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1.
The peroxisome biogenesis disorders (PBDs) are a set of lethal genetic diseases characterized by peroxisomal metabolic deficiencies, multisystem abnormalities, mental retardation, and premature death. These disorders are genetically heterogeneous and are caused by mutations in genes, termedPEXgenes, required for import of proteins into the peroxisomal matrix. We have previously reported the identification of humanPEX13,the gene encoding the docking factor for the PTS1 receptor, or PEX5 protein. As such, mutations inPEX13would be expected to abrogate peroxisomal protein import and result in PBD phenotypes. We report here the structure of the humanPEX13gene.PEX13spans approximately 11 kb on chromosome 2 and contains four exons, one more than previously thought. The corrected PEX13 cDNA is predicted to encode a protein product with a molecular mass of 44,312 Da. We examined the ability ofPEX13expression to rescue the peroxisomal protein import defects of fibroblast cells representing all known PBD complementation groups. No complementation was observed, suggesting that this gene is not mutated in any set of existing patients. However, given that complementation group assignments have been determined for only a subset of PBD patients, it is possible thatPEX13-deficient patients may exist at a low frequency within our existing PBD patient population or within ethnic groups underrepresented in our patient pool. 相似文献
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C. Salvoro S. Bortoluzzi A. Coppe G. Valle E. Feltrin M. L. Mostacciuolo G. Vazza 《Molecular neurobiology》2018,55(9):7366-7376
Schizophrenia (SCZ) and bipolar disorder (BPD) are highly heritable disorders with an estimated co-heritability of 68%. Hundreds of common alleles have been implicated, but recently a role for rare, high-penetrant variants has been also suggested in both disorders. This study investigated a familial cohort of SCZ and BPD patients from a closed population sample, where the high recurrence of the disorders and the homogenous genetic background indicate a possible enrichment in rare risk alleles. A total of 230 subjects (161 cases, 22 unaffected relatives, and 47 controls) were genetically investigated through an innovative strategy that integrates identity-by-descent (IBD) mapping and whole-exome sequencing (WES). IBD analysis allowed to track high-risk haplotypes (IBDrisk) shared exclusively by multiple patients from different families and possibly carrying the most penetrant alleles. A total of 444 non-synonymous sequence variants, of which 137 disruptive, were identified in IBDrisk haplotypes by WES. Interestingly, gene sets previously implicated in SCZ (i.e., post-synaptic density (PSD) proteins, voltage-gated calcium channels (VGCCs), and fragile X mental retardation protein (FMRP) targets) were found significantly enriched in genes carrying IBDrisk variants. Further, IBDrisk variants were preferentially affecting genes involved in the extracellular matrix (ECM) biology and axon guidance processes which appeared to be functionally connected in the pathway-derived meta-network analysis. Results thus confirm rare risk variants as key factors in SCZ and BPD pathogenesis and highlight a role for the development of neuronal connectivity in the etiology of both disorders. 相似文献
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Carina Quast Serena Cuboni Daniel Bader André Altmann Peter Weber Janine Arloth Simone R?h Tanja Brückl Marcus Ising Anna Kopczak Angelika Erhardt Felix Hausch Susanne Lucae Elisabeth B. Binder 《PloS one》2013,8(7)
SLC6A15 is a neuron-specific neutral amino acid transporter that belongs to the solute carrier 6 gene family. This gene family is responsible for presynaptic re-uptake of the majority of neurotransmitters. Convergent data from human studies, animal models and pharmacological investigations suggest a possible role of SLC6A15 in major depressive disorder. In this work, we explored potential functional variants in this gene that could influence the activity of the amino acid transporter and thus downstream neuronal function and possibly the risk for stress-related psychiatric disorders. DNA from 400 depressed patients and 400 controls was screened for genetic variants using a pooled targeted re-sequencing approach. Results were verified by individual re-genotyping and validated non-synonymous coding variants were tested in an independent sample (N = 1934). Nine variants altering the amino acid sequence were then assessed for their functional effects by measuring SLC6A15 transporter activity in a cellular uptake assay. In total, we identified 405 genetic variants, including twelve non-synonymous variants. While none of the non-synonymous coding variants showed significant differences in case-control associations, two rare non-synonymous variants were associated with a significantly increased maximal 3H proline uptake as compared to the wildtype sequence. Our data suggest that genetic variants in the SLC6A15 locus change the activity of the amino acid transporter and might thus influence its neuronal function and the risk for stress-related psychiatric disorders. As statistically significant association for rare variants might only be achieved in extremely large samples (N >70,000) functional exploration may shed light on putatively disease-relevant variants. 相似文献
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Min-Jie Liang Quan Zhou Kan-Rong Yang Xiao-Ling Yang Jin Fang Wen-Li Chen Zheng Huang 《PloS one》2013,8(12)
Background
To identify changes in brain activation patterns in bipolar disorder (BD) and unipolar depression (UD) patients.Methodology/Principal Findings
Resting-state fMRI scans of 16 healthy controls, 17 BD and 16 UD patients were obtained. T-test of normalized regional homogeneity (ReHo) was performed in a voxel-by-voxel manner. A combined threshold of á = 0.05, minimum cluster volume of V = 10503 mm3 (389 voxels) were used to determine ReHo differences between groups. In UD group, fMRI revealed ReHo increases in the left middle occipital lobe, right inferior parietal lobule, right precuneus and left convolution; and ReHo decreases in the left parahippocampalgyrus, right precentralgyrus, left postcentralgyrus, left precentralgyrus and left cingulated. In BD group, ReHo increases in the right insular cortex, left middle frontal gyrus, left precuneus, left occipital lobe, left parietal, left superior frontal gyrus and left thalamus; and ReHo decreases in the right anterior lobe of cerebellum, pons, right precentralgyrus, left postcentralgyrus, left inferior frontal gyrus, and right cingulate. There were some overlaps in ReHo profiles between UD and BD groups, but a marked difference was seen in the thalamus of BD.Conclusions/Significance
The resting-state fMRI and ReHo mapping are a promising tool to assist the detection of functional deficits and distinguish clinical and pathophysiological signs of BD and UD. 相似文献5.
