Human molecular genetics最新文献

{"title":"Heart is the most susceptible organ in an isogenic background to loss of function mutations in the mitochondrial metallochaperone SCO1.","authors":"Sampurna Ghosh, Kimberly A Jett, Zakery N Baker, Aren Boulet, Amzad Hossain, Stanley A Moore, Martina Ralle, Binbing Ling, Paul A Cobine, Scot C Leary","doi":"10.1093/hmg/ddaf123","DOIUrl":"10.1093/hmg/ddaf123","url":null,"abstract":"<p><p>SCO1 is a nuclear-encoded protein with roles in cytochrome c oxidase (COX) assembly and the regulation of copper homeostasis. It remains unclear, however, why mutations in this ubiquitously expressed gene product cause distinct, tissue-specific forms of disease that primarily affect heart, liver or brain function. To gain a better understanding of the clinical heterogeneity observed across SCO1 pedigrees, we deleted Sco1 in the murine brain and observed a severe COX deficiency in the absence of altered tissue copper content that was tied to early, neonatal lethality. We therefore transitioned to whole body knockin mice expressing allelic variants of SCO1 that are pathogenic in humans to more accurately reflect the patient condition and avoid the lethality associated with tissue-specific Sco1 knockout. Sco1M277V mice exhibited the most severe COX deficiency in their brain, modeling the pathophysiological consequences of the p.Met294Val variant in humans and supporting the idea that the primary role of SCO1 in this tissue is to promote COX assembly. Phenotyping of Sco1G115S, Sco1P157L and Sco1M277V mice nonetheless emphasized that the heart generally displayed the most severe, combined COX and copper deficiency, with Sco1G115S and Sco1P157L hearts developing a dilated cardiomyopathy that was accompanied by significant depletion of their mitochondrial copper pool. Taken together, our findings suggest that in an isogenic context the heart is the most susceptible organ to loss of SCO1 function, and that single nucleotide polymorphisms at modifier loci in an outbred population likely contribute to the clinical heterogeneity observed across SCO1 pedigrees.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1599-1609"},"PeriodicalIF":3.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12449214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659050","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}

{"title":"Silencing of SOD1 sensitises ATRX-deficient cells to camptothecin treatment through increased activity of the alternative lengthening of telomeres pathway.","authors":"Natalie Mattis, Tomas Goncalves, Kanggeon Kim, Ester M Hammond, Anna M Rose","doi":"10.1093/hmg/ddaf118","DOIUrl":"10.1093/hmg/ddaf118","url":null,"abstract":"<p><p>The alternative lengthening of telomeres (ALT) pathway is a telomere maintenance mechanism that is driven by formation of DNA double-strand breaks at telomeres. ALT-positive malignancies often have mutational deletion of ATRX, but formation of DNA-protein complexes (DPCs) and elevated reactive oxygen species (ROS) also play a role in the induction of the ALT pathway. It has been recognised that excessive ALT activation can lead to rapid cell death, due to genome instability. Our objectives were to assess whether combining ROS-forming and DPC-forming treatments had a synergistic effect in ATRX-deficient cells. We found that SOD1 silencing was an effective method for inducing cell death in ATRX-deficient osteosarcoma cell lines; further, this approach was more effective in ATRX-null HeLa-LT than ATRX-wildtype cells. We also observed that dual treatment with DPC-forming chemotherapy (camptothecin) and SOD1 silencing led to a significantly higher level of DPCs, as well as signs of ALT pathway overactivity. Finally, our investigation demonstrated that pre-treatment of ATRX-null cells with shSOD1 significantly increased cellular sensitivity to camptothecin, with synergy between the two treatments. This research provides critical understanding to inform new treatment approaches-which might eventually improve survival for affected individuals, and reduce long-term effects, for survivors of ALT-positive malignancies.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1638-1647"},"PeriodicalIF":3.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12449190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759898","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}

{"title":"Retraction: The ERK1/2 pathway modulates nuclear PTEN-mediated cell cycle arrest by cyclin D1 transcriptional regulation.","authors":"","doi":"10.1093/hmg/ddaf130","DOIUrl":"10.1093/hmg/ddaf130","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1679"},"PeriodicalIF":3.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12449233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834953","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}

{"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":"10.1093/hmg/ddaf107","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1621-1627"},"PeriodicalIF":3.2,"publicationDate":"2025-09-19","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}

{"title":"Novel compound heterozygous variants in NBAS underlying fever-dependent infantile liver failure syndrome type 2: potential implications of protein thermostability.","authors":"Jiexin Tang, Xiaoru Wang, Hongmei Qiu, Lin Wei, Yuan Gao, Yan Sun","doi":"10.1093/hmg/ddaf120","DOIUrl":"10.1093/hmg/ddaf120","url":null,"abstract":"<p><strong>Background & aims: </strong>Infant liver failure syndrome type 2 (ILFS2), a rare autosomal recessive disorder manifesting as recurrent acute liver failure (ALF) triggered by febrile illness, is associated with neuroblastoma amplified sequence (NBAS) mutations. This study employs molecular dynamics simulation (MDS) to investigate how missense variants in the Sec39 domain influence protein conformation and thermostability.</p><p><strong>Approach & results: </strong>We identified novel compound heterozygous variants in the NBAS gene, c.2231 T > C (p.Leu744Pro) and c.2266C > T (p.Arg756Cys), in two Chinese siblings diagnosed with ILFS2. According to ACMG guideline, both variants were initially classified as variants of uncertain significance. To elucidate the potential functional impact, MDS was performed to compare structural dynamics between wild-type (WT) and mutant (MUT) NBASs at physiological temperature (37°C) and under thermal stress (42°C). The results revealed distinct thermal responses. WT demonstrated robust thermotolerance, with comparable trajectory patterns and curve parameters across two temperatures. In contrast, specific variants induced localized conformational perturbations and secondary structural reorganization. Notably, while MUT exhibited kinetic profiles similar to WT at 37°C, it showed pronounced fluctuations in flexible regions under thermal stress, with disrupted hydrogen-bonding networks and significant conformational changes, indicating compromised thermostability.</p><p><strong>Conclusions: </strong>The diagnosis of ILFS2 primarily relies on clinical presentation and genetic confirmation. Although the exact pathogenesis remains unclear, our findings suggest that temperature-sensitive structural destabilization induced by missense mutations within the Sec39 domain of NBAS probably underlies the fever-associated ALF. This provides critical guidance for subsequent protein structural elucidation and mechanism research, and regions exhibiting significantly reduced thermostability represent promising therapeutic targets.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1610-1620"},"PeriodicalIF":3.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144663892","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}

{"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":"10.1093/hmg/ddaf108","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1628-1637"},"PeriodicalIF":3.2,"publicationDate":"2025-09-19","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}

{"title":"Correction to: Modeling familial Alzheimer's disease with induced pluripotent stem cells.","authors":"","doi":"10.1093/hmg/ddaf134","DOIUrl":"10.1093/hmg/ddaf134","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1677-1678"},"PeriodicalIF":3.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834951","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}

{"title":"Correction to: Critical role of the SPAK protein kinase CCT domain in controlling blood pressure.","authors":"","doi":"10.1093/hmg/ddaf133","DOIUrl":"10.1093/hmg/ddaf133","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1674-1675"},"PeriodicalIF":3.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12449223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882805","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}

{"title":"Correction to: MED12-related XLID disorders are dose-dependent of immediate early genes (IEGs) expression.","authors":"","doi":"10.1093/hmg/ddaf138","DOIUrl":"10.1093/hmg/ddaf138","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1676"},"PeriodicalIF":3.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859132","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}

{"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":"10.1093/hmg/ddaf126","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1648-1664"},"PeriodicalIF":3.2,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12449191/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}