gene are significantly lower than in an age-matched control group. Consequently, in these subjects, there is a window of opportunity estimated as at least 4 to 12 years to evaluate the ability of any putative prophylactic therapy to decrease, arrest, or reverse abnormalities in Abeta42 metabolism many years before clinical symptoms of Alzheimer disease are otherwise likely to occur.
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2,337,066 |
New calcium channel mutations predict aberrant RNA splicing in episodic ataxia.
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Episodic ataxia type 2 (EA2) is an autosomal dominant channelopathy characterized by paroxysmal cerebellar ataxia. Previous studies suggest that most EA2 cases are associated with mutations in the alpha1A subunit of the P/Q-type voltage-gated calcium channel gene CACNA1A. In a UK national study, the authors analyzed 15 index cases with typical EA2 and identified two unreported intronic mutations that predict aberrant splicing.
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2,337,067 |
Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene.
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Axonal neuropathy linked to the CMT2A locus was originally associated with a mutation in the KIF1B gene. However, mutations in this gene have not been described associated with any other CMT2A families. Recently, mutations in the MFN2 gene, encoding the mitochondrial GTPase mitofusin 2 (Mfn2), have been identified as causative of CMT2A in seven families. The authors report three additional CMT2A families associated with novel mutations in highly conserved regions of the Mfn2 GTPase domain.</AbstractText>The authors performed a standardized neuromuscular and nerve conduction examination, genotyped known CMT loci, and analyzed the MFN2 gene by direct sequencing in three pedigrees and 10 additional probands affected by axonal CMT.</AbstractText>Sequencing of the MFN2 gene revealed a novel mutation in each family (c.818T>G, c.638T>C, and c.314C>T). The largest family demonstrated an age-independent variable expression such that approximately one quarter of individuals with the mutation presented with features mild enough as to remain occult even with electrophysiologic evaluation.</AbstractText>These results confirm that the majority of cases of CMT linked to the CMT2A locus are due to MFN2 mutations. The phenotype is largely indistinguishable from KIF1B-related CMT and from CMT2E and CMT2F. At least in some families, as many as 25% of individuals with MFN2 mutations may be asymptomatic and have a normal electrophysiologic examination, although a detailed neuromuscular examination may suggest the trait. Given the frequency of MFN2 mutations among CMT2 probands (3/13, or 23%), genetic testing of CMT2 patients should begin with a screen of the MFN2 gene.</AbstractText>
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2,337,068 |
Polymorphisms in the promoter region of the alpha1A-adrenoceptor gene are associated with schizophrenia/schizoaffective disorder in a Spanish isolate population.
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Animal models have implicated the alpha(1)-adrenergic subtypes in cognitive functions relevant to schizophrenia, but no consensus exists with regard to the status of noradrenergic receptor populations in psychiatric patients. We focused on one alpha(1)-adrenergic subtype, the alpha(1A)-adrenergic receptor, and proposed that genetic variants within the regulatory region of this gene (ADRA1A) alter the expression of this receptor, influencing susceptibility toward schizophrenia.</AbstractText>This study examined this proposal by testing the hypothesis that single nucleotide polymorphisms (SNPs) in the promoter region of the alpha(1A)-adrenergic gene were associated with schizophrenia by performing case-control association analysis on SNPs found in a 5' upstream region, which included the putative promoter region and 5' untranslated region. Our sample consisted of 103 schizophrenia and 14 schizoaffective disorder patients and 176 control subjects. All recruits were from a Spanish population isolate of Basque origin that is characterized by low heterogeneity, which was selected with the intent that it might facilitate the identification of disease-related polymorphisms.</AbstractText>A total of eight SNPs (-9625 G/A, -7255 A/G, -6274 C/T, -4884 A/G, -4155 C/G, -2760 A/C, -1873 G/A, and -563 C/T) were confirmed at a rare allele frequency of >5%. Association with schizophrenia and schizoaffective disorder was found for the -563 C/T SNP (p = .0005 for allele and p = .007 for genotype, Bonferroni corrected) and -9625 G/A SNP (p = .02 for allele and p = .03 for genotype, Bonferroni corrected). Significant differences in the 54 haplotypes formed by these eight SNPs were also found between patients and control subjects (p = .008, Bonferroni corrected).</AbstractText>Because of the strength of these results and the location of these SNPs in the regulatory region of this gene, functional studies investigating the possible influence of these SNPs on receptor expression levels in schizophrenia are warranted.</AbstractText>
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2,337,069 |
CXCR3 polymorphisms associated with risk of asthma.
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The chemokine (C-X-C motif) receptor 3 (CXCR3) gene, on chromosome Xq13, is known to have critical roles in inflammatory and immune responses. In an effort to discover polymorphisms have been implicated in asthma, we investigated the genetic polymorphisms in CXCR3 to evaluate it as a potential candidate gene for a host genetic study of asthma. Statistical analysis revealed that one SNP in intron 1, c.12+234G > A, showed significant association with the risk of asthma development (P = 0.007, OR = 0.81). By subgroup analyses stratified by gender and atopic status, the genetic effect of c.12+234G > A on asthma was more apparent among male atopic subjects (P = 0.0009, OR = 0.61). Our findings suggest that polymorphisms in CXCR3 might be one of the genetic factors for the risk of asthma development, especially in male atopic subjects. CXCR3 variation/haplotype information identified in this study will provide valuable information and insight into strategies for the control of asthma and its subgroup, atopy.
