Human molecular genetics最新文献

{"title":"Calcium homeostasis modulator 2 aggravates α-synuclein-induced neurotoxicity in Parkinson's disease by activating PARP-1 depended Parthanatos.","authors":"Qi Pan, Huanjun Xu, Zongyu Xiao, Guanghao Liu, Huaming Zhang, Yiying Li","doi":"10.1093/hmg/ddaf091","DOIUrl":"10.1093/hmg/ddaf091","url":null,"abstract":"<p><strong>Background: </strong>Parkinson 's disease (PD) is a common neurodegenerative disease. Aggregates formed by α-synuclein (α-Syn) are the main pathological changes of PD. In this study, the effects of Calcium homeostasis modulator 2 (Calhm2) on α-syn-induced neurotoxicity in PD were evaluated.</p><p><strong>Methods: </strong>Primary neurons were treated with α-Syn PFF to mimic the PD cellular model. Genes and proteins were evaluated utilizing RT-qPCR, Western blot and immunofluorescence, respectively. Cell damage was assessed using CCK-8 and LDH assay. Cellular oxidative stress was assessed via the detection of SOD, GSH and ROS level. Mitochondrial membrane potential, ATP level, AIF nuclear translocation and intracellular Ca2+ were determined for the assessment of Parthanatos. HE and immunofluorescence of TH and NeuN was detected pathological changes in vivo.</p><p><strong>Results: </strong>α-Syn PFF administration greatly resulted in oxidative stress, calcium overload and PARP-1 dependent Parthanatos in primary neurons. Following α-Syn PFF administration, Calhm2 and Calhm3, key calcium homeostasis modulator (Calhm) proteins, were markedly elevated in neurons, while Calhm1 expression exhibited a little change. In addition, suppression of Calhm2 obviously mitigated α-Syn PFF-induced oxidative stress injury, calcium overload and PARP-1 dependent Parthanatos in vitro. Similarly, in vivo results demonstrated that α-Syn PFF treatment led to PARP-1-dependent Parthanatos and nerve injury, while these effects were reversed by Calhm2 knockdown.</p><p><strong>Conclusion: </strong>Calhm2 repression lightened α-Syn aggregation-induced neurotoxicity and PARP-1-dependent Parthanatos in PD, providing a novel therapeutic target for PD treatment.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1419-1431"},"PeriodicalIF":3.2,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301978","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":"COQ8B gene deficiency as a potential cause of retinal abnormalities in Pediatric kidney transplant recipients.","authors":"Yonghua Feng, Yi Feng, Zhigang Wang, Wenjing Li, Haowei Zhu, Zhou Li, Chenghao Feng, Hongen Xu, Guiwen Feng, Di Zhang, Wenjun Shang","doi":"10.1093/hmg/ddaf084","DOIUrl":"10.1093/hmg/ddaf084","url":null,"abstract":"<p><p>Coenzyme Q10 synthesis disorder caused by COQ8B gene deficiency is among the most prevalent causes of end-stage renal disease (ESRD) in children, which usually presents as isolated kidney disease, with sporadic cases associated with extrarenal symptoms such as retinitis pigmentosa (RP). Through long-term follow-up of 26 renal transplant children with COQ8B variants at our center, it is observed that, despite favorable renal transplant outcomes, 23.1% of children experienced night blindness or other ocular symptoms. Nine children were recruited for systematic ophthalmic examination and found that three of them were definitely diagnosed with RP, and the remaining children had varying degrees of retinal abnormalities regardless of perceived ocular discomfort. Compared with kidney transplant children without this genetic variant, children with the COQ8B genetic variant had significantly worse ERG results, which was an important indicator for the early diagnosis of RP. No known RP-associated pathogenic gene mutations were identified in the WES data of these children upon screening. Transcriptome analysis suggested that the potential association between COQ8B gene mutations and RP was related to ATP synthesis, oxidative phosphorylation, and phototransduction pathways. This study was the first to propose that COQ8B gene deficiency leading to retinal disorders in kidney transplanted children is not sporadic. Coenzyme Q10 supplementation may have a protective effect on the retina after renal transplantation in children with COQ8B mutations, requiring further research and clinical attention.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1368-1379"},"PeriodicalIF":3.2,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198903","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":"Old vs. new local ancestry inference in HCHS/SOL: a comparative study.","authors":"Xueying Chen, Hao Wang, Iris Broce, Anders Dale, Bing Yu, Laura Y Zhou, Xihao Li, Maria Argos, Martha L Daviglus, Jianwen Cai, Nora Franceschini, Tamar Sofer","doi":"10.1093/hmg/ddaf093","DOIUrl":"10.1093/hmg/ddaf093","url":null,"abstract":"<p><p>Hispanic/Latino populations are admixed, with genetic contributions from multiple ancestral populations. To uncover genetic associations in these populations, researchers often turn to admixture mapping, which relies on inferred counts of \"local\" ancestry, i.e. the source ancestral population at a locus. Local ancestries are inferred using external reference panels that represent ancestral populations, making the choice of inference method and reference panel critical. This study used a dataset of Hispanic/Latino individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) to evaluate how updates in local ancestry inference (LAI) affect results, specifically, the 'old' LAI performed using a popular inference method RFMix alongside 'new' inferences performed using Fast Local Ancestry Estimation (FLARE) with an updated reference panel. We compared their performance in terms of global and local ancestry correlations, as well as admixture mapping-based associations. Overall, the old and new inferences produced highly similar global and local ancestry estimates, with FLARE-based results closely matching those from RFMix in admixture mapping analyses. However, in some genomic regions, the old and new local ancestries showed relatively lower correlations (Pearson R < 0.9). Most of these regions (86.42%) were mapped to either ENCODE blacklist regions or gene clusters, compared to 7.67% of randomly-matched regions with high correlations (Pearson R > 0.97). These findings show that old and new inferences largely agree and suggest that regions of lower agreement are mostly due to genomic sequence contexts that lead to less stable inference, rather than due to the LAI software or genotyping technology used.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1405-1418"},"PeriodicalIF":3.2,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12361116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247663","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":"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":"<p><p>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.</p>","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}