Carla P. D. Fernandes Andrea Christoforou Sudheer Giddaluru Kari M. Ersland Srdjan Djurovic Manuel Mattheisen Astri J. Lundervold Ivar Reinvang Markus M. N?then Marcella Rietschel Roel A. Ophoff Genetic Risk Outcome of Psychosis Albert Hofman André G. Uitterlinden Thomas Werge Sven Cichon Thomas Espeseth Ole A. Andreassen Vidar M. Steen Stephanie Le Hellard 《PloS one》2013,8(12)
Background
Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function in healthy individuals and in the dysfunction observed in psychiatric disorders.Methods
Sets of genes associated with a range of cognitive functions often impaired in schizophrenia and bipolar disorder were generated from a genome-wide association study (GWAS) on a sample comprising 670 healthy Norwegian adults who were phenotyped for a broad battery of cognitive tests. These gene sets were then tested for enrichment of association in GWASs of schizophrenia and bipolar disorder. The GWAS data was derived from three independent single-centre schizophrenia samples, three independent single-centre bipolar disorder samples, and the multi-centre schizophrenia and bipolar disorder samples from the Psychiatric Genomics Consortium.Results
The strongest enrichments were observed for visuospatial attention and verbal abilities sets in bipolar disorder. Delayed verbal memory was also enriched in one sample of bipolar disorder. For schizophrenia, the strongest evidence of enrichment was observed for the sets of genes associated with performance in a colour-word interference test and for sets associated with memory learning slope.Conclusions
Our results are consistent with the increasing evidence that cognitive functions share genetic factors with schizophrenia and bipolar disorder. Our data provides evidence that genetic studies using polygenic and pleiotropic models can be used to link specific cognitive functions with psychiatric disorders. 相似文献6.
Three Genome-wide Association Studies and a Linkage Analysis Identify HERC2 as a Human Iris Color Gene
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Manfred Kayser Fan Liu A. Cecile J.W. Janssens Fernando Rivadeneira Oscar Lao Kate van Duijn Mark Vermeulen Pascal Arp Mila M. Jhamai Wilfred F.J. van IJcken Johan T. den Dunnen Simon Heath Diana Zelenika Dominiek D.G. Despriet Caroline C.W. Klaver Johannes R. Vingerling Paulus T.V.M. de Jong Albert Hofman Yurii S. Aulchenko Andre G. Uitterlinden Ben A. Oostra Cornelia M. van Duijn 《American journal of human genetics》2008,82(3):801
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Mona H. Fenstad Matthew P. Johnson Linda T. Roten Per A. Aas Siri Forsmo Kjetil Klepper Christine E. East Lawrence J. Abraham John Blangero Shaun P. Brennecke Rigmor Austgulen Eric K. Moses 《PloS one》2010,5(9)
Background
Preeclampsia is a serious pregnancy complication, demonstrating a complex pattern of inheritance. The elucidation of genetic liability to preeclampsia remains a major challenge in obstetric medicine. We have adopted a positional cloning approach to identify maternal genetic components, with linkages previously demonstrated to chromosomes 2q, 5q and 13q in an Australian/New Zealand familial cohort. The current study aimed to identify potential functional and structural variants in the positional candidate gene TNFSF13B under the 13q linkage peak and assess their association status with maternal preeclampsia genetic susceptibility.Methodology/Principal Findings
The proximal promoter and coding regions of the positional candidate gene TNFSF13B residing within the 13q linkage region was sequenced using 48 proband or founder individuals from Australian/New Zealand families. Ten sequence variants (nine SNPs and one single base insertion) were identified and seven SNPs were successfully genotyped in the total Australian/New Zealand family cohort (74 families/480 individuals). Borderline association to preeclampsia (p = 0.0153) was observed for three rare SNPs (rs16972194, rs16972197 and rs56124946) in strong linkage disequilibrium with each other. Functional evaluation by electrophoretic mobility shift assays showed differential nuclear factor binding to the minor allele of the rs16972194 SNP, residing upstream of the translation start site, making this a putative functional variant. The observed genetic associations were not replicated in a Norwegian case/control cohort (The Nord-Trøndelag Health Study (HUNT2), 851 preeclamptic and 1,440 non-preeclamptic women).Conclusion/Significance
TNFSF13B has previously been suggested to contribute to the normal immunological adaption crucial for a successful pregnancy. Our observations support TNFSF13B as a potential novel preeclampsia susceptibility gene. We discuss a possible role for TNFSF13B in preeclampsia pathogenesis, and propose the rs16972194 variant as a candidate for further functional evaluation. 相似文献8.