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2,337,070 |
Allele epsilon 4 of APOE is a stronger predictor of Alzheimer risk in Sicily than in continental South Italy.
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The genotype of apolipoprotein E was examined in 173 sporadic Alzheimer's disease (AD) patients, 132 with late onset (LOAD) and 41 with early onset (EOAD), and in 174 healthy matched controls from Sicily. Despite a low frequency of the epsilon 4 allele (6.3%, 95% CI: 4.2--9.4) in controls, epsilon 4 allele was a stronger predictor of AD risk (odds ratio: 5.8, 95% CI: 3.5--9.4; p<0.0001) than in most of the studies performed in other regions of Italy, and it has no influence on age at onset. epsilon 4/epsilon 4 and epsilon 4/epsilon 3 genotypes were similar predictors of AD risk. Conversely, a decreased risk was found in epsilon 3 allele carriers (odds ratio: 0.3, 95% CI: 0.2--0.4; p<0.0001), which remained significant when considering EOAD cases only (odds ratio: 0.2, 95% CI: 0.1--0.4, p<0.0001). In conclusion, differences in association strength of epsilon 4 allele with AD between Sicily and other regions of Italy suggest an influence of complex gene-gene and gene-environment interactions.
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2,337,071 |
Custom zinc-finger nucleases for use in human cells.
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Genome engineering through homologous recombination (HR) is a powerful instrument for studying biological pathways or creating treatment options for genetic disorders. In mammalian cells HR is rare but the creation of targeted DNA double-strand breaks stimulates HR significantly. Here, we present a method to generate, evaluate, and optimize rationally designed endonucleases that promote HR. The DNA-binding domains were synthesized by assembling predefined zinc-finger modules selected by phage display. Attachment of a transcriptional activation domain allowed assessment of DNA binding in reporter assays, while fusion with an endonuclease domain created custom nucleases that were tested for their ability to stimulate HR in episomal and chromosomal gene repair assays. We demonstrate that specificity, expression kinetics, and protein design are crucial parameters for efficient gene repair and that our two-step assay allows one to go quickly from design to testing to successful employment of the custom nucleases in human cells.
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2,337,072 |
Use of community genetic screening to prevent HFE-associated hereditary haemochromatosis.
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HFE-associated hereditary haemochromatosis is a recessive, iron-overload disorder that affects about one in 200 north Europeans and that can be easily prevented. However, genetic screening for this disease is controversial, and so we assessed whether such screening was suitable for communities. Cheek-brush screening for the Cys282Tyr HFE mutation was offered to individuals in the workplace. Outcomes were assessed by questionnaires before and after testing. 11,307 individuals were screened. We recorded no increase in anxiety in individuals who were homozygous for the Cys282Tyr mutation or non-homozygous. Self-reported tiredness before testing was significantly higher in homozygous participants than in non-homozygous participants (chi2 test, p=0.029). Of the 47 homozygous individuals identified, 46 have taken steps to treat or prevent iron accumulation. Population genetic screening for HFE-associated hereditary haemochromatosis can be practicable and acceptable.
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2,337,073 |
Polymorphisms of myelin-associated glycoprotein gene are associated with schizophrenia in the Chinese Han population.
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Results of gene expression microarray and quantitative PCR studies have suggested abnormalities in the expression of myelin-related genes including myelin-associated glycoprotein (MAG) in schizophrenic patients. Research provides strong evidence for oligodendrocyte dysfunction in schizophrenics. In order to further assess the role of MAG in schizophrenia, we examined four single nucleotide polymorphisms (SNPs), namely rs2301600, rs3746248, rs720309 and rs720308, of this gene in Chinese schizophrenic patients (n=470) and healthy controls (n=470). The distribution of rs720309 T/A genotypes showed a strong association with schizophrenia (chi(2)=14.58, d.f.=2, P=0.0008). A haplotype constructed of rs720309-rs720308 also revealed a significant association with schizophrenia (chi(2)=11.914, d.f.=3, P=0.0084). Our findings of a significant associations between schizophrenia and the MAG gene suggest that this gene may be involved in susceptibility to schizophrenia in the Chinese Han population.
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2,337,074 |
Human p53 tumor suppressor gene (TP53) and schizophrenia: case-control and family studies.
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The human p53 tumor suppressor gene (TP53) is considered as a candidate susceptibility gene for schizophrenia because of its functions in neurodevelopment. To test for an association between TP53 and schizophrenia, both the case-control study and the transmission disequilibrium test (TDT) were performed on genotype data from eight polymorphisms in TP53. Our samples included 286 Toronto schizophrenia cases and 264 controls, and 163 Portuguese nuclear families. In the Toronto case-control study significant differences of allele frequencies of the CAA Ins/Del (p=0.027) and the 16bp Ins/Del (p=0.022) were detected. In TDT analysis we found significant differences for transmission of the CAA Ins/Del (p=0.017) in Portuguese schizophrenia families. Haplotype analysis also showed a significant association between TP53 and schizophrenia. These results provide further evidence that TP53 may play a role in the pathogenesis of schizophrenia.
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2,337,075 |
P-selectin glycoprotein ligand-1 variable number of tandem repeats (VNTR) polymorphism in patients with multiple sclerosis.
