Human Genetics最新文献_第6页

Genetic analysis of preaxial polydactyly: identification of novel variants and the role of ZRS duplications in a Chinese cohort of 102 cases. 前轴多指畸形的遗传分析：在 102 例中国人队列中鉴定新型变异和 ZRS 重复的作用。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-12-01 Epub Date: 2024-10-24 DOI: 10.1007/s00439-024-02709-7

Siyu Pu, Zhibo Wang, Xueyang Tang, Daoxi Wang, Xiaodong Yang, Jun Jiang, Yifan Deng, Bo Xiang, Jiayin Yang, Xiaoli Wang, Xuesong Guo, Miao Sun, Bin Wang, Jing Chen

{"title":"Genetic analysis of preaxial polydactyly: identification of novel variants and the role of ZRS duplications in a Chinese cohort of 102 cases.","authors":"Siyu Pu, Zhibo Wang, Xueyang Tang, Daoxi Wang, Xiaodong Yang, Jun Jiang, Yifan Deng, Bo Xiang, Jiayin Yang, Xiaoli Wang, Xuesong Guo, Miao Sun, Bin Wang, Jing Chen","doi":"10.1007/s00439-024-02709-7","DOIUrl":"10.1007/s00439-024-02709-7","url":null,"abstract":"Preaxial polydactyly (PPD) is a congenital limb malformation, previously reported to be caused primarily by variants in the ZRS and upstream preZRS regions. This study investigated genetic variations associated with PPD, focusing on point variants and copy number variations (CNVs) in the ZRS and preZRS regions. Comprehensive genetic analyses were conducted on 102 patients with PPD, including detailed clinical examinations and Sanger sequencing of the ZRS and preZRS regions. Additionally, real-time quantitative PCR (qPCR) was used to detect CNVs in the ZRS region. The evolutionary conservation and population frequencies of identified variants were also evaluated. Six point variants were identified, among which four are likely pathogenic novel variants: 93G > T (g.156584477G > T), 106G > A (g.156584464G > A), 278G > A (g.156584292G > A), and 409A > C (g.156585378A > C). Additionally, qPCR analysis revealed that 66.67% of patients exhibited ZRS duplications. Notably, these duplications were also present in cases with newly identified potential pathogenic point variants. These findings suggest the possible interaction of point variants in ZRS and preZRS through a common pathogenic mechanism, leading jointly to PPD. The findings expand the variant spectrum associated with non-syndromic polydactyly and highlight that, despite different classifications, anterior polydactyly caused by variants in ZRS and nearby regions may share common pathogenic mechanisms. The incorporation of various variant types in genetic screening can effectively enhance the rate of pathogenic variant detection and contribute to the cost-effectiveness of genetic testing for limb developmental defects, thereby promoting healthy births.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1433-1444"},"PeriodicalIF":3.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The MorbidGenes panel: a monthly updated list of diagnostically relevant rare disease genes derived from diverse sources. MorbidGenes 面板：每月更新的罕见疾病诊断相关基因列表，这些基因来自不同来源。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-12-01 Epub Date: 2024-10-28 DOI: 10.1007/s00439-024-02711-z

Robin-Tobias Jauss, Bernt Popp, Joachim Bachmann, Rami Abou Jamra, Konrad Platzer

