Human molecular genetics最新文献_第3页

Correction to: Modeling familial Alzheimer's disease with induced pluripotent stem cells. 更正：用诱导多能干细胞模拟家族性阿尔茨海默病。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-08-10 DOI: 10.1093/hmg/ddaf134

引用次数: 0

Retraction: The ERK1/2 pathway modulates nuclear PTEN-mediated cell cycle arrest by cyclin D1 transcriptional regulation. 撤回：ERK1/2通路通过cyclin D1转录调控核pten介导的细胞周期阻滞。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-08-07 DOI: 10.1093/hmg/ddaf130

引用次数: 0

A case report of SPONASTRIME dysplasia with novel TONSL mutation: genetic analysis, clinical manifestations, and the effect of growth hormone treatment. SPONASTRIME发育不良伴新型TONSL突变1例：基因分析、临床表现及生长激素治疗效果。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-08-06 DOI: 10.1093/hmg/ddaf128

Minglan Yao, Cai Zhang, Sujuan Li, Anran Tian, Furong Liang, Xiaoping Luo

引用次数: 0

Bidirectional role of Costameres in the pathophysiology of mdx skeletal muscles. 肋肌在骨骼肌病理生理中的双向作用。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-08-01 DOI: 10.1093/hmg/ddaf127

Glen B Banks, Darren R Bisset, Jeffrey S Chamberlain

{"title":"Bidirectional role of Costameres in the pathophysiology of mdx skeletal muscles.","authors":"Glen B Banks, Darren R Bisset, Jeffrey S Chamberlain","doi":"10.1093/hmg/ddaf127","DOIUrl":"https://doi.org/10.1093/hmg/ddaf127","url":null,"abstract":"Skeletal muscles in Duchenne Muscular Dystrophy (DMD) are most susceptible to injury at a point in maturation when dystrophin is absent and utrophin dissipates from the membrane. The lack of the dystrophin glycoprotein complex (DGC) leaves a residual costameric scaffold that structurally connects the peripheral sarcomeres to the sarcolemma. However, the residual costameres are weak and transmit less lateral force making it unclear how they contribute to the pathophysiology of DMD. Here we found that costameres were near absent in mature mdx4cv:desmin double knockout (dko) fast 2b myofibers where the compensating utrophin protein is not upregulated at costameres. The lack of costameres decoupled sarcomere strain injury from tearing the membrane leading to isolated necrotic myofibers. Despite a 30% reduction in the proportion of myofibers with centrally located nuclei (a marker of degenerating/regenerating myofibers), the fast 2b dko muscles were atrophic and profoundly weakened by the sarcomere strain injury. Thus, our data is consistent with the DGC protecting the membrane and peripheral sarcomeres from the bidirectional forces that propagate through the desmin-fortified costameres.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759896","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

Huntingtin reduction results in altered nuclear structure and heterochromatic instability. 亨廷顿蛋白还原导致核结构改变和异色不稳定性。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-08-01 DOI: 10.1093/hmg/ddaf126

Jessica C Barron, Sean T Coady, Abigayle C Fleming, Samantha J Carew, Makenna C A Taylor, Emily P Hurley, Firoozeh Nafar, Matthew P Parsons

{"title":"Huntingtin reduction results in altered nuclear structure and heterochromatic instability.","authors":"Jessica C Barron, Sean T Coady, Abigayle C Fleming, Samantha J Carew, Makenna C A Taylor, Emily P Hurley, Firoozeh Nafar, Matthew P Parsons","doi":"10.1093/hmg/ddaf126","DOIUrl":"https://doi.org/10.1093/hmg/ddaf126","url":null,"abstract":"Huntington's disease (HD), a fatal neurodegenerative disease, arises due to a CAG repeat expansion in the huntingtin (HTT) gene. Non-pathogenic wild type HTT (wtHTT) is essential for neurodevelopment as well as many vital cellular functions within the adult brain; however, the consequences of wtHTT reduction in adulthood and particularly in extrastriatal regions of the brain have not been well characterized. Understanding the implications of wtHTT loss is essential as numerous genetic therapies for HD non-specifically reduce the expression levels of both mutant and wtHTT. The aim of the current study was to characterize the effect of wtHTT reduction from the whole cell to synaptic level in primary hippocampal neurons using conventional and super-resolution imaging methods. Our results identified the nucleus as an organelle that is particularly vulnerable to wtHTT reduction, with hippocampal neurons exhibiting increased nuclear size relative to the soma, DNA decompaction and a progressive loss of heterochromatin, and biphasic changes in nuclear pCREB signaling following siRNA-mediated wtHTT knockdown. Other structural assessments including dendritic complexity, spine density and synaptic morphology appeared to be largely unaffected in our wtHTT-lowered cells. These findings highlight the nucleus as an organelle that may be particularly sensitive to huntingtin-lowering in the mammalian brain.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759897","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