Jubao Duan Jianxin Shi Alessia Fiorentino Catherine Leites Xiangning Chen Winton Moy Jingchun Chen Boian?S. Alexandrov Anny Usheva Deli He Jessica Freda Niamh?L. O’Brien MGS GPC Andrew McQuillin Alan?R. Sanders Elliot?S. Gershon Lynn?E. DeLisi Alan?R. Bishop Hugh?M.D. Gurling Michele?T. Pato Douglas?F. Levinson Kenneth?S. Kendler Carlos?N. Pato Pablo?V. Gejman 《American journal of human genetics》2014,95(6):744-753
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Priyesh C. Suryavanshi C. A. Sasidharan A. Bhandary R. Behere R. V. Nayak K. R. 《Neurophysiology》2022,53(2):120-131
Neurophysiology - Social cognition abilities are significantly impaired in serious mental illnesses. Facial emotion recognition deficits (FERD) have been consistently reported in schizophrenia... 相似文献
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Ying Wang Yigang Feng Yanbin Jia Yanping Xie Wensheng Wang Yufang Guan Shuming Zhong Dan Zhu Li Huang 《PloS one》2013,8(12)
Background
Whether schizophrenia and bipolar disorder are the clinical outcomes of discrete or shared causative processes is much debated in psychiatry. Several studies have demonstrated anomalous structural and functional superior temporal gyrus (STG) symmetries in schizophrenia. We examined bipolar patients to determine if they also have altered STG asymmetry.Methods
Whole-head magnetoencephalography (MEG) recordings of auditory evoked fields were obtained for 20 subjects with schizophrenia, 20 with bipolar disorder, and 20 control subjects. Neural generators of the M100 auditory response were modeled using a single equivalent current dipole for each hemisphere. The source location of the M100 response was used as a measure of functional STG asymmetry.Results
Control subjects showed the typical M100 asymmetrical pattern with more anterior sources in the right STG. In contrast, both schizophrenia and bipolar disorder patients displayed a symmetrical M100 source pattern. There was no significant difference in the M100 latency and strength in bilateral hemispheres within three groups.Conclusions
Our results indicate that disturbed asymmetry of temporal lobe function may reflect a common deviance present in schizophrenia and bipolar disorder, suggesting the two disorders might share etiological and pathophysiological factors. 相似文献13.