{"title":"The MorbidGenes panel: a monthly updated list of diagnostically relevant rare disease genes derived from diverse sources.","authors":"Robin-Tobias Jauss, Bernt Popp, Joachim Bachmann, Rami Abou Jamra, Konrad Platzer","doi":"10.1007/s00439-024-02711-z","DOIUrl":"10.1007/s00439-024-02711-z","url":null,"abstract":"Purpose: With exome sequencing now standard, diagnostic labs are in need of a, in principle, to-the-day-accurate list of genes associated with rare diseases. Manual curation efforts are slow and often disease specific, while efforts relying on single sources are too inaccurate and may result in false-positive or false-negative genes.Methods: We established the MorbidGenes panel based on a list of publicly available databases: OMIM, PanelApp, SysNDD, ClinVar, HGMD and GenCC. A simple logic allows inclusion of genes that are supported by at least one of these sources, providing a list of all genes with diagnostic relevance.Results: The panel is freely available at https://morbidgenes.uni-leipzig.de and currently includes 5037 genes (as of October 2024) with minimally sufficient evidence on disease causality to classify them as diagnostically relevant.Conclusion: The MorbidGenes panel is an open and comprehensive overview of diagnostically relevant rare disease genes based on a diverse set of resources. The panel is updated monthly to keep up with the ever increasing number of rare disease genes.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1459-1463"},"PeriodicalIF":3.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11576763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Polymorphic pseudogenes in the human genome - a comprehensive assessment. 人类基因组中的多态假基因--全面评估。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-12-01 Epub Date: 2024-11-02 DOI: 10.1007/s00439-024-02715-9

Mónica Lopes-Marques, M João Peixoto, David N Cooper, M João Prata, Luísa Azevedo, L Filipe C Castro

{"title":"Polymorphic pseudogenes in the human genome - a comprehensive assessment.","authors":"Mónica Lopes-Marques, M João Peixoto, David N Cooper, M João Prata, Luísa Azevedo, L Filipe C Castro","doi":"10.1007/s00439-024-02715-9","DOIUrl":"10.1007/s00439-024-02715-9","url":null,"abstract":"Background: Over the past decade, variations of the coding portion of the human genome have become increasingly evident. In this study, we focus on polymorphic pseudogenes, a unique and relatively unexplored type of pseudogene whose inactivating mutations have not yet been fixed in the human genome at the global population level. Thus, polymorphic pseudogenes are characterized by the presence in the population of both coding alleles and non-coding alleles originating from Loss-of-Function (LoF) mutations. These alleles can be found both in heterozygosity and in homozygosity in different human populations and thus represent pseudogenes that have not yet been fixed in the population.Results: A methodical cross-population analysis of 232 polymorphic pseudogenes, including 35 new examples, reveals that human olfactory signalling, drug metabolism and immunity are among the systems most impacted by the variable presence of LoF variants at high frequencies. Within this dataset, a total of 179 genes presented polymorphic LoF variants in all analysed populations. Transcriptome and proteome analysis confirmed that although these genes may harbour LoF alleles, when the coding allele is present, the gene remains active and can play a functional role in various metabolic pathways, including drug/xenobiotic metabolism and immunity. The observation that many polymorphic pseudogenes are members of multigene families argues that genetic redundancy may play a key role in compensating for the inactivation of one paralogue.Conclusions: The distribution, expression and integration of cellular/biological networks in relation to human polymorphic pseudogenes, provide novel insights into the architecture of the human genome and the dynamics of gene gain and loss with likely functional impact.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1465-1479"},"PeriodicalIF":3.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11576641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Biallelic germline DDX41 variants in a patient with bone dysplasia, ichthyosis, and dysmorphic features. 一名骨发育不良、鱼鳞病和畸形患者的双侧基因DDX41变体。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-12-01 Epub Date: 2024-10-25 DOI: 10.1007/s00439-024-02708-8

Prashant Sharma, Jason R McFadden, F Graeme Frost, Thomas C Markello, Dorothy K Grange, Wendy J Introne, William A Gahl, May Christine V Malicdan

{"title":"Biallelic germline DDX41 variants in a patient with bone dysplasia, ichthyosis, and dysmorphic features.","authors":"Prashant Sharma, Jason R McFadden, F Graeme Frost, Thomas C Markello, Dorothy K Grange, Wendy J Introne, William A Gahl, May Christine V Malicdan","doi":"10.1007/s00439-024-02708-8","DOIUrl":"10.1007/s00439-024-02708-8","url":null,"abstract":"DDX41 (DEAD‑box helicase 41) is a member of the largest family of RNA helicases. The DEAD-box RNA helicases share a highly conserved core structure and regulate all aspects of RNA metabolism. The functional role of DDX41 in innate immunity is also highly conserved. DDX41 acts as a sensor of viral DNA and activates the STING-TBK1-IRF3-type I IFN signaling pathway. Germline heterozygous variants in DDX41 have been reported in familial myelodysplasia syndrome (MDS)/acute myeloid leukemia (AML) patients; most patients also acquired a somatic variant in the second DDX41 allele. Here, we report a patient who inherited compound heterozygous DDX41 variants and presented with bone dysplasia, ichthyosis, and dysmorphic features. Functional analyses of the patient-derived dermal fibroblasts revealed a reduced abundance of DDX41 and abrogated activation of the IFN genes through the STING-type I interferon pathway. Genome-wide transcriptome analyses in the patient's fibroblasts revealed significant gene dysregulation and changes in the RNA splicing events. The patient's fibroblasts also displayed upregulation of periostin mRNA expression. Using an RNA binding protein assay, we identified DDX41 as a novel regulator of periostin expression. Our results suggest that functional impairment of DDX41, along with dysregulated periostin expression, likely contributes to this patient's multisystem disorder.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1445-1457"},"PeriodicalIF":3.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11576897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Homozygosity for a hypomorphic mutation in frizzled class receptor 5 causes syndromic ocular coloboma with microcornea in humans. frizzled 类受体 5 的同基因低态突变会导致人类眼部黑瘤伴小角膜综合征。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-12-01 Epub Date: 2024-11-06 DOI: 10.1007/s00439-024-02712-y

Vianney Cortés-González, Miguel Rodriguez-Morales, Paris Ataliotis, Claudine Mayer, Julie Plaisancié, Nicolas Chassaing, Hane Lee, Jean-Michel Rozet, Florencia Cavodeassi, Lucas Fares Taie

{"title":"Homozygosity for a hypomorphic mutation in frizzled class receptor 5 causes syndromic ocular coloboma with microcornea in humans.","authors":"Vianney Cortés-González, Miguel Rodriguez-Morales, Paris Ataliotis, Claudine Mayer, Julie Plaisancié, Nicolas Chassaing, Hane Lee, Jean-Michel Rozet, Florencia Cavodeassi, Lucas Fares Taie","doi":"10.1007/s00439-024-02712-y","DOIUrl":"10.1007/s00439-024-02712-y","url":null,"abstract":"Ocular coloboma (OC) is a congenital disorder caused by the incomplete closure of the embryonic ocular fissure. OC can present as a simple anomaly or, in more complex forms, be associated with additional ocular abnormalities. It can occur in isolation or as part of a broader syndrome, exhibiting considerable genetic heterogeneity. Diagnostic yield for OC remains below 30%, indicating the need for further genetic exploration. Mutations in the Wnt receptor FZD5, which is expressed throughout eye development, have been linked to both isolated and complex forms of coloboma. These mutations often result in a dominant-negative effect, where the mutated FZD5 protein disrupts WNT signaling by sequestering WNT ligands. Here, we describe a case of syndromic bilateral OC with additional features such as microcornea, bone developmental anomalies, and mild intellectual disability. Whole exome sequencing revealed a homozygous rare missense variant in FZD5. Consistent with a loss-of-function effect, overexpressing of fzd5 mRNA harboring the missense variant in zebrafish embryos does not influence embryonic development, whereas overexpression of wild-type fzd5 mRNA results in body axis duplications. However, in vitro TOPFlash assays revealed that the missense variant only caused partial loss-of-function, behaving as a hypomorphic mutation. We further showed that the mutant protein still localized to the cell membrane and maintained proper conformation when modeled in silico, suggesting that the impairment lies in signal transduction. This hypothesis is further supported by the fact that the variant affects a highly conserved amino acid known to be crucial for protein-protein interactions.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1509-1521"},"PeriodicalIF":3.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11576812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Interpreting the actionable clinical role of rare variants associated with short QT syndrome. 解读与短 QT 综合征相关的罕见变异的可操作临床作用。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-12-01 Epub Date: 2024-11-06 DOI: 10.1007/s00439-024-02713-x