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P-selectin glycoprotein ligand-1 (PSGL-1) is an important adhesion molecule involved in lymphocyte recruitment into the brain, which represents a crucial step in the pathogenesis of multiple sclerosis (MS). Three hundred twenty-one MS patients and 342 controls were genotyped for the presence of a polymorphism in the PSGL-1 gene, consisting of a variable number of tandem repeats (VNTR) originating three possible alleles: A, B and C, in order to test whether they influence the susceptibility and the course of the disease. No significant differences among allelic frequencies of A, B and C alleles in MS as compared with controls were observed. Stratifying patients according to the course of the disease, a significantly increased frequency of the shortest C allele in PP-MS was found (7.1%), either in comparison with controls (P=0.011) or with all other MS patients, who had acute inflammatory attacks at onset and an initial RR form (P=0.036). Besides, none of SP-MS patients was a carrier of the C allele and B carriers converted later from RR to SP course as compared with A/A subjects (after 15.8 rather than 8.8 years, P=0.01). In conclusion, the C allele of the VNTR polymorphism in PSGL-1 is likely to be associated with PP-MS. As this allele has been demonstrated to have a very low efficiency in mediating lymphocyte binding to brain endothelium during attacks, its high frequency in PP-MS could be related to the absence of exacerbations in such patients.
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2,337,076 |
Pfeiffer syndrome: systemic and ocular implications.
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In 1964, Pfeiffer described a three-generation family in which eight individuals had a syndrome consisting of craniosynostosis, broad thumbs and great toes, and partial syndactyly of the hands and feet. Pfeiffer syndrome affects males and females equally, and is most commonly a result of de novo mutations, but can be inherited in an autosomal dominant fashion. Pfeiffer syndrome is considered Type V of the five acrocephalosyndactly syndromes (ACS), a group of rare genetic diseases that involve premature closure of the cranial sutures. Cohen, in 1993, further described Pfeiffer syndrome and it's various expression patterns by creating three subgroups of the syndrome.</AbstractText>While Pfeiffer syndrome is clearly a rare disorder, affecting 15 of every 1 million births, there has been a series of publications reviewing the difficult differential diagnosis among Pfeiffer types and between the other acrocephalosyndactly syndromes. While these publications individually focus on a variety of specific systemic and ocular implications of the syndrome, together they encompass the scope of the syndrome. Since Pfeiffer syndrome mainly affects the craniofacial regions, the eye care professional plays an essential role in diagnosis and management. What follows are guidelines to aid in the diagnosis, ophthalmic and functional testing, and management of this disorder.</AbstractText>
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2,337,077 |
Screening for mutations in the IMPDH1 gene in Japanese patients with autosomal dominant retinitis pigmentosa.
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To determine the presence and frequency of mutations in the IMPDH1 gene in Japanese patients with autosomal dominant retinitis pigmentosa (ADRP), and to characterize the clinical characteristics of patients with the Lys238Arg mutation in the IMPDH1 gene.</AbstractText>Case reports and results of DNA analysis.</AbstractText>All 14 coding exons of the IMPDH1 gene were directly sequenced in 96 unrelated patients with ADRP. The clinical features were determined by visual acuity, slit-lamp biomicroscopy, and kinetic visual field tests.</AbstractText>Two novel mutations, a Leu227Pro and Lys238Arg, in the IMPDH1 gene were identified in two unrelated families with ADRP. The clinical features associated with the Lys238Arg mutation were an early-onset and severe retinal degeneration.</AbstractText>The most commonly reported Asp226Asn mutation was not found in the Japanese population, instead two novel mutations were found. These findings suggest that mutations of the IMPDH1 gene cause ADRP in the Japanese population.</AbstractText>
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2,337,078 |
[Advances in the studies on the molecular and genetic aspects of epilepsy].
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Epilepsy is one of the most common and debilitating neurological diseases that affects more than 40 million people worldwide. Genetic factors contribute to the pathogenesis of epilepsy. Molecular genetic studies have identified 15 disease-causing genes for epilepsy. The majority of the genes encode ion channels, including voltage-gated potassium channels KCNQ2 and KCNQ3, sodium channels SCN1A, SCN2A, and SCN1B, chloride channels CLCN2, and ligand-gated ion channels CHRNA4, CHRNB2, GABRG2, and GABRA1. Interestingly, non-ion channel genes have also been identified as epilepsy genes, and these genes include G-protein-coupled receptor MASS1/VLGR1, GM3 synthase, and proteins with unknown functions such as LGI1, NHLRC1, and EFHC1. These studies make genetic testing possible in some patients, and further characterization of the identified epilepsy genes may lead to the development of new drugs and new treatments for patients with epilepsy.
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2,337,079 |
[Disease gene identification: opportunities and challenges].
|
The recent achievements of the Human Genome Project make it increasingly feasible to determine the genetic basis of human diseases, especially complex traits. Genomics will provide powerful means to discover hereditary elements that interact with environmental factors leading to diseases. However, the expected transformation toward genomics-based medicine will occur over decades, which requires the joint efforts of many scientists and physicians. Such transformation provides both opportunities and challenges to everyone involved in this field.
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2,337,080 |
NMD microarray analysis for rapid genome-wide screen of mutated genes in cancer.
