Human molecular genetics最新文献

{"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":"https://doi.org/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":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated multi-omics analysis revealed the molecular networks and potential targets of cellular senescence in Alzheimer's disease.","authors":"Yudi Xu, Shutong Liu, Zhaokai Zhou, Hongzhuo Qin, Yuyuan Zhang, Ge Zhang, Hongxuan Ma, Xinwei Han, Huimin Liu, Zaoqu Liu","doi":"10.1093/hmg/ddae189","DOIUrl":"https://doi.org/10.1093/hmg/ddae189","url":null,"abstract":"<p><p>Cellular senescence (CS) is a hallmark of Alzheimer's disease (AD). However, the mechanisms through which CS contributes to AD pathogenesis remain poorly understood. We found that CS level in AD was higher compared with the healthy control group. Transcriptome-based differential expression analysis identified 113 CS-related genes in blood and 410 in brain tissue as potential candidate genes involved in AD. To further explore the causal role of these genes, an integrative mendelian randomization analysis was conducted, combining AD genome-wide association study summary statistics with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) data from blood samples, which identified five putative AD-causal genes (CENPW, EXOSC9, HSPB11, SLC44A2, and SLFN12) and 18 corresponding DNA methylation probes. Additionally, integrative analysis between eQTLs and mQTLs from blood uncovered two genes and 12 corresponding regulatory elements involved in AD. Furthermore, two genes (CDKN2B and ITGAV) were prioritized as putative causal genes in brain tissue and were validated through in vitro experiments. The multi-omics integration study revealed the potential role and underlying biological mechanisms of CS driven by genetic predisposition in AD. This study contributed to fundamental understanding of CS in AD pathogenesis and facilitated the identification of potential therapeutic targets for AD prevention and treatment.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846508","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":"Motor pool selectivity of neuromuscular degeneration in type I spinal muscular atrophy is conserved between human and mouse.","authors":"Justin C Lee, Wendy K Chung, David J Pisapia, Christopher E Henderson","doi":"10.1093/hmg/ddae190","DOIUrl":"https://doi.org/10.1093/hmg/ddae190","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA) is caused by low levels of the survival motor neuron (SMN) protein. Even though SMN is ubiquitously expressed, the disease selectively affects motor neurons, leading to progressive muscle weakness. Even among motor neurons, certain motor units appear more clinically resistant to SMA. To quantitatively survey selective resistance, we studied extensive neuromuscular autopsies of Type I SMA patients and age-matched controls. We found highly divergent degrees of degeneration of neighboring motor units, even within individual cranial nerves or a single anatomical area such as the neck. Examination of a Type I SMA patient maintained on life support for 17 years found that most muscles were atrophied, but the diaphragm was strikingly preserved. Nevertheless, some resistant human muscles with preserved morphology displayed nearly complete conversion to slow Type I myofibers. Remarkably, a similar pattern of selective resistance was observed in the SMNΔ7 mouse model. Overall, differential motor unit vulnerability in human Type I SMA suggests the existence of potent, motor unit-specific disease modifiers. Mechanisms that confer selective resistance to SMA may represent therapeutic targets independent of the SMN protein, particularly in patients with neuromuscular weakness refractory to current treatments.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846572","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":"Dissecting the shared genetic architecture between nonalcoholic fatty liver disease and type 2 diabetes.","authors":"Zhenqiu Liu, Xiaochen Chen, Huangbo Yuan, Li Jin, Tiejun Zhang, Xingdong Chen","doi":"10.1093/hmg/ddae184","DOIUrl":"https://doi.org/10.1093/hmg/ddae184","url":null,"abstract":"<p><p>Observational studies have reported a bidirectional correlation between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D), but the shared genetic basis between the two conditions remains unclear. Using genome-wide association study (GWAS) summary data from European-ancestry populations, we examined the cross-trait genetic correlation and identified genomic overlaps and shared risk loci. We employed a latent causal variable model and Mendelian randomization (MR) analysis to infer causal relationships. Colocalization analysis and conditional/conjunctional false discovery rate (condFDR/conjFDR) were used to identify genomic overlaps and shared risk loci. Two-step MR analysis was utilized to identify potential mediators. We observed a strong positive genomic correlation between NAFLD and T2D (rg = 0.652, P = 5.67 × 10-6) and identified tissue-specific transcriptomic correlations in the pancreas, liver, skeletal muscle, subcutaneous adipose, and blood. Genetic enrichment was observed in NAFLD conditional on associations with T2D and vice versa, indicating significant polygenic overlaps. We found robust evidence for the causal effect of NAFLD on T2D, particularly insulin-related T2D, rather than vice versa. Colocalization analysis identified shared genomic regions between NAFLD and T2D, including GCKR, FTO, MAU2-TM6SF2, and PNPLA3-SAMM50. High-density lipoprotein cholesterol and insulin were partly mediated the association between NAFLD and T2D. These findings unveil a close genetic link between NAFLD and T2D, shedding light on the biological mechanisms connecting NAFLD progression to T2D.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846505","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":"Mouse models of type I interferonopathies.","authors":"Domnica Luca, Hiroki Kato","doi":"10.1093/hmg/ddae187","DOIUrl":"https://doi.org/10.1093/hmg/ddae187","url":null,"abstract":"<p><p>Type I interferonopathies are severe monogenic diseases caused by mutations that result in chronically upregulated production of type I interferon. They present with a broad variety of symptoms, the mechanisms of which are being extensively studied. Mouse models of type I interferonopathies are an important resource for this purpose, and in this context, we review several key molecular and phenotypic findings that are advancing our understanding of the respective diseases. We focus on genotypes related to nucleic acid metabolism, sensing by cytosolic receptors and downstream signalling.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142835527","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":"Identification of ZNF850 as a novel CTG repeat expansion-related gene in myotonic dystrophy type 1 patient-derived iPSCs.","authors":"Masayoshi Kamon, Shuji Wakatsuki, Masayuki Nakamori, Masanori P Takahashi, Madoka Mori-Yoshimura, Hirofumi Komaki, Toshiyuki Araki","doi":"10.1093/hmg/ddae186","DOIUrl":"https://doi.org/10.1093/hmg/ddae186","url":null,"abstract":"<p><p>Myotonic dystrophy type 1 (DM1) is a dominantly inherited multi-system disease caused by expanded CTG repeats in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Similar to other repeat disorders, the expanded trinucleotide repeat is unstable and demonstrates a tendency to increase repeat size with age in affected tissues. DNA mismatch repair system is implicated in somatic instability. It has been demonstrated that DM1 patient-derived induced pluripotent stem cells (DM1-iPSCs) show repeat instability, in which involvement of mismatch repair proteins has been suggested. Here we identified ZNF850 as a novel CTG repeat expansion-related molecule in DM1-iPSCs. ZNF850 was downregulated in a DM1-iPSC clone whose CTG repeat is exceptionally stable. We found that RNAi-mediated ZNF850 downregulation in DM1-iPSCs significantly reduced the repeat expansion and resulting instability. In adult skeletal muscle tissue of DM1 patients, ZNF850 expression levels were positively correlated with the repeat size. Furthermore, we found that ZNF850 protein can bind to the expanded CTG repeat sequence, and is located in proximity to MutSβ components. These results suggest that ZNF850 might play a role in repeat instability in DM1 by recruiting MutSβ to the repeat sequence.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828382","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":"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":"https://doi.org/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":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-15","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}

