Human molecular genetics最新文献_第2页

Shared genetic architecture of schizophrenia and lupus identifies pleiotropic loci with distinct downstream mechanisms. 精神分裂症和狼疮的共同遗传结构确定了具有不同下游机制的多效位点。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2026-09-11 DOI: 10.1093/hmg/ddag099

Chen Gong, Nick Dand, Amy W Butler, Ariella Amar, Lu Liu, Pinelopi Maria Triantafyllou, David L Morris, Timothy J Vyse

{"title":"Shared genetic architecture of schizophrenia and lupus identifies pleiotropic loci with distinct downstream mechanisms.","authors":"Chen Gong, Nick Dand, Amy W Butler, Ariella Amar, Lu Liu, Pinelopi Maria Triantafyllou, David L Morris, Timothy J Vyse","doi":"10.1093/hmg/ddag099","DOIUrl":"https://doi.org/10.1093/hmg/ddag099","url":null,"abstract":"Schizophrenia (SCZ) and systemic lupus erythematosus (SLE) exhibit epidemiological overlap, suggesting shared genetic underpinnings. Using the largest SLE genome-wide association study (GWAS) to date, we identified a significant genetic correlation between SCZ and SLE (rg = 0.25, p = 9.0 × 10-4). Cross-trait analysis nominated multiple candidate shared loci outside the major histocompatibility complex (MHC), most with aligned effects. The strongest candidate shared association was found at the FURIN-FES locus, previously implicated in SCZ and newly associated with SLE. In addition to FURIN-FES, FCGR2A, DOT1L and an intergenic noncoding RNA locus on chromosome 2 showed additional evidence consistent with shared association. Functional annotation showed that this locus modulated the expression of FURIN, which encodes a proprotein convertase involved in diverse biological processes, and FES, which encodes a tyrosine kinase important in innate immune signalling. The shared risk allele was also associated with altered plasma levels of FURIN, FES, and their functional partners (GDF2, BMP10, NTF4, FER). Tissue- and cell-type-specific eQTL analysis revealed distinct regulatory effects: FURIN expression was perturbed in neuronal and immune cells, while FES expression was altered in immune cells. Mendelian randomisation supported a causal role for FES protein in both disorders. These findings highlight that pleiotropy at the FURIN-FES locus for SCZ and SLE is compatible with disease-specific mechanisms. This underscores that shared genetics across traits does not necessarily mean shared biology.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 20","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13630456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108750","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

Coding, modifier, and regulatory effects shape circulating APOL1 levels. 编码、修饰和调节作用形成循环APOL1水平。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2026-09-11 DOI: 10.1093/hmg/ddag087

Walt E Adamson, Harry Noyes, John Ogunsola, Rulan S Parekh, Anneli Cooper, Annette MacLeod

{"title":"Coding, modifier, and regulatory effects shape circulating APOL1 levels.","authors":"Walt E Adamson, Harry Noyes, John Ogunsola, Rulan S Parekh, Anneli Cooper, Annette MacLeod","doi":"10.1093/hmg/ddag087","DOIUrl":"10.1093/hmg/ddag087","url":null,"abstract":"APOL1 variants G1 and G2 are major genetic risk factors for chronic kidney disease in people with recent sub-Saharan African ancestry, yet the mechanisms linking genotype to disease remain poorly defined. Circulating APOL1 is likely to play a critical role, although how specific genotypes and regulatory variants influence circulating APOL1 levels is incompletely understood. We analysed Olink-measured APOL1 NPX (Normalized Protein eXpression) levels from 43 587 UK Biobank participants. Associations between APOL1 NPX and known genotypes were assessed in individuals with recent sub-Saharan African ancestry, including analyses of G1, G2, E150K (rs2239785) and N264K (rs73885316). We also investigated protein quantitative trait loci and cis-acting variants across the APOL1 locus, including predicted microRNA binding sites. Results indicated that APOL1 NPX varied in an APOL1 genotype-dependent manner. E150K, G1, and G2 demonstrate a clear dose-dependent relationship with APOL1 NPX, with the largest effect for G2. After accounting for APOL1 genotype, APOL1 NPX remained higher in individuals with self-reported Black or Black British ethnicity, consistent with additional regulatory elements. Multiple cis-regulatory variants near APOL1 were independently associated with APOL1 NPX, and are likely to contribute to ancestry-related differences. Together these findings demonstrate that APOL1 genotype is a major determinant of APOL1 NPX, and that G1 and G2 have distinct biological effects. Regulatory variation adds another layer of control over APOL1 NPX and may help explain population differences. These findings provide a biological framework for understanding genotype-specific molecular effects of APOL1 variation.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 19","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13626210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001787","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

Molecular analysis of individuals with suspected 46,XY differences of sex development in a homogenous and understudied population. 在同质性和未充分研究的人群中可疑的46，XY性发育差异个体的分子分析。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2026-09-11 DOI: 10.1093/hmg/ddag089

Firman P Idris, Tara Hussein Tayeb, Gorjana Robevska, Khalid Hama Salih H Sharef, Dalya Bikhtiyar Jalal, Jocelyn van den Bergen, Gabby Atlas, Katrina M Bell, Tiong Yang Tan, Andrew H Sinclair, Katie L Ayers

{"title":"Molecular analysis of individuals with suspected 46,XY differences of sex development in a homogenous and understudied population.","authors":"Firman P Idris, Tara Hussein Tayeb, Gorjana Robevska, Khalid Hama Salih H Sharef, Dalya Bikhtiyar Jalal, Jocelyn van den Bergen, Gabby Atlas, Katrina M Bell, Tiong Yang Tan, Andrew H Sinclair, Katie L Ayers","doi":"10.1093/hmg/ddag089","DOIUrl":"10.1093/hmg/ddag089","url":null,"abstract":"Differences of sex development (DSD) are a group of rare congenital conditions defined by atypical chromosomal, gonadal, and/or hormonal sex. Despite advances in massively parallel sequencing (MPS), more than half of DSD cases have an unknown genetic aetiology. We recruited and analysed 21 individuals with 46,XY DSD from the Greater Middle East population using chromosomal microarray and whole exome sequencing. Participants had DSD ranging from micropenis to anorchia (absence of testes) with extra-genital features reported in four individuals (19%). Using a combination of microarray and WES, a genetic diagnosis (variants curated as likely pathogenic or pathogenic) was identified in 12/21 (57%) individuals. Microarray analysis showed two DSD participants with extra genital features had chromosomal abnormalities (48,XXXY and mosaic Y chromosomal rearrangement). Microarray also indicated a high degree of consanguinity, with extensive long contiguous stretches of homozygosity (LCSH) (>3% of the genome) in 6/21 (28.6%) individuals, all of whom received a genetic diagnosis. WES analysis revealed variants in the NR5A1 (three individuals), SRD5A2 (three individuals), TALDO1 (one individual) and AR (two individuals) genes. This includes the novel frameshift variant, c.1309del (p.Leu437Cysfs*59), in NR5A1. This study contributes to the characterisation of clinical features and molecular findings in individuals with DSD in this understudied and homogenous population and highlights the challenges with DSD diagnosis in the region. The genetic diagnoses identified may contribute to improved patient care and management.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 19","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13626209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944814","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

Pleiotropy and eQTL analysis identify shared genetic architecture of lipid traits in African-ancestry populations. 多效性和等qtl分析确定了非洲血统人群中脂质性状的共同遗传结构。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2026-09-11 DOI: 10.1093/hmg/ddag100

Knightess Oyibo, Michael Zhong, Clement Adebamowo, Ananyo Choudhury, Segun Fatumo, Scott Hazelhurst, Braxton D Mitchell, Michele Ramsay, Bamidele Tayo, Yuji Zhang, Sally N Adebamowo

{"title":"Pleiotropy and eQTL analysis identify shared genetic architecture of lipid traits in African-ancestry populations.","authors":"Knightess Oyibo, Michael Zhong, Clement Adebamowo, Ananyo Choudhury, Segun Fatumo, Scott Hazelhurst, Braxton D Mitchell, Michele Ramsay, Bamidele Tayo, Yuji Zhang, Sally N Adebamowo","doi":"10.1093/hmg/ddag100","DOIUrl":"10.1093/hmg/ddag100","url":null,"abstract":"Dyslipidemia is a leading modifiable risk factor for cardiovascular disease (CVD), yet the shared genetic architecture of lipid traits remains poorly characterized, particularly in African-ancestry populations who bear a disproportionate CVD burden but are underrepresented in genomic research. We conducted multi-trait meta-analyses of genome-wide association summary statistics for HDL cholesterol, LDL cholesterol, triglycerides, and total cholesterol in 34 039 individuals of African ancestry, comprising 27 289 discovery participants from three continental African cohorts (ACCME, AWI-Gen, and UGR) and 6750 replication participants from the UK Biobank. Multi-trait analysis and eQTL colocalization across metabolic and cardiovascular tissues were then performed to identify shared genetic signals and characterize their tissue-specific regulatory mechanisms. Multi-trait analysis identified 90 genome-wide significant variants. Of these, 43 were novel variants with no prior exact-variant lipid association records. Eight variants across six genomic regions reached genome-wide significance in the multi-trait analysis and 70 of the 90 primary signals remained significant after total cholesterol was excluded. The strongest associations localized to established lipid loci including APOE/NECTIN2/TOMM40 (P = 8.09 × 10-133), CETP (P = 9.44 × 10-108), LIPC (P = 9.42 × 10-51), and LPL (P = 5.79 × 10-22), with 92% of signals replicating in the UK Biobank cohort. eQTL colocalization linked seven lead variants to tissue-specific gene expression and prioritized candidate regulatory genes. Together, these findings characterize shared lipid-associated signals with heterogeneous, trait-dependent effects in continental African populations and provide population-relevant evidence for candidate regulatory mechanisms.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 20","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108716","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

Motor dysfunction phenotypes in a drosophila model validate DAO as an ALS gene. 果蝇模型中的运动功能障碍表型证实DAO是ALS基因。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2026-09-11 DOI: 10.1093/hmg/ddag093

Sylvana Tabone, Rebecca Cacciottolo, Ruben J Cauchi

{"title":"Motor dysfunction phenotypes in a drosophila model validate DAO as an ALS gene.","authors":"Sylvana Tabone, Rebecca Cacciottolo, Ruben J Cauchi","doi":"10.1093/hmg/ddag093","DOIUrl":"10.1093/hmg/ddag093","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by progressive motor neuron (MN) loss. Although rare pathogenic variants in the D-amino acid oxidase (DAO) gene have been proposed to cause familial ALS, inconsistent findings across mammalian models have hindered functional validation. Here, we establish and characterise a Drosophila model of DAO loss-of-function by targeting its highly conserved orthologue, Daao1. Constitutive Daao1 knockdown caused early developmental lethality, while surviving adult escapers exhibited profound flight and climbing impairments. Contrary to expectations, Daao1 deficiency did not elevate D-serine levels in larval or adult brains, and simultaneous knockdown of serine racemase (Srr), the enzyme responsible for D-serine synthesis, failed to rescue locomotor phenotypes. Tissue-specific silencing revealed that Daao1 is essential within both MNs and muscles, but not glia, for maintaining motor performance. RNA-seq of Daao1-deficient flies uncovered widespread transcriptional dysregulation affecting metabolism, peptide transport, immune activation and developmental pathways, accompanied by alternative splicing changes in genes required for neuronal morphology and synaptic organisation. Consistent with these molecular alterations, neuromuscular junctions (NMJs) displayed reduced axonal branching and bouton numbers, indicating disrupted neuromuscular connectivity. Remarkably, ubiquitous expression of human DAO rescued lethality and motor defects, demonstrating functional conservation and supporting a role for DAO in maintaining neuromuscular health. Together, our findings reveal a previously unrecognised, D-serine-independent role for DAO in neuromuscular integrity and provide functional evidence connecting DAO dysfunction to ALS-relevant phenotypes. The DAO-ALS Drosophila model provides a powerful platform for mechanistic studies and for evaluating human DAO variants of uncertain significance in ALS.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 20","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13626214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080469","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

CaMKIIβ Signaling drives expression of metabolic and stress response genes in skeletal muscle, and its loss contributes to the LGMDR1 phenotype. CaMKIIβ信号驱动骨骼肌代谢和应激反应基因的表达，其缺失导致LGMDR1表型。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2026-09-11 DOI: 10.1093/hmg/ddag090

Irina Kramerova, Frieda Anastopulos, Diana Becerra, Ruby Goldstein de Salazar, Alexander R Keeble, Jeffrey S Chamberlain, Steven A Moore, Elizabeth M McNally, Melissa J Spencer

{"title":"CaMKIIβ Signaling drives expression of metabolic and stress response genes in skeletal muscle, and its loss contributes to the LGMDR1 phenotype.","authors":"Irina Kramerova, Frieda Anastopulos, Diana Becerra, Ruby Goldstein de Salazar, Alexander R Keeble, Jeffrey S Chamberlain, Steven A Moore, Elizabeth M McNally, Melissa J Spencer","doi":"10.1093/hmg/ddag090","DOIUrl":"10.1093/hmg/ddag090","url":null,"abstract":"Calcium calmodulin kinase II (CaMKII) signaling is activated by muscle use and drives gene expression that promotes slow oxidative muscle phenotype. Previously, we showed that the calpain 3 knockout (C3KO) mouse model of limb girdle muscular dystrophy R1 (LGMDR1) exhibits impaired slow-oxidative gene expression and these deficits were associated with reduced levels of the CaMKIIβ isoform and attenuated CaMKII signaling in C3KO muscles. To investigate the contribution of CaMKIIβ signaling to the calpain 3-deficient phenotype, we generated both loss-of-function (muscle-specific conditional knockout, Camk2b cKO) and gain-of-function (muscle-specific overexpression of a constitutively active CaMK2b) models. Camk2b cKO muscles exhibited myopathic features and weakness and their muscles failed to upregulate genes that promote oxidative metabolism and stress-responses following endurance exercise, similarly to C3KO muscles. Mitochondrial respiration showed reduced activity of complex I, complex II and fatty acid oxidation. RNA sequencing of LGMDR1 patient biopsies revealed a similar reduction in genes involved in oxidative metabolism, aligning human and mouse findings. Overexpression of a constitutively active Camk2b in C3KO muscles enhanced oxidative metabolism and improved functional performance. Our results support the hypothesis that blunted CaMKIIβ signaling contributes to the failed upregulation of genes involved in oxidative metabolism and stress-responses in C3KO muscles. These studies highlight metabolic insufficiency as a central contributor to LGMDR1 pathogenesis and support the therapeutic potential of targeting CaMKII signaling to ameliorate disease features in LGMDR1.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 19","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13626206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944845","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

Parkinson's disease-associated LRRK2 risk variant, G2385R, enhances Rab substrate phosphorylation and impairs neuronal integrity. 帕金森病相关LRRK2风险变异体G2385R增强Rab底物磷酸化并损害神经元完整性

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2026-09-11 DOI: 10.1093/hmg/ddag103

An Phu Tran Nguyen, Roger Moser, Nicole Bryant, Lindsey A Cunningham, Evan J Worden, Darren J Moore

{"title":"Parkinson's disease-associated LRRK2 risk variant, G2385R, enhances Rab substrate phosphorylation and impairs neuronal integrity.","authors":"An Phu Tran Nguyen, Roger Moser, Nicole Bryant, Lindsey A Cunningham, Evan J Worