Human molecular genetics最新文献

{"title":"The evaluation of targeted exome sequencing of candidate genes in a Han Chinese population with primary open-angle glaucoma.","authors":"Yiwen Zhou, Youjia Zhang, Qingdan Xu, Xinghuai Sun, Yuhong Chen","doi":"10.1093/hmg/ddae198","DOIUrl":"10.1093/hmg/ddae198","url":null,"abstract":"<p><p>Primary open-angle glaucoma (POAG), known as a common ocular disease with genetic heterogeneity, is characterized by progressive optic disc atrophy and visual field defects. This study aimed to assess the contribution of previously reported POAG-associated genes and investigate potential functional variations and genotype-phenotype correlations in a Han Chinese population. DNA from 500 cases and 500 controls was pooled and sequenced using a customized panel of 398 candidate genes. After prioritization, 21 SNPs from 16 genes were genotyped in the first replication cohort (500 cases and 500 controls), and 9 SNPs were genotyped in the second replication cohort (500 cases and 500 controls). Allelic associations and odds ratios were adjusted for age and sex, while linear regression assessed SNP correlations with POAG endophenotypes. Haplotype analysis and linkage disequilibrium were performed using Haploview. In silico prediction tools were used to predict pathogenicity and function. SNPs from MFN2, DGKG, PKHD1, PTPRJ, and LTBP2 were associated with POAG in at least one cohort, and SNPs from EXOC2, PTPRJ, and LTBP2 showed significant correlations with intraocular pressure. Additionally, haplotype analysis revealed a significant association between the EXOC2 TGC haplotype and POAG risk. We validated several candidate genes and identified novel SNPs, providing further insight into the genetic architecture of POAG in the Han Chinese population.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"435-443"},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948182","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":"Expression of Concern: Aqua-soluble DDQ reduces the levels of Drp1 and Aβ and inhibits abnormal interactions between Aβ and Drp1 and protects Alzheimer's disease neurons from Aβ- and Drp1-induced mitochondrial and synaptic toxicities.","authors":"","doi":"10.1093/hmg/ddae204","DOIUrl":"10.1093/hmg/ddae204","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"468"},"PeriodicalIF":3.1,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004628","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":"5-aza-2-deoxycytidine improves skeletal muscle function in a mouse model for recessive RYR1-related congenital myopathy.","authors":"Alexis Ruiz, Faiza Noreen, Hervé Meier, Katarzyna Buczak, Francesco Zorzato, Susan Treves","doi":"10.1093/hmg/ddaf021","DOIUrl":"https://doi.org/10.1093/hmg/ddaf021","url":null,"abstract":"<p><p>RYR1-related congenital myopathies are rare disorders that severely impair muscle function and the quality of life of patients and their families. To date no pharmacological therapies are available to treat the severe muscle weakness of affected patients. The most severe forms of RYR1-related congenital myopathies are caused by compound heterozygous mutations (nonsense/frameshift in one allele and a missense mutation in the other), leading to reduced RyR1 protein levels and altered biochemical composition of muscles. In this pre-clinical study, we treated a mouse model carrying the RyR1 p.Q1970fsX16 + p.A4329D compound heterozygous pathogenic variants (dHT mice) for 15 weeks with 0.05 mg/kg 5-aza-2'-deoxycytidine, an FDA-approved drug targeting DNA methyltransferases. We evaluated muscle strength, calcium homeostasis and muscle proteome and report that drug treatment improves all investigated parameters in dHT mice. Importantly, the beneficial effects were particularly significant in fast twitch muscles which are the first muscles to be impaired in patients. In conclusion, this study provides proof of concept for the pharmacological treatment of patients with recessive RYR1-related congenital myopathies with the FDA approved 5-aza-2'-deoxycytidine, supporting its use in a phase 1/2 clinical trial.