Amy Murphy Kelan G. Tantisira Manuel E. Soto-Quirós Barbara J. Klanderman Stephen Lake Juan C. Celedón 《American journal of human genetics》2009,85(1):87-96
Asthma incidence and prevalence are higher in obese individuals. A potential mechanistic basis for this relationship is pleiotropy. We hypothesized that significant linkage and candidate-gene association would be found for body mass index (BMI) in a population ascertained on asthma affection status. Linkage analysis for BMI was performed on 657 subjects in eight Costa Rican families enrolled in a study of asthma. Family-based association studies were conducted for BMI with SNPs within a positional candidate gene, PRKCA. SNPs within PRKCA were also tested for association with asthma. Association studies were conducted in 415 Costa Rican parent-child trios and 493 trios participating in the Childhood Asthma Management Program (CAMP). Although only modest evidence of linkage for BMI was obtained for the whole cohort, significant linkage was noted for BMI in females on chromosome 17q (peak LOD = 3.39). Four SNPs in a candidate gene in this region (PRKCA) had unadjusted association p values < 0.05 for BMI in both cohorts, with the joint p value for two SNPs remaining significant after adjustment for multiple comparisons (rs228883 and rs1005651, joint p values = 9.5 × 10−5 and 5.6 × 10−5). Similarly, eight SNPs had unadjusted association p values < 0.05 for asthma in both populations, with one SNP remaining significant after adjustment for multiple comparisons (rs11079657, joint p value = 2.6 × 10−5). PRKCA is a pleiotropic locus that is associated with both BMI and asthma and that has been identified via linkage analysis of BMI in a population ascertained on asthma. 相似文献
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Thegna Mavroconstanti Stefan Johansson Ingeborg Winge Per M. Knappskog Jan Haavik 《PloS one》2013,8(8)
The CDH13 gene codes for T-cadherin, a GPI-anchored protein with cell adhesion properties that is highly expressed in the brain and cardiovascular system. Previous studies have suggested that CDH13 may be a promising candidate gene for Attention Deficit/Hyperactivity Disorder (ADHD). The aims of this study were to identify, functionally characterize, and estimate the frequency of coding CDH13 variants in adult ADHD patients and controls. We performed sequencing of the CDH13 gene in 169 Norwegian adult ADHD patients and 63 controls and genotyping of the identified variants in 641 patients and 668 controls. Native and green fluorescent protein tagged wild type and variant CDH13 proteins were expressed and studied in CHO and HEK293 cells, respectively. Sequencing identified seven rare missense CDH13 variants, one of which was novel. By genotyping, we found a cumulative frequency of these rare variants of 2.9% in controls and 3.2% in ADHD patients, implying that much larger samples are needed to obtain adequate power to study the genetic association between ADHD and rare CDH13 variants. Protein expression and localization studies in CHO cells and HEK293 cells showed that the wild type and mutant proteins were processed according to the canonical processing of GPI-anchored proteins. Although some of the mutations were predicted to severely affect protein secondary structure and stability, no significant differences were observed between the expression levels and distribution of the wild type and mutant proteins in either HEK293 or CHO cells. This is the first study where the frequency of coding CDH13 variants in patients and controls is reported and also where the functional properties of these variants are examined. Further investigations are needed to conclude whether CDH13 is involved in the pathogenesis of ADHD or other conditions. 相似文献
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Eveliina Jakkula Virpi Leppä Anna-Maija Sulonen Teppo Varilo Suvi Kallio Anu Kemppinen Shaun Purcell Keijo Koivisto Marja-Liisa Sumelahti Tuula Pirttilä Arpo Aromaa Helle Bach Søndergaard Inger-Lise Mero Stacey B. Gabriel Stephen L. Hauser Chris Polman David A. Hafler Mark J. Daly Aarno Palotie Janna Saarela Leena Peltonen 《American journal of human genetics》2010,86(2):285-5259
Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10−4 were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 × 10−10, OR 0.87, confidence interval 0.83–0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits. 相似文献
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Misha Angrist Shuqian Jing Stacey Bolk Kimberly Bentley Sudha Nallasamy Marc Halushka Gary M. Fox Aravinda Chakravarti 《Genomics》1998,48(3):354
Congenital aganglionic megacolon, commonly known as Hirschsprung disease (HSCR), is the most frequent cause of congenital bowel obstruction. Germline mutations in theRETreceptor tyrosine kinase have been shown to cause HSCR. Knockout mice forRETand for its ligand, glial cell line-derived neurotrophic factor (GDNF), exhibit both complete intestinal aganglionosis and renal defects. Recently, GDNF and GFRA1 (GDNF family receptor, also known as GDNFR-α), its GPI-linked coreceptor, were demonstrated to be components of a functional ligand for RET. Moreover,GDNFhas been implicated in rare cases of HSCR. We have mappedGFRA1to human chromosome 10q25, isolated human and mouse genomic clones, determined the gene's intron–exon boundaries, isolated a highly polymorphic microsatellite marker adjacent to exon 7, and scanned forGFRA1mutations in a large panel of HSCR patients. No evidence of linkage was detected in HSCR kindreds, and no sequence variants were found to be in significant excess in patients. These data suggest thatGFRA1's role in enteric neurogenesis in humans remains to be elucidated and that RET signaling in the gut may take place via alternate pathways, such as the recently described GDNF-related molecule neurturin and its GFRA1-like coreceptor, GFRA2. 相似文献
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Eva C. Schulte Maria Kousi Perciliz L. Tan Erik Tilch Franziska Knauf Peter Lichtner Claudia Trenkwalder Birgit Högl Birgit Frauscher Klaus Berger Ingo Fietze Magdolna Hornyak Wolfgang H. Oertel Cornelius G. Bachmann Alexander Zimprich Annette Peters Christian Gieger Thomas Meitinger Bertram Müller-Myhsok Nicholas Katsanis Juliane Winkelmann 《American journal of human genetics》2014