Estefanía Martínez-Barrios, Andrea Greco, José Cruzalegui, Sergi Cesar, Nuria Díez-Escuté, Patricia Cerralbo, Fredy Chipa, Irene Zschaeck, Leonel Slanovic, Alipio Mangas, Rocío Toro, Josep Brugada, Georgia Sarquella-Brugada, Oscar Campuzano

{"title":"Interpreting the actionable clinical role of rare variants associated with short QT syndrome.","authors":"Estefanía Martínez-Barrios, Andrea Greco, José Cruzalegui, Sergi Cesar, Nuria Díez-Escuté, Patricia Cerralbo, Fredy Chipa, Irene Zschaeck, Leonel Slanovic, Alipio Mangas, Rocío Toro, Josep Brugada, Georgia Sarquella-Brugada, Oscar Campuzano","doi":"10.1007/s00439-024-02713-x","DOIUrl":"10.1007/s00439-024-02713-x","url":null,"abstract":"Genetic testing is recommended in the diagnosis of short QT syndrome. This rare inherited lethal entity is characterized by structural normal hearts with short QT intervals in the electrocardiogram. Few families diagnosed with this arrhythmogenic disease have been reported worldwide so far, impeding a comprehensive understanding of this syndrome. Unraveling the origin of the disease helps to the early identification of genetic carriers at risk. However, only rare variants with a definite deleterious role should be actionable in clinical practice. Our aim was to perform a comprehensive update and reinterpretation, according to the American College of Medical Genetics and Genomics recommendations of all rare variants currently associated with short QT syndrome. We identified 34 rare variants. Reanalysis showed that only nine variants played a deleterious role associated with a definite short QT syndrome phenotype. These variants were located in the four main genes: KCNQ1, KCNH2, KCNJ2 or SLC4A3. Additional rare variants located in other genes were associated with other conditions with phenotypic shortened QT intervals, but not definite diagnosis of short QT syndrome. Periodically updating of rare variants, especially those previously classified as unknown, helps to clarify the role of rare variants and translate genetic data into clinical practice.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1499-1508"},"PeriodicalIF":3.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11576798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Germline copy number variants and endometrial cancer risk. 基因拷贝数变异与子宫内膜癌风险。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-12-01 Epub Date: 2024-11-04 DOI: 10.1007/s00439-024-02707-9

Cassie E Stylianou, George A R Wiggins, Vanessa L Lau, Joe Dennis, Andrew N Shelling, Michelle Wilson, Peter Sykes, Frederic Amant, Daniela Annibali, Wout De Wispelaere, Douglas F Easton, Peter A Fasching, Dylan M Glubb, Ellen L Goode, Diether Lambrechts, Paul D P Pharoah, Rodney J Scott, Emma Tham, Ian Tomlinson, Manjeet K Bolla, Fergus J Couch, Kamila Czene, Thilo Dörk, Alison M Dunning, Olivia Fletcher, Montserrat García-Closas, Reiner Hoppe, Helena Jernström, Rudolf Kaaks, Kyriaki Michailidou, Nadia Obi, Melissa C Southey, Jennifer Stone, Qin Wang, Amanda B Spurdle, Tracy A O'Mara, John Pearson, Logan C Walker