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414173","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":"HHIP protein interactions in lung cells provide insight into COPD pathogenesis.","authors":"Dávid Deritei, Hiroyuki Inuzuka, Peter J Castaldi, Jeong Hyun Yun, Zhonghui Xu, Wardatul Jannat Anamika, John M Asara, Feng Guo, Xiaobo Zhou, Kimberly Glass, Wenyi Wei, Edwin K Silverman","doi":"10.1093/hmg/ddaf016","DOIUrl":"10.1093/hmg/ddaf016","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. The primary causes of COPD are environmental, including cigarette smoking; however, genetic susceptibility also contributes to COPD risk. Genome-Wide Association Studies (GWASes) have revealed more than 80 genetic loci associated with COPD, leading to the identification of multiple COPD GWAS genes. However, the biological relationships between the identified COPD susceptibility genes are largely unknown. Genes associated with a complex disease are often in close network proximity, i.e. their protein products often interact directly with each other and/or similar proteins. In this study, we use affinity purification mass spectrometry (AP-MS) to identify protein interactions with HHIP, a well-established COPD GWAS gene which is part of the sonic hedgehog pathway, in two disease-relevant lung cell lines (IMR90 and 16HBE). To better understand the network neighborhood of HHIP, its proximity to the protein products of other COPD GWAS genes, and its functional role in COPD pathogenesis, we create HUBRIS, a protein-protein interaction network compiled from 8 publicly available databases. We identified both common and cell type-specific protein-protein interactors of HHIP. We find that our newly identified interactions shorten the network distance between HHIP and the protein products of several COPD GWAS genes, including DSP, MFAP2, TET2, and FBLN5. These new shorter paths include proteins that are encoded by genes involved in extracellular matrix and tissue organization. We found and validated interactions to proteins that provide new insights into COPD pathobiology, including CAVIN1 (IMR90) and TP53 (16HBE). The newly discovered HHIP interactions with CAVIN1 and TP53 implicate HHIP in response to oxidative stress.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143407352","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":"Characterization of a novel GRHL2 mutation reveals molecular mechanisms underlying autosomal dominant hearing loss (DFNA28): insights from structural and functional studies.","authors":"Dominika Oziębło, Natalia Bałdyga, Marcin L Leja, Adam Jarmuła, Tomasz Wilanowski, Henryk Skarżyński, Monika Ołdak","doi":"10.1093/hmg/ddaf013","DOIUrl":"https://doi.org/10.1093/hmg/ddaf013","url":null,"abstract":"<p><p>The GRHL2 gene, encoding the Grainyhead-like 2 transcription factor, is essential for various biological processes. While GRHL2 has a complex role in cancer biology, its genetic variants have been also implicated in different forms of hearing loss (HL), including autosomal dominant non-syndromic hearing loss (DFNA28). Here, we report a novel c.1061C>T, p.(Ala354Val) mutation within the DNA binding domain (DBD) of GRHL2 that was identified in a three-generation HL family using a targeted multi-gene panel covering 237 HL-related genes. Unlike the previously reported DFNA28-causing variants that result in protein truncation, the impact of the p.(Ala354Val) missense change cannot be attributed to GRHL2 transcript level or composition, but to an alteration in protein function. Molecular dynamics simulations revealed destabilization of the p.(Ala354Val) mutant GRHL2 dimer interface and an altered DNA binding dynamics, leading to chaotic interaction patterns despite increased binding affinity to DNA. Functional assays demonstrated that the p.(Ala354Val) mutation and other DFNA28-related mutations in the DBD lead to loss of GRHL2 transcriptional transactivation activity, while the p.(Arg537Profs*11) mutation in the dimerization domain results in a gain-of-function effect. The findings indicate that both GRHL2 haploinsufficiency and gain-of-function contribute to HL and underscore the complex regulatory role of GRHL2 in maintaining proper function of the auditory system. Our study emphasizes the need to consider structural and functional aspects of gene variants to better understand their pathogenic potential. As GRHL2 is involved in a multitude of cellular processes, the data gathered here can be also applicable to other conditions.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390823","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-genome sequencing reveals the impact of lipid pathway and APOE genotype on brain amyloidosis.","authors":"Maulikkumar Patel, Cyril Pottier, Kang-Hsien Fan, Arda Cetin, Matthew Johnson, Muhammad Ali, Menghan Liu, Priyanka Gorijala, John Budde, Ruyu Shi, Ann D Cohen, James T Becker, Beth E Snitz, Howard Aizenstein, Oscar L Lopez, John C Morris, M Ilyas Kamboh, Carlos Cruchaga","doi":"10.1093/hmg/ddaf017","DOIUrl":"https://doi.org/10.1093/hmg/ddaf017","url":null,"abstract":"<p><p>Amyloid-PET imaging tracks the accumulation of amyloid beta (Aβ) deposits in the brain. Amyloid plaques accumulation may begin 10 to 20 years before the individual experiences clinical symptoms associated with Alzheimer's diseases (ad). Recent large-scale genome-wide association studies reported common risk factors associated with brain amyloidosis, suggesting that this endophenotype is driven by genetic variants. However, these loci pinpoint to large genomic regions and the functional variants remain to be identified. To identify new risk factors associated with brain amyloid deposition, we performed whole-genome sequencing on a large cohort of European descent individuals with amyloid PET imaging data (n = 1,888). Gene-based analysis for coding variants was performed using SKAT-O for amyloid PET as a quantitative endophenotype that identified genome-wide significant association for APOE (P = 2.45 × 10-10), and 26 new candidate genes with suggestive significance association (P < 5. 0 × 10-03) including SCN7A (P = 7.31 × 10-05), SH3GL1 (P = 7.56 × 10-04), and MFSD12 (P = 8.51 × 10-04). Enrichment analysis highlighted the lipid binding pathways as associated with Aβ deposition in brain driven by PITPNM3 (P = 4.27 × 10-03), APOE (P = 2.45 × 10-10), AP2A2 (P = 1.06 × 10-03), and SH3GL1 (P = 7.56 × 10-04). Overall, our data strongly support a connection between lipid metabolism and the deposition of Aβ in the brain. Our study illuminates promising avenues for therapeutic interventions targeting lipid metabolism to address brain amyloidosis.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382258","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":"Genetic analysis of elevated levels of creatinine and cystatin C biomarkers reveals novel genetic loci associated with kidney function.","authors":"Matteo D'Antonio, Timothy D Arthur, Wilfredo G Gonzalez Rivera, Ximei Wu, Jennifer P Nguyen, Melissa Gymrek, Park Woo-Yeong, Kelly A Frazer","doi":"10.1093/hmg/ddaf018","DOIUrl":"10.1093/hmg/ddaf018","url":null,"abstract":"<p><p>The rising prevalence of chronic kidney disease (CKD), affecting an estimated 37 million adults in the United States, presents a significant global health challenge. CKD is typically assessed using estimated Glomerular Filtration Rate (eGFR), which incorporates serum levels of biomarkers such as creatinine and cystatin C. However, these biomarkers do not directly measure kidney function; their elevation in CKD results from diminished glomerular filtration. Genome-wide association studies (GWAS) based on eGFR formulas using creatinine (eGFRcre) or cystatin C (eGFRcys) have identified distinct non-overlapping loci, raising questions about whether these loci govern kidney function or biomarker metabolism. In this study, we show that GWAS on creatinine and cystatin C levels in healthy individuals reveal both nonoverlapping genetic loci impacting their metabolism as well as overlapping genetic loci associated with kidney function; whereas GWAS on elevated levels of these biomarkers uncover novel loci primarily associated with kidney function in CKD patients.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382300","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":"The chromatin remodeler Brg1 is essential for cochlear sensory epithelium differentiation and patterning.","authors":"Yuning Song, Zhilin Dou, Wenwen Liu, Aizhen Zhang, Xiaotong Gao, Hongbiao Shi, Zhixiong Zhang, Jiangang Gao, Yecheng Jin","doi":"10.1093/hmg/ddaf019","DOIUrl":"https://doi.org/10.1093/hmg/ddaf019","url":null,"abstract":"<p><p>Human genome analyses have revealed that abnormal BAF (BRG1/BRM-associated factor) complex is highly associated with hearing loss. However, the underlying pathogenesis remains largely unknown. Disrupted structure and function of the organ of Corti is the most prevalent cause of sensorineural hearing loss in mammals. Here, we investigated the role of Brg1-based BAF complex during the differentiation and development of the auditory sensory epithelium, a crucial period for the formation of the organ of Corti. Our findings indicate that deletion of Brg1 leads to premature hair cell (HC) differentiation by inactivating Sonic hedgehog (Shh) signaling. Despite the formation of HCs, subsequent differentiation of inner hair cells (IHCs) and outer hair cells (OHCs) was impaired. Additionally, we observed that the mosaic-like arrangement of HCs and supporting cells (SCs) was disrupted resulting in abnormal sensory epithelium patterning. Furthermore, we found the planar cell polarity of the Brg1-deficient cochlea was abnormal. Our study demonstrates the pivotal role of Brg1 in the differentiation and patterning of the organ of Corti.