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Gene mutations play a critical role in cancer development and progression, and their identification offers possibilities for accurate diagnostics and therapeutic targeting. Finding genes undergoing mutations is challenging and slow, even in the post-genomic era. A new approach was recently developed by Noensie and Dietz to prioritize and focus the search, making use of nonsense-mediated mRNA decay (NMD) inhibition and microarray analysis (NMD microarrays) in the identification of transcripts containing nonsense mutations. We combined NMD microarrays with array-based CGH (comparative genomic hybridization) in order to identify inactivation of tumor suppressor genes in cancer. Such a "mutatomics" screening of prostate cancer cell lines led to the identification of inactivating mutations in the EPHB2 gene. Up to 8% of metastatic uncultured prostate cancers also showed mutations of this gene whose loss of function may confer loss of tissue architecture. NMD microarray analysis could turn out to be a powerful research method to identify novel mutated genes in cancer cell lines, providing targets that could then be further investigated for their clinical relevance and therapeutic potential.
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2,337,081 |
The association between knowledge and attitudes about genetic testing for cancer risk in the United States.
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Attitudes about genetic testing are likely to be an important determinant of uptake of predictive genetic tests among the general public. Several prior studies have suggested that positive attitudes about genetic testing may be inversely related to knowledge about genetic testing. We conducted a random-digit-dialing (RDD) telephone survey of 961 adults in the continental United States to determine the associations among knowledge of, attitudes about, and perceptions of eligibility for genetic testing for cancer risk. Knowledge about genetic testing for cancer risk was generally high, with a mean accuracy score of 72%. Attitudes about genetic testing for cancer risk were also generally positive, with 87% of respondents reporting genetic testing for cancer risk would be used to help doctors manage their health care and 85% to help scientists find cures for diseases. In contrast, 58% of respondents thought genetic testing for cancer risk would be used to prevent them from getting health insurance and 31% to allow the government to label groups as inferior. Twenty-nine percent of respondents thought they were currently eligible for testing. After adjustment for sociodemographic characteristics and family cancer history, higher knowledge was correlated with more positive attitudes about testing, but not with negative attitudes or perceptions of testing eligibility. Family history was positively associated with perceptions of eligibility (OR 3.49, 95% CI 2.36-5.18), and higher levels of education were inversely associated with perceptions of eligibility (OR 0.55, 95% CI 0.32-0.94 for comparison of college or higher vs. less than high school). These results suggest that most members of the general public are knowledgeable and have positive attitudes about genetic testing for cancer risk and that greater knowledge is correlated with more positive attitudes about the benefits of testing.
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2,337,082 |
Screening the metallothionein III gene in sporadic amyotrophic lateral sclerosis.
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Metallothioneins are proteins involved in antioxidant defence, essential metal homoeostasis and heavy metal detoxification, all mechanisms implicated in sporadic amyotrophic lateral sclerosis (SALS). We therefore looked for changes in the gene for nervous system-specific metallothionein III (MT3) that might explain susceptibility to SALS. DNA was extracted from 87 sporadic ALS and 174 matched controls. The gene for MT3 was sequenced in 20 SALS and 5 control subjects to identify single nucleotide polymorphisms (SNPs). These SNPs were then screened in all subjects. Eight novel SNPs were found in the 5' untranslated region and intron 2 of MT3. No differences were found in the frequency distribution of alleles or haplotypes for these SNPs between the SALS and control groups. The genotype distribution of one SNP (A1422C) was significantly different between ALS and control groups (p<0.02) but this is not likely to be biologically relevant. We conclude that changes in the MT3 gene are unlikely to be responsible for susceptibility to SALS.
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2,337,083 |
Primary lateral sclerosis, hereditary spastic paraplegia and amyotrophic lateral sclerosis: discrete entities or spectrum?
|
Among the motor neuron diseases, three share the clinical features of prominent upper motor neuron signs--amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS) and the hereditary spastic paraplegias (HSP). While genetic testing can assist in the identification of several variants of the latter, in the remaining cases, including those in which spasticity may be associated with amyotrophy, clinical differentiation of the three disorders may prove difficult. In this paper we review the evidence that these are distinct disorders and conclude that, for ALS and PLS particularly, there may be justification in considering them as single points along a continuum of multisystem disorders with conspicuous motor neuron involvement. Only through the development and application of exacting clinical diagnostic criteria to epidemiological studies, along with greater numbers of post-mortem examinations, however, will these questions be answered fully.
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2,337,084 |
Characterization of a population of monozygotic twins with asthma.