{"title":"Germline copy number variants and endometrial cancer risk.","authors":"Cassie E Stylianou, George A R Wiggins, Vanessa L Lau, Joe Dennis, Andrew N Shelling, Michelle Wilson, Peter Sykes, Frederic Amant, Daniela Annibali, Wout De Wispelaere, Douglas F Easton, Peter A Fasching, Dylan M Glubb, Ellen L Goode, Diether Lambrechts, Paul D P Pharoah, Rodney J Scott, Emma Tham, Ian Tomlinson, Manjeet K Bolla, Fergus J Couch, Kamila Czene, Thilo Dörk, Alison M Dunning, Olivia Fletcher, Montserrat García-Closas, Reiner Hoppe, Helena Jernström, Rudolf Kaaks, Kyriaki Michailidou, Nadia Obi, Melissa C Southey, Jennifer Stone, Qin Wang, Amanda B Spurdle, Tracy A O'Mara, John Pearson, Logan C Walker","doi":"10.1007/s00439-024-02707-9","DOIUrl":"10.1007/s00439-024-02707-9","url":null,"abstract":"Known risk loci for endometrial cancer explain approximately one third of familial endometrial cancer. However, the association of germline copy number variants (CNVs) with endometrial cancer risk remains relatively unknown. We conducted a genome-wide analysis of rare CNVs overlapping gene regions in 4115 endometrial cancer cases and 17,818 controls to identify functionally relevant variants associated with disease. We identified a 1.22-fold greater number of CNVs in DNA samples from cases compared to DNA samples from controls (p = 4.4 × 10-63). Under three models of putative CNV impact (deletion, duplication, and loss of function), genome-wide association studies identified 141 candidate gene loci associated (p < 0.01) with endometrial cancer risk. Pathway analysis of the candidate loci revealed an enrichment of genes involved in the 16p11.2 proximal deletion syndrome, driven by a large recurrent deletion (chr16:29,595,483-30,159,693) identified in 0.15% of endometrial cancer cases and 0.02% of control participants. Together, these data provide evidence that rare copy number variants have a role in endometrial cancer susceptibility and that the proximal 16p11.2 BP4-BP5 region contains 25 candidate risk gene(s) that warrant further analysis to better understand their role in human disease.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1481-1498"},"PeriodicalIF":3.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11576655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

VCAT: an integrated variant function annotation tools. VCAT：综合变异功能注释工具。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-08-27 DOI: 10.1007/s00439-024-02699-6

Bi Huang, Cong Fan, Ken Chen, Jiahua Rao, Peihua Ou, Chong Tian, Yuedong Yang, David N Cooper, Huiying Zhao

{"title":"VCAT: an integrated variant function annotation tools.","authors":"Bi Huang, Cong Fan, Ken Chen, Jiahua Rao, Peihua Ou, Chong Tian, Yuedong Yang, David N Cooper, Huiying Zhao","doi":"10.1007/s00439-024-02699-6","DOIUrl":"10.1007/s00439-024-02699-6","url":null,"abstract":"The development of sequencing technology has promoted discovery of variants in the human genome. Identifying functions of these variants is important for us to link genotype to phenotype, and to diagnose diseases. However, it usually requires researchers to visit multiple databases. Here, we presented a one-stop webserver for variant function annotation tools (VCAT, https://biomed.nscc-gz.cn/zhaolab/VCAT/ ) that is the first one connecting variant to functions via the epigenome, protein, drug and RNA. VCAT is also the first one to make all annotations visualized in interactive charts or molecular structures. VCAT allows users to upload data in VCF format, and download results via a URL. Moreover, VCAT has annotated a huge number (1,262,041,068) of variants collected from dbSNP, 1000 Genomes projects, gnomAD, ICGC, TCGA, and HPRC Pangenome project. For these variants, users are able to searcher their functions, related diseases and drugs from VCAT. In summary, VCAT provides a one-stop webserver to explore the potential functions of human genomic variants including their relationship with diseases and drugs.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1311-1322"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Age-dependent somatic expansion of the ATXN3 CAG repeat in the blood and buccal swab DNA of individuals with spinocerebellar ataxia type 3/Machado-Joseph disease. 脊髓小脑共济失调 3 型/马加多-约瑟夫病患者血液和口腔拭子 DNA 中 ATXN3 CAG 重复的体细胞扩增与年龄有关。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-10-08 DOI: 10.1007/s00439-024-02698-7