Long-read sequencing for NF1 gene analysis: enhancing diagnostic accuracy for Neurofibromatosis type 1. NF1基因分析的长读测序：提高1型神经纤维瘤病的诊断准确性。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-07-28 DOI: 10.1093/hmg/ddaf108

Yu Zheng, Miaomiao Chen, Shuju Zhang, Yu Peng, Xinghan Wu, Danni Guo, Yaoxi Liu, Aiping Mao, Danhua Li, Tiantian Xie, Haibo Mei, Guanghui Zhu, Hua Wang

{"title":"Long-read sequencing for NF1 gene analysis: enhancing diagnostic accuracy for Neurofibromatosis type 1.","authors":"Yu Zheng, Miaomiao Chen, Shuju Zhang, Yu Peng, Xinghan Wu, Danni Guo, Yaoxi Liu, Aiping Mao, Danhua Li, Tiantian Xie, Haibo Mei, Guanghui Zhu, Hua Wang","doi":"10.1093/hmg/ddaf108","DOIUrl":"https://doi.org/10.1093/hmg/ddaf108","url":null,"abstract":"The Clinical diagnosis of Neurofibromatosis type 1 (NF1) in pediatric patients is challenged by incomplete manifestation of age-dependent phenotypes, and molecular genetic testing is usually required to confirm the diagnosis. Early differential diagnosis is particularly crucial for children presenting solely with multiple Cafe-au-lait spots (CALMs). Here we developed a comprehensive analysis of the NF1 gene (CANF1) based on long-range PCR and long-read sequencing (LRS) for genetic testing of NF1. This blinded retrospective study evaluated the clinical utility of CANF1 in 191 samples from 189 individuals (180 probands, 9 NF1 family members) by comparing it to next-generation sequencing (NGS), primarily exome sequencing (ES), as control methods. The results demonstrated concordant findings in 97.4% (186/191) of samples and 97.2% (175/180) of probands, and discordant results in 2.6% (5/191) of samples and 2.8% (5/180) of probands, including one newly established diagnosis due to a patient harboring the pathogenic deep intronic variant c.5812 + 332A > G. Among 126 pediatric probands with NF1, this assay achieved a diagnostic yield of 92.1%, outperforming ES with cost-competitive advantages. In conclusion, this study established an NF1 genetic assay employing LRS, demonstrating reliable detection for various variant types of the NF1 gene. The CANF1 assay provides an alternative screening approach for precise and cost-effective NF1 diagnosis, particularly valuable for pediatric cases not fulfilling NF1 clinical diagnostic criteria but presenting with a characteristic NF1 feature such as CALMs.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144730087","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

Three decades of caspases and RIPKs in life and death. 30年来半胱天冬酶和RIPKs的生死关系。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-07-25 DOI: 10.1093/hmg/ddaf106