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Asthma is a complex inflammatory lung disease that results from allergic and nonallergic environmental exposures in genetically susceptible individuals. The interrelationship and impact of environmental and genetic determinants on the development of asthma is still unclear. Monozygotic twins (MZT) have been considered a potentially useful population to investigate the role of genetic and environmental factors on asthma because of their identical genetic background, similar childhood environmental exposures, and expected high concordance rate for asthma.</AbstractText>A detailed questionnaire designed to obtain demographic information, medical history/severity of asthma, and environmental exposures was distributed to 43 pairs of MZT pairs where one or both probands had a history of asthma. All twin pairs were clinically evaluated for atopy by skin testing. Asthma was assessed by questionnaire, baseline spirometry, disease severity, airway reactivity, and medication scores.</AbstractText>Based on a history of physician-diagnosed asthma, disease severity, airway reactivity, and medication scores, 22 MZT pairs were identified as concordant (C) for asthma while 21 MZT pairs were discordant (D) for asthma. Those MZT-C for asthma were on average older and more often female. Adjusted odds ratios for age and gender revealed that MZT-C for asthma had a 2.3 greater likelihood of childhood tobacco exposure and a 1.8 greater likelihood of early exposure to a pet compared to MZT-D pairs. In addition, MZT-C for asthma had a 2.4 greater likelihood of being full term vs. premature at birth. None of these odds ratios were statistically significant due to a small sample size. However, a trend for a greater likelihood of earlier environmental exposures was observed for MZT-C asthma pairs. Among MZT-D probands, a history of asthma in one proband was supported by a lower FEV1 and higher airway reactivity, disease severity, asthma symptom, and medication scores compared to the nonasthma proband. There was significant intrapair heterogeneity among MZT-C and MZT-D probands in their positive skin test responses to specific aeroallergens.</AbstractText>Cross-sectional evaluation of larger MZT populations where one or both proband has asthma with a long-term prospective follow-up may be a feasible way for identifying the impact of environmental determinants as independent risk factors for the development of asthma.</AbstractText>
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2,337,085 |
Treatment of low bone mass in premenopausal women: when may it be appropriate?
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The diagnosis and treatment of osteoporosis in postmenopausal women has been well defined. Criteria for making a diagnosis using bone density testing has been established and widely disseminated. However, the definition established by the World Health Organization for osteoporosis cannot be used for other populations such as premenopausal women without further study. Measuring bone mass in premenopausal women should be done infrequently and only if specific and significant risk factors are present. Premenopausal women have a low risk for fracturing but women with low bone mass are at a greater risk for developing fractures before and after menopause. The major reason for low bone mass is the failure to reach peak bone mass because of genetic influences, although some environ-mental factors may also play a role. Hormonal therapy for hypogonadism, treatment of diseases such as hyperpara-thyroidism, and keeping medications with detrimental effects on bone to a minimum are important components of treatment. Pharmacologic treatment of low bone mass in premenopausal women has not been well studied although on rare occasions it may be appropriate in women with low bone mass, defined as a Z score of -2 or less, and the presence of other diseases or risk factors. Caution is urged because of the unknown effects of treatment in this population. Further study of the implications of low bone mass and the effects of treatment in this group of women is needed.
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2,337,086 |
Diagnosis and management of fragile X syndrome.
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To complement the 2005 Annual Clinical Focus on medical genomics, AFP will be publishing a series of short reviews on genetic syndromes. This series was designed to increase awareness of these diseases so that family physicians can recognize and diagnose children with these disorders and understand the kind of care they might require in the future. The first review in this series discusses fragile X syndrome.
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2,337,087 |
Huntington disease: a nursing perspective.<Pagination><StartPage>167</StartPage><EndPage>173</EndPage><MedlinePgn>167-72, quiz 173</MedlinePgn></Pagination><Abstract><AbstractText>Huntington disease is a serious neurogenetic disease that affects the physical, cognitive, and psychiatric health of the patient, and has a significant impact on the social life of the family. Nurses play a vital role as health care providers and advocates for the patient with Huntington disease.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Skirton</LastName><ForeName>Heather</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Health Genetics, Faculty of Health and Social Work, University of Plymouth, Somerset, UK.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Medsurg Nurs</MedlineTA><NlmUniqueID>9300545</NlmUniqueID><ISSNLinking>1092-0811</ISSNLinking></MedlineJournalInfo><MeshHeadingList><MeshHeading><DescriptorName UI="D005820" MajorTopicYN="N">Genetic Testing</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="N">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006816" MajorTopicYN="N">Huntington Disease</DescriptorName><QualifierName UI="Q000175" MajorTopicYN="N">diagnosis</QualifierName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000451" MajorTopicYN="Y">nursing</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D024802" MajorTopicYN="N">Nurse's Role</DescriptorName></MeshHeading></MeshHeadingList><NumberOfReferences>37</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>7</Month><Day>23</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>9</Month><Day>2</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>7</Month><Day>23</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16035633</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16035391</PMID><DateCompleted><Year>2005</Year><Month>11</Month><Day>07</Day></DateCompleted><DateRevised><Year>2019</Year><Month>11</Month><Day>09</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">1368-504X</ISSN><JournalIssue CitedMedium="Print"><Issue>143</Issue><PubDate><Year>2004</Year><Month>Oct</Month></PubDate></JournalIssue><Title>International journal of clinical practice. Supplement</Title><ISOAbbreviation>Int J Clin Pract Suppl</ISOAbbreviation></Journal>Searching for genes in diabetes and the metabolic syndrome.
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Huntington disease is a serious neurogenetic disease that affects the physical, cognitive, and psychiatric health of the patient, and has a significant impact on the social life of the family. Nurses play a vital role as health care providers and advocates for the patient with Huntington disease.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Skirton</LastName><ForeName>Heather</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Health Genetics, Faculty of Health and Social Work, University of Plymouth, Somerset, UK.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Medsurg Nurs</MedlineTA><NlmUniqueID>9300545</NlmUniqueID><ISSNLinking>1092-0811</ISSNLinking></MedlineJournalInfo><MeshHeadingList><MeshHeading><DescriptorName UI="D005820" MajorTopicYN="N">Genetic Testing</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="N">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006816" MajorTopicYN="N">Huntington Disease</DescriptorName><QualifierName UI="Q000175" MajorTopicYN="N">diagnosis</QualifierName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000451" MajorTopicYN="Y">nursing</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D024802" MajorTopicYN="N">Nurse's Role</DescriptorName></MeshHeading></MeshHeadingList><NumberOfReferences>37</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2005</Year><Month>7</Month><Day>23</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2005</Year><Month>9</Month><Day>2</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2005</Year><Month>7</Month><Day>23</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16035633</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16035391</PMID><DateCompleted><Year>2005</Year><Month>11</Month><Day>07</Day></DateCompleted><DateRevised><Year>2019</Year><Month>11</Month><Day>09</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">1368-504X</ISSN><JournalIssue CitedMedium="Print"><Issue>143</Issue><PubDate><Year>2004</Year><Month>Oct</Month></PubDate></JournalIssue><Title>International journal of clinical practice. Supplement</Title><ISOAbbreviation>Int J Clin Pract Suppl</ISOAbbreviation></Journal><ArticleTitle>Searching for genes in diabetes and the metabolic syndrome.</ArticleTitle><Pagination><StartPage>3</StartPage><EndPage>8</EndPage><MedlinePgn>3-8</MedlinePgn></Pagination><Abstract>Evidence for a genetic basis for type 2 diabetes and the metabolic syndrome has been derived from studies of families, twins and populations with genetic admixture. Identification of genes associated with disease pathogenesis is now underway using techniques such as genome scanning by positional cloning and the candidate gene approach. Genome scanning in several different ethnic groups has identified chromosome regions harbouring type 2 diabetes susceptibility genes such as the novel gene, calpain 10 (CAPN10). The hepatic nuclear factor 4alpha (HNF4alpha) gene partly explains the linkage peak on chromosome 20, while the upstream transcription factor (USF1) is associated with familial combined hyperlipidaemia (FCHL) and maps close to the type 2 diabetes associated 1q peak. Peroxisome proliferator-activated receptor gamma (PPARgamma) was identified as a candidate gene based on its biology. A Pro12Ala variant of this gene has been associated with an increased risk of type 2 diabetes. Many genes accounting for monogenic forms of diabetes have been identified--such as maturity onset diabetes of the young (MODY); glucokinase (GCK) and HNF1alpha mutations being the most common causes of MODY. GCK variants result in 'mild' diabetes or impaired glucose tolerance (IGT) and relatively few cardiovascular complications, while HNF1alpha-associated MODY is more typical of type 2 diabetes, frequently being treated with sulphonylureas or insulin and resulting in microvascular complications. Testing for single gene disorders associated with type 2 diabetes and obesity may determine cause, prognosis and appropriate treatment; however, for the more common polygenic diseases this is not the case. In type 2 diabetes, molecular genetics has the potential to enhance understanding of disease pathogenesis, and help formulate preventative and treatment strategies.
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2,337,088 |
[Neurofibromatosis: the most frequent hereditary tumor predisposition syndrome].
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With an incidence of one in 3000 to 4000 individuals, neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic diseases and very likely the most frequent disorder with increased cancer risk. Approximately fifty percent of all patients are familial cases and the remaining half consists of sporadic cases with no affected parent. The hallmark clinical features present in over 90% of all patients are café-au-lait spots and neurofibromas. However, the disorder should not be underestimated as a "mere cosmetic problem", since NF1 patients are at increased risk to also develop malignant tumours, such as malignant peripheral nerve sheath tumours (MPNST), juvenile myelomonocytic leukaemia (JMML), optic glioma and pheochomocytoma. Renovascular disease represents an additional risk factor for NF1 patients. The NF1 gene is a classic example for a tumour suppressor gene. It functions as a negative regulator of the protooncogene Ras. This function explains well its involvement in tumour formation. During the last 15 years, since the cloning of the gene, enormous progress has been made towards a better understanding of the natural history of the disorder. However, it cannot be said if and when a cure of the disorder will be possible. Great advantages have been achieved in the monitoring and management of several NF1 complications, for instance in the treatment of tibia pseudarthrosis and optic gliomas. Owing to the technical improvements of the approaches applied to identify NF1-mutations molecular-genetic testing with high mutation detection rates may help nowadays in patients in which the clinical diagnosis may not readily be established, such as in young children or atypical cases. A greater awareness of the complications and the different expression forms of NF1 and NF2 on the part of all types of physicians will further help to offer all patients adequate and timely counselling and treatment. The establishment of multi-disciplinary counselling and treatment centres for neurofibromatosis could be an important step towards a better management of NF1 and NF2 patients.
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2,337,089 |
[Cystic fibrosis--the most frequent life-shortening autosomal recessive disease].
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Cystic Fibrosis (CF) is one of the most frequent genetic diseases in the white populations of Europe and North America. Its clinical manifestations are highly variable, ranging from a characteristic life-shortening pathology of the lungs and the pancreas in classical CF to symptoms mainly restricted to male sterility in patients with congenital bilateral aplasia of the vasa deferentia (CBAVD). The genetic basis of CF is mutations in both copies of the CFTR gene, which codes for an ion channel. Even though one single mutation, deltaF508, is responsible for two-thirds of all mutated CFTR alleles, a total of over 1000 CFTR mutations have been described, whose relative frequencies vary between different ethnic groups, and whose biochemical consequences are correlated to the clinical manifestations of the disease. Since 4% of white Europeans and North Americans are healthy heterozygous carriers of CF, the molecular diagnosis of this disease, offered in the context of genetic counselling by a specialist in human genetics, is of great importance.