Ahmed M Sidky, Ana Rosa Vieira Melo, Teresa T Kay, Mafalda Raposo, Manuela Lima, Darren G Monckton

{"title":"Age-dependent somatic expansion of the ATXN3 CAG repeat in the blood and buccal swab DNA of individuals with spinocerebellar ataxia type 3/Machado-Joseph disease.","authors":"Ahmed M Sidky, Ana Rosa Vieira Melo, Teresa T Kay, Mafalda Raposo, Manuela Lima, Darren G Monckton","doi":"10.1007/s00439-024-02698-7","DOIUrl":"10.1007/s00439-024-02698-7","url":null,"abstract":"Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is caused by the expansion of a genetically unstable polyglutamine-encoding CAG repeat in ATXN3. Longer alleles are generally associated with earlier onset and frequent intergenerational expansions mediate the anticipation observed in this disorder. Somatic expansion of the repeat has also been implicated in disease onset and slowing the rate of somatic expansion has been proposed as a therapeutic strategy. Here, we utilised high-throughput ultra-deep MiSeq amplicon sequencing to precisely define the number and sequence of the ATXN3 repeat, the genotype of an adjacent single nucleotide variant and quantify somatic expansion in blood and buccal swab DNA of a cohort of individuals with SCA3 from the Azores islands (Portugal). We revealed systematic mis-sizing of the ATXN3 repeat and high levels of inaccuracy of the traditional fragment length analysis that have important implications for attempts to identify modifiers of clinical and molecular phenotypes. Quantification of somatic expansion in blood DNA and multivariate regression revealed the expected effects of age at sampling and CAG repeat length, although the effect of repeat length was surprisingly modest with much stronger associations with age. We also observed an association of the downstream rs12895357 single nucleotide variant with the rate of somatic expansion, and a higher level of somatic expansion in buccal swab DNA compared to blood. These data suggest that the ATXN3 locus in SCA3 patients in blood or buccal swab DNA might serve as a good biomarker for clinical trials testing suppressors of somatic expansion with peripheral exposure.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1363-1378"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GBF1 deficiency causes cataracts in human and mouse. GBF1 缺乏会导致人类和小鼠白内障。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-08-07 DOI: 10.1007/s00439-024-02697-8

Weimin Jia, Chenming Zhang, Yalin Luo, Jing Gao, Chao Yuan, Dazhi Zhang, Xiaopei Zhou, Yongyao Tan, Shuang Wang, Zhuo Chen, Guigang Li, Xianqin Zhang

{"title":"GBF1 deficiency causes cataracts in human and mouse.","authors":"Weimin Jia, Chenming Zhang, Yalin Luo, Jing Gao, Chao Yuan, Dazhi Zhang, Xiaopei Zhou, Yongyao Tan, Shuang Wang, Zhuo Chen, Guigang Li, Xianqin Zhang","doi":"10.1007/s00439-024-02697-8","DOIUrl":"10.1007/s00439-024-02697-8","url":null,"abstract":"Any opacification of the lens can be defined as cataracts, and lens epithelium cells play a crucial role in guaranteeing lens transparency by maintaining its homeostasis. Although several causative genes of congenital cataracts have been reported, the mechanisms underlying lens opacity remain unclear. In this study, a large family with congenital cataracts was collected and genetic analysis revealed a pathological mutation (c.3857 C > T, p.T1287I) in the GBF1 gene; all affected individuals in the family carried this heterozygous mutation, while unaffected family members did not. Functional studies in human lens epithelium cell line revealed that this mutation led to a reduction in GBF1 protein levels. Knockdown of endogenous GBF1 activated XBP1s in the unfolded protein response signal pathway, and enhances autophagy in an mTOR-independent manner. Heterozygous Gbf1 knockout mice also displayed typic cataract phenotype. Together, our study identified GBF1 as a novel causative gene for congenital cataracts. Additionally, we found that GBF1 deficiency activates the unfolded protein response and leads to enhanced autophagy, which may contribute to lens opacity.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1281-1291"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0