R K Subbarao Malireddi, Thirumala-Devi Kanneganti

{"title":"Three decades of caspases and RIPKs in life and death.","authors":"R K Subbarao Malireddi, Thirumala-Devi Kanneganti","doi":"10.1093/hmg/ddaf106","DOIUrl":"10.1093/hmg/ddaf106","url":null,"abstract":"Caspases and RIPKs are critical regulators of life and death. These molecules have roles in innate immunity and cell death that drive host defense, development, and tumor immunity, but their activation can also contribute to aberrant inflammation and inflammatory disease. This review revisits three decades of genetic studies that have elucidated the critical functions of caspases and RIPKs, synthesizing seminal findings in development, lytic cell death pathways, inflammation, disease pathology, and therapeutic innovation. These studies have led to the paradigm-shifting concept of PANoptosis, defined as an innate immune, inflammatory cell death pathway initiated by innate immune sensors and driven by caspases and RIPKs through PANoptosome complexes. PANoptosis can occur in response to pathogens, pathogen- and damage-associated molecular patterns, homeostatic alterations, cytokines, and the lytic cell death of surrounding cells. Caspase-8 has emerged as a critical core component of PANoptosomes, with other caspases and RIPKs also being key to the molecular activation of PANoptosis. Further genetic studies have established the significance of caspases and RIPKs, including their role in PANoptosis, across the disease spectrum, in infections, inflammatory conditions, cytokine storm, and cancer. Collectively, genetic and biochemical evidence suggests that targeting PANoptosome pathway molecules, including innate immune sensors, caspases, and RIPKs, provides a promising therapeutic strategy for a wide range of conditions, such as neurodegeneration, metabolic disorders, cancers, and chronic inflammatory or autoimmune diseases.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12393794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144707313","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

Regulatory roles of rs2192932 and rs10487150 in autism spectrum disorder: insights from fine-mapping and cross-population validation. rs2192932和rs10487150在自闭症谱系障碍中的调控作用：来自精细定位和跨群体验证的见解

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-07-21 DOI: 10.1093/hmg/ddaf107

Shuai Zhao, Haoxue Wang, Fang Hou, Yanlin Chen, Kaiheng Zhu, Rundong Liu, Zhen Xiang, Jiao Zhang, Xi Liang, Li Li, Ranran Song

{"title":"Regulatory roles of rs2192932 and rs10487150 in autism spectrum disorder: insights from fine-mapping and cross-population validation.","authors":"Shuai Zhao, Haoxue Wang, Fang Hou, Yanlin Chen, Kaiheng Zhu, Rundong Liu, Zhen Xiang, Jiao Zhang, Xi Liang, Li Li, Ranran Song","doi":"10.1093/hmg/ddaf107","DOIUrl":"https://doi.org/10.1093/hmg/ddaf107","url":null,"abstract":"Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with increasing global prevalence. GWAS have identified many ASD risk loci, but most are in non-coding regions, and the genetic value of nearby loci remains underexplored. We aim to conduct a fine-mapping analysis of ASD-associated SNPs and validate the signals across ethnic groups, focusing on their regulatory effects on gene expression. Variants within ±500 kb of known ASD loci were selected. Functional annotations were performed using RegulomeDB and CADD. ASD susceptibility genes were obtained from AutDB and SFARI, and screened for validation using 11 high-quality GEO datasets. eQTL analysis was conducted using GTEx database. For Chinese children, a case-control study design was adopted. Biological samples and demographic information were collected from 1244 children between 2010-2024. Extracted DNA was used for ASAMD chip. For European children, GWAS data from 46351 samples were obtained from iPSYCH-PGC-ASD project. 158 ASD susceptibility SNPs with cis-eQTL signals in brain tissue were identified. Notably, rs2192932 and rs10487150 showed consistent associations with ASD in both populations. In additive model, a G to A change at rs2192932 increased ASD risk by 29.5% (OR = 1.295, 95% CI: 1.046-1.605, P = 0.018), while an A to C change at rs10487150 increased risk by 22.7% (OR = 1.227, 95% CI: 1.008-1.495, P = 0.042). Additionally, rs2192932 and rs10487150 may influence ASD onset by regulating SERPINE1 expression. These findings offer new insights into the molecular genetics of ASD and support the potential of genetic markers for risk prediction and early screening.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144674569","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

Pathogenic mutations disrupt stress granules assembly in patients with DDX3X neurodevelopmental disorder. 致病突变破坏DDX3X神经发育障碍患者的应激颗粒组装。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-07-20 DOI: 10.1093/hmg/ddaf083

Yan Bi, Jingjing Sun, Decheng Ren, Xiaohui Gong, Lei Ji, Pei Lu, Fan Yuan, Yanlin Wang, Keyi Li, Lili Long, Guang He, Li Ma