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2,337,090 |
[Genetic causes of mental retardation].
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Mental retardation (MR) is defined as congenital or early onset lifelong impairment of cognitive and adaptive functioning (IQ < 70). It effects approximately 3% of the Western population. The causes are heterogenous. Numerical or structural chromosome abnormalities are responsible for 10-20% of the mild cases (MMR) and 40% of the severe cases (SMR). Among them Down syndrome represents the most frequent chromosome aberration and the most frequent defined MR syndrome. Gonosomal aberrations do not coincide with MR, as long as only one gonosome is lost or gained. Nearly all unbalanced structural autosomal aberrations cause SMR. Recent studies suggested that sub-microscopic chromosomal microdeletions or subtelomeric rearrangements account for approximately 10% of the undiagnosed cases. They represent a group of newly defined disorders. Single gene mutations are responsible for > 1200 known syndromal conditions with MR. But only few causative genes have been identified as yet. However, an increasing number of genes causing X-linked mental retardation (XLMR) have been localized and cloned, namely 38 genes of the 136 known syndromic conditions and 19 for the non-syndromic conditions. XLMR explains the 20 % excess of males over females. Despite the increasing knowledge about the causes of MR, about half of the cases remain undiagnosed. Guidelines for the diagnostic procedure in children with MR have been proposed.
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2,337,091 |
[Genetic counselling].
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'Genetic counselling is the process by which patients or relatives at risk of a disorder that may be hereditary are advised of the consequences of the disorder, the probability of developing and transmitting it and of the ways in which this may be prevented or ameliorated.' The genetic counsellor will discuss the genetic basis and medical facts and also possible personal, familial, social and insurance implications of the respective disorder with the consultand. Further diagnostic investigations, such as genetic tests, may be helpful or necessary for risk predictions or may be required to reach a firm diagnosis. In asymptomatic individuals at risk for a late-onset genetic disorder genetic counselling is obligatory for predictive genetic testing. Genetic counselling also should be offered to symptomatic patients before a diagnostic test is performed. Thereby the patients might become aware in time about the personal, familial and social consequences of the test result that may exceed that of their actual illness. Due to medical confidentiality the geneticist is not allowed to contact other family members and to inform them about a familial disorder and warn them about their own genetic risk. This is the concern of the consultand. Various aspects make up genetic counselling as a specific process which concerns genetic diagnosis, risk estimation and accurate information on medical and genetic facts, but also has a supportive role ensuring that consultands may benefit from given advice and possible preventive measures.
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2,337,092 |
Chemical genetics and genomics and drug discovery. Highlights from the Society for Medicines Research symposium held Thursday March 10, 2005, in London, United Kingdom.
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The SMR Symposium Chemical Genetics and Genomics: What Are They and Are They Helping Drug Discovery was held on March 10, 2005 at the National Heart and Lung Institute, Imperial College London. The conference program brought together an international line up of speakers representing academia, biotechnology and large pharmaceutical companies to discuss a variety of drug discovery strategies, falling under the umbrella terminology Chemical Genomics and Genetics. Highlights of the meeting are discussed.
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2,337,093 |
Gene delivery to human sweat glands: a model for cystic fibrosis gene therapy.
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Gene therapy vectors are mostly studied in cultured cells, rodents, and sometimes in non-human primates, but it is useful to test them in human tissue prior to clinical trials. In this study, we investigated the possibility of using human sweat glands as a model for testing cystic fibrosis (CF) gene therapy vectors. Human sweat glands are relatively easy to obtain from skin biopsy, and can be tested for CFTR function. Using patients' sweat glands could provide a safe model to study the efficacy of CF gene therapy. As the first step to explore using sweat glands as a model for CF gene therapy, we examined various ex vivo gene delivery methods for a helper-dependent adenovirus (HD-Ad) vector. Gene delivery to sweat glands in skin organ culture was studied by topical application, intradermal injection or submerged culture. We found that transduction efficiency can be enhanced by pretreating isolated sweat glands with dispase, which suggests that the basement membrane is a critical barrier to gene delivery by adenoviral vectors. Using this approach, we showed that Cftr could be efficiently delivered to and expressed by the epithelial cells of sweat glands with our helper-dependent adenoviral vector containing cytokeratin 18 regulatory elements. Based on this study we propose that sweat glands might be used as an alternative model to study CF gene therapy in humans.
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2,337,094 |
Targeting gonadotropin receptor genes: reproductive biology, aging, and related health implications.
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This review highlights observations gleaned from recent reports on the deletion of FSH and LH receptors in mice. Gonadal differentiation does not depend on the presence of gonadotropin receptors but development is affected to varying degrees in both sexes. In both knockouts the null females are infertile with severely underdeveloped gonads and accessory structures. Sexual maturity and/or pubertal delay occur depending on the sex and knockout. Male null FSH-R mice have reduced fertility but null LH-R males are sterile due to cryptorchid testes and deficient spermatogenesis. In null FSH-R females hormonal imbalances are due to deficient estrogen and hyperandrogenemia. LH-R deficient females have low estrogen and testosterone. Females in both knockouts display phenotypes such as obesity, bone deficiency, and changes in brain structure and function in addition to manifestation of different types of reproductive tract tumors. Both types of mice represent good models for testing hormone replacement therapy in different combinations. The FSH-R heterozygous females could also be useful for studying age-dependent phenotypes.
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2,337,095 |
Genetic services for familial cancer patients: a follow-up survey of National Cancer Institute Cancer Centers.
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Anecdotal reports suggest that the volume of services offered to individuals concerned with hereditary cancer risk has increased substantially in recent years. As a follow-up to our 1993 survey, we sought to determine how the scope and volume of genetic services has changed between 1993 and 2002.</AbstractText>We surveyed the 61 National Cancer Institute-designated cancer centers in operation in 2002 using an updated version of the questionnaire from 1993. Analysis included frequencies and summary statistics.</AbstractText>The majority of cancer centers responding (46 of 56 centers; 82.1%) provided some genetic services for evaluation of familial cancer, which is a higher proportion than in 1993 (50%; P < .01). Almost all centers (42 of 46 centers; 91.3%) provided services not only to cancer patients and their families, but also to individuals concerned with risk, which is a change (P = .01) from 1993, when 64.7% of centers offered such services. In addition, increases have been found for most other measures of services rendered for familial genetic services.</AbstractText>As public awareness of cancer susceptibility genes has grown markedly in recent years, the demand has also grown for genetic services to assess familial cancer risk. Major deleterious genetic mutations are rare, and much of the current research in genetic variation focuses on higher prevalence variants that carry lower risks. This may suggest that testing for mutations will move from genetics clinics to primary care and specialty practices. Thus, it is unclear whether the scope and volume of cancer center genetics services will continue to grow as rapidly as they have over the last decade.</AbstractText>
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2,337,096 |
Congruence, consensus, and the comparative phylogeography of codistributed species in California.
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Comparative phylogeography has emerged as a means of understanding the spatial patterns of genetic divergence of codistributed species. However, researchers are often frustrated because of the lack of appropriate statistical tests to assess concordancy of multiple phylogeographic trees. We develop a method for testing congruence across multiple species and synthesizing the data into a regional supertree. Nine phylogeographic data sets of species with different life histories and ecologies were statistically compared using maximum agreement subtrees (MAST) and showed a high degree of concordancy. A supertree combining the different phylogeographic trees was then computed using matrix representation with parsimony, and the groups defined by this supertree were tested against climatic data to investigate a potential mechanism driving divergence. Our data suggest that species and genetic lineages in California are shaped by climatic regimes. The supertree method in combination with MAST represents a new approach to test congruence hypotheses and detect common geographic signals in comparative phylogeography.
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2,337,097 |
Genetic diversity in german and European populations: looking for substructures and genetic patterns.
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A classical case-control study is a powerful and cost-efficient approach to detect association of genetic markers with complex disease phenotypes. However, only a small fraction of significant association results has been replicated by other studies. Undetected genetic substructures in the population may be one of the reasons for spurious or biased results. The German "Genomic Control" study aims at detecting genetic differentiation between one Southern German population, represented by the KORA study (KORA Survey S4 (1999/2001)), and two Northern German populations (SHIP, Greifswald, and POPGEN, Schleswig-Holstein). Relevant population-substructures will be assessed, as well as their influence on case-control studies. Since KORA samples are used as controls for different German genetic association studies, the knowledge gained through this Genomic Control project will influence the planning of further genetic association studies. A second project, the European LD study, deals with the detection and comparison of linkage disequilibrium (LD) patterns in the human genome for eight distinct European populations. In general, a conservation of LD patterns across European samples can be observed for most gene regions. However, there are chromosomal regions with variable LD structure which may have implications on the fine-mapping of genes in different populations.
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2,337,098 |
KORA-gen--resource for population genetics, controls and a broad spectrum of disease phenotypes.
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KORA-gen is a resource for genetic epidemiological research, based on the KORA platform (Cooperative Health Research in the Region of Augsburg). Biosamples and phenotypic characteristics as well as environmental parameters of 18,000 adults from Augsburg and the surrounding counties are available. The age range of the participants was 25 to 74 years of recruitment and is 30 to 90 years in 2005. KORA-gen can be used by external partners. Interested parties can inform themselves interactively via internet about the available data and the rules of access. The genotypic data base is a common resource of all partners.
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2,337,099 |
Deletion and duplication screening in the DMD gene using MLPA.
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We have designed a multiplex ligation-dependent probe amplification (MLPA) assay to simultaneously screen all 79 DMD gene exons for deletions and duplications in Duchenne and Becker muscular dystrophy (DMD/BMD) patients. We validated the assay by screening 123 unrelated patients from Serbia and Montenegro already screened using multiplex PCR. MLPA screening confirmed the presence of all previously detected deletions. In addition, we detected seven new deletions, nine duplications, one point mutation, and we were able to precisely determine the extent of all rearrangements. To facilitate MLPA-based screening in laboratories lacking specific equipment, we designed the assay such that it can also be performed using agarose gel analysis and ethidium bromide staining. The MLPA assay as described provides a simple and cheap method for deletion and duplication screening in DMD/BMD patients. The assay outperforms the Beggs and Chamberlain multiplex-PCR test, and should be considered as the method of choice for an initial DNA analysis of DMD/BMD patients.
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