{"title":"Identification of hub genes and biological pathways related to central post-stroke pain in ischemic stroke.","authors":"Fude Liu, Yawen Cheng, Xiangning Han, Ning Zhu, Shiliang Jiang, Jiahao Li, Wenlong Ma, Jia Yu","doi":"10.1093/hmg/ddae178","DOIUrl":"https://doi.org/10.1093/hmg/ddae178","url":null,"abstract":"<p><p>This investigation aims to screen ischemic stroke (IS)-related hub genes of central post-stroke pain (CPSP) from public databases and predict their potential roles through bioinformatics analysis to better interpret CPSP in IS. First, based on differential analysis, Venn analysis, and enrichment analyses, we identified 13 differently expressed genes in CPSP (CPSP-DEGs) related to the TNF signaling pathway, Vascular smooth muscle contraction, and IL-17 signaling pathway. Subsequently, through screening and analysis of the PPI network constructed by the Search Tool for the Retrieval of Interacting Genes (STRING) database, we obtained 3 CPSP-related hub genes (CD163, MMP9, and ARG1). They were all highly expressed in the IS group, exhibiting good diagnostic performance, with area under curve (AUC) value > 0.85. The immune-related analysis demonstrated that the infiltration levels of various immune cells in the IS group and the normal group were substantially different. In addition, by utilizing some online websites, we not only predicted some microRNAs (miRNAs) and transcription factors (TFs) that may target hub genes but also mined small molecular drugs that may target differentially expressed genes (DEGs) in IS. In conclusion, this project first investigated the role of CPSP-related genes in IS and identified 3 hub genes. At the same time, we predicted some miRNAs, TFs, and candidate drugs that may target hub genes. Our research uncovered the potential mechanism of CPSP-related genes in IS from multiple perspectives. Furthermore, it also laid a research foundation for the future study of the mechanisms of IS disease.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806867","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 role of miR-129-5p in regulating γ-globin expression and erythropoiesis in β-thalassemia.","authors":"Jingmin Li, Meihuan Chen, Wantong Zhao, Aixiang Lv, Siyang Lin, Yanping Zheng, Meiying Cai, Na Lin, Liangpu Xu, Hailong Huang","doi":"10.1093/hmg/ddae180","DOIUrl":"https://doi.org/10.1093/hmg/ddae180","url":null,"abstract":"<p><p>The regulation of γ-globin expression is crucial due to its beneficial effects on diseases like β-thalassemia and sickle cell disease. B-cell lymphoma/leukemia 11A (BCL11A) is a significant suppressor of γ-globin, and microRNAs (miRNAs) targeting BCL11A have been shown to alleviate this suppression. In our previous high-throughput sequencing, we identified an 11.32-fold increase in miR-129-5p expression in β-thalassemia patients. However, the regulatory mechanisms of miR-129-5p in the context of erythroid differentiation remain to be elucidated. Our study aimed to elucidate the role of miR-129-5p in γ-globin regulation and erythropoiesis. We measured miR-129-5p levels in peripheral blood from β-thalassemia major and intermedia patients. Fluorescence in situ hybridization, dual-luciferase reporter assays, miRNA pull down assays and western blot analyses were conducted to examine the effects of miR-129-5p on γ-globin expression and BCL11A repression. Cell proliferation, apoptosis, and erythroid differentiation were assessed using cell counting kit-8, Wright-Giemsa, and benzidine staining, and flow cytometry assays. The expression levels of miR-129-5p were significantly elevated in β-thalassemia patients and positively correlated with γ-globin synthesis while negatively correlating with liver damage. miR-129- 5p enhanced γ-globin gene expression in K562 and HUDEP-2 cells by effectively repressing BCL11A. Overexpression of miR-129-5p inhibited cell proliferation, induced cell cycle arrest at the G1/G0 phase, promoted apoptosis and stimulated erythroid differentiation and maturation. Conversely, inhibition of miR-129-5p produced opposite cellular effects. miR-129-5p acts as a positive regulator of erythroid differentiation and γ-globin synthesis. It offers a promising miRNA target for activating the γ-globin gene and reducing ineffective erythropoiesis in β-thalassemia patients.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806899","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: Reduced levels of MRE11 cause disease phenotypes distinct from ataxia telangiectasia-like disorder.","authors":"","doi":"10.1093/hmg/ddae145","DOIUrl":"10.1093/hmg/ddae145","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"2177"},"PeriodicalIF":3.1,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545150","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}