{"title":"Pathogenic mutations disrupt stress granules assembly in patients with DDX3X neurodevelopmental disorder.","authors":"Yan Bi, Jingjing Sun, Decheng Ren, Xiaohui Gong, Lei Ji, Pei Lu, Fan Yuan, Yanlin Wang, Keyi Li, Lili Long, Guang He, Li Ma","doi":"10.1093/hmg/ddaf083","DOIUrl":"10.1093/hmg/ddaf083","url":null,"abstract":"DDX3X neurodevelopmental disorder (DDX3X-NDD) represents a recently identified genetic syndrome characterized by intellectual disability (ID) and developmental delays, primarily caused by pathogenic variants in the DDX3X gene. The physiological ramifications of these mutations remain largely unexplored. In this study, we reported 21 DDX3X variants from 22 Chinese patients with DDX3X-NDD by whole exome sequencing. We selected five variants for further functional analyses, including two previously reported by our group. Three frameshift variants (c.280_281dup p.R95Efs*127, c.669_670del p.A224Pfs*70, and c.1579del p.H527Ifs*9) resulted in either the loss of DDX3X protein or the production of truncated proteins. Additionally, two missense variants (c.1051C > G p.R351G and c.1501G > A p.A501T) significantly reduced DDX3X protein expression. Notably, variants DDX3X-R95Efs*127 and DDX3X-A224Pfs*70 triggered marked apoptosis induction and failed to form stress granules in HEK293T cells compared to wild-type DDX3X. This defect may stem from their inability to interact with the stress particle marker PABPC1, as evidenced by co-immunoprecipitation assays. Moreover, DDX3X-H527Ifs*9 and DDX3X-R351G variants were found to disrupt the cell cycle, extending the S phase relative to the wild type. Collectively, our findings provide mechanistic insights into the pathogenic consequences of DDX3X-NDD associated mutations, suggesting that the loss-of-function variants of DDX3X lack a context-dependent survival advantage, potentially contributing to the pathology of this syndrome.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1328-1336"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142441","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

Whole-exome sequencing identifies 5 novel genes associated with carpal tunnel syndrome. 全外显子组测序鉴定出5个与腕管综合征相关的新基因。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2025-07-20 DOI: 10.1093/hmg/ddaf076

Zi-Yi Wang, Xiao-Yu He, Bang-Sheng Wu, Liu Yang, Jia You, Wei-Shi Liu, Jian-Feng Feng, Wei Cheng, Jin-Tai Yu

{"title":"Whole-exome sequencing identifies 5 novel genes associated with carpal tunnel syndrome.","authors":"Zi-Yi Wang, Xiao-Yu He, Bang-Sheng Wu, Liu Yang, Jia You, Wei-Shi Liu, Jian-Feng Feng, Wei Cheng, Jin-Tai Yu","doi":"10.1093/hmg/ddaf076","DOIUrl":"10.1093/hmg/ddaf076","url":null,"abstract":"Carpal tunnel syndrome (CTS), a common peripheral nerve entrapment disorder, has a high estimated heritability index. Although previous genome-wide association studies have assessed common genetic components of CTS, the risk contributed by coding variants is still not well understood. Here, we performed the largest exome-wide analyses using UK Biobank data from 350 770 participants to find coding variants associated with CTS. We then explored the relative contribution of both rare mutations and polygenic risk score (PRS) to CTS risk in survival analyses. Finally, we investigated the functional pathways of the CTS-related coding genes identified above. Aside from conforming 6 known CTS genes, 5 novel genes were identified (SPSB1, SYNC, ITGB5, MUC13 and LOXL4). The associations of most genes we identified with incident CTS were striking in survival analyses. Additionally, we provided evidence that combining rare coding alleles and polygenic risk score can improve the genetic prediction of CTS. Functional enrichment analyses revealed potential roles of the identified coding variants in CTS pathogenesis, where they contributed to extracellular matrix organization. Our results evaluated the contribution to CTS etiology from quantities of coding variants accessible to exome sequencing data.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1255-1264"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093476","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