{"title":"Correction to: ATP13A2/PARK9 regulates endo-/lysosomal cargo sorting and proteostasis through a novel PI(3, 5)P2-mediated scaffolding function.","authors":"","doi":"10.1093/hmg/ddaf095","DOIUrl":"10.1093/hmg/ddaf095","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1337-1340"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309882","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: TTC7A missense variants in intestinal disease can be classified by molecular and cellular phenotypes.","authors":"","doi":"10.1093/hmg/ddaf094","DOIUrl":"10.1093/hmg/ddaf094","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1342"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484093","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":"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":"<p><p>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.</p>","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}

{"title":"Correction to: The modifying effect of mutant LRRK2 on mutant GBA1-associated Parkinson disease.","authors":"","doi":"10.1093/hmg/ddaf112","DOIUrl":"10.1093/hmg/ddaf112","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1341"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484092","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":"Genome sequencing reveals CCDC88A variants in malformations of cortical development and immune dysfunction.","authors":"Johanna Lehtonen, Anna H Hakonen, Antti Hassinen, Sanne Iversen Lurås, Meri Kaustio, Virpi Glumoff, Francisca Hinrichsen, Weiwei Li, Anna-Maija Sulonen, Sanna Wickman, Henrikki Almusa, Minttu Polso, Maarit Palomäki, Sirpa Kivirikko, Kristiina Avela, Kaarina Heiskanen, Vilja Pietiäinen, Kristiina Aittomäki, Janna Saarela","doi":"10.1093/hmg/ddaf081","DOIUrl":"10.1093/hmg/ddaf081","url":null,"abstract":"<p><p>Malformations of cortical development (MCDs) encompass a diverse group of genetic and clinical disorders. Here, we aimed to determine a genetic etiology for two siblings manifesting MCD, microcephaly, epilepsy, intellectual disability, and susceptibility to infections. A missense variant (NM_018084:c.929A > C, p.Asp310Ala) and an intragenic deletion (exons 14-16) in CCDC88A were identified as compound heterozygous in patients by genome sequencing. Truncating homozygous CCDC88A variants are known to cause an ultra-rare syndrome manifesting with MCD, microcephaly, seizures, and severe neurological impairment. CCDC88A encodes girdin, which is essential for various cell functions, such as actin remodeling and cell proliferation. Western blot analysis showed that the missense variant allele was expressed in fibroblasts at a level compatible with a heterozygous allele, whereas a truncated protein from the deletion allele was barely detectable. Proliferation and wound-healing assays revealed that girdin-deficient fibroblasts proliferated faster and migrated slower than controls. High-content imaging highlighted girdin-deficient fibroblasts as smaller and their actin remodeling disrupted, leading to perinuclear accumulation of endolysosomal organelles. To confirm these cellular phenotypes resulted from girdin loss, CRISPR-Cas9 edited knockout models of healthy fibroblasts were created, replicating the observations in patient cells. Additionally, the siblings exhibited reduced monocytoid and plasmacytoid dendritic cells, suggesting compromised immunity due to girdin deficiency. In summary, the study describes the first case of a CCDC88A missense variant and intragenic deletion associated with MCD. It demonstrates altered immunity and girdin-related cellular changes, such as cell morphology and proliferation-migration dichotomy, in patient and knockout fibroblasts, reinforcing the pathogenic relevance of these variants.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1294-1312"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119502","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":"Expression of Concern: Protective effects of antidepressant citalopram against abnormal APP processing and amyloid beta-induced mitochondrial dynamics, biogenesis, mitophagy and synaptic toxicities in Alzheimer's disease.","authors":"","doi":"10.1093/hmg/ddaf104","DOIUrl":"10.1093/hmg/ddaf104","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1343"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511753","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}