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382315","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":"Use of patient-derived cell models for characterization of compound heterozygous hypomorphic C2CD3 variants in a patient with isolated nephronophthisis.","authors":"Zachary T Sentell, Lina Mougharbel, Zachary W Nurcombe, Sima Babayeva, Marc Henein, Lee Lee Chu, Murielle M Akpa, Chen-Fang Chung, Jean-Baptiste Rivière, Mihaela Pupavac, Rui Li, David S Rosenblatt, Jacek Majewski, Paul R Goodyer, Elena Torban, Thomas M Kitzler","doi":"10.1093/hmg/ddae182","DOIUrl":"10.1093/hmg/ddae182","url":null,"abstract":"<p><strong>Background: </strong>Primary ciliopathies are a heterogeneous group of rare disorders predominantly caused by autosomal-recessive genetic variants that disrupt non-motile ciliary function. They often manifest as a syndromic phenotype, frequently involving the kidney. Biallelic pathogenic variants in C2CD3 disrupt ciliogenesis and Sonic Hedgehog (SHH) signaling, resulting in a severe ciliopathy (Orofaciodigital syndrome XIV, OMIM 615948). We present compound heterozygous missense variants in C2CD3 that partially disrupt ciliary function in a patient with isolated renal disease.</p><p><strong>Methods: </strong>Exome sequencing identified biallelic C2CD3 missense variants (p.Pro168Leu; p.Thr2079Met). Patient-derived fibroblasts and urinary renal epithelial cells (URECs), and human RPE-1 C2CD3 knockout (KO) cell-lines were used for in vitro studies.</p><p><strong>Results: </strong>Cilia length was significantly shorter in patient-derived fibroblasts compared to an unaffected sibling (2.309 vs. 2.850 μm, P < 0.0001), while URECs showed significantly shortened cilia (2.068 vs. 2.807 μm, P < 0.0001) and a 40.8% reduction in ciliation (P < 0.001). The latter was not observed in fibroblasts, suggesting a kidney-specific effect. SHH signaling was dysregulated in patient cells as expression of GLI3 activator protein and GLI1 mRNA was significantly reduced. C2CD3 localization to the basal body was significantly reduced in patient URECs. Finally, rescue experiments in C2CD3 KO RPE-1 cells corroborated these findings by demonstrating a reduced capacity to restore ciliogenesis for each variant.</p><p><strong>Conclusion: </strong>Biallelic hypomorphic missense variants in C2CD3 may contribute to an isolated nephronophthisis phenotype with impaired ciliogenesis and SHH signaling. Our findings underscore the importance of functional testing to characterize candidate gene-disease relationships in patients with nephropathy of unknown etiology.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"368-380"},"PeriodicalIF":3.1,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846575","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":"TTC7A missense variants in intestinal disease can be classified by molecular and cellular phenotypes.","authors":"Zahra Shojaei Jeshvaghani, Marjolein Mijnders, Irena Muffels, Sander van Beekhuizen, Daniel Kotlarz, Caroline A Lindemans, Sibylle Koletzko, Christoph Klein, Michal Mokry, Edward Nieuwenhuis, Ewart Kuijk","doi":"10.1093/hmg/ddae185","DOIUrl":"10.1093/hmg/ddae185","url":null,"abstract":"<p><p>Biallelic mutations in tetratricopeptide repeat domain 7A (TTC7A) give rise to intestinal and immune disorders. However, our understanding of the genotype-phenotype relationship is limited, because TTC7A variants are mostly compound heterozygous and the disease phenotypes are highly diverse. This study aims to clarify how different TTC7A variants impact the severity of intestinal epithelial disorders. We individually characterized the molecular and cellular consequences of 11 different TTC7A missense mutations in TTC7A knockout Caco-2 cells. We examined variant-specific RNA expression profiles, TTC7A protein abundance, and endoplasmic reticulum (ER) stress by using RNA sequencing and imaging flow cytometry. For six variants we detected no significant alterations on these assays, suggesting that protein function may not be severely compromised. However, for five variants we observed molecular phenotypes, with overlapping gene expression signatures between specific variants. Remarkably, the TTC7AE71K variant displayed a unique expression profile, along with reduced TTC7A RNA and protein expression, which set it apart from all other variants. The findings from this study offer a better understanding of the role of specific TTC7A variants in disease and provide a framework for the classification of the variants based on the severity of impact. We propose a classification system for TTC7A variants that could help diagnosis, guide future treatment decisions and may aid in developing effective molecular therapies for patients that carry specific TTC7A variants.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"313-326"},"PeriodicalIF":3.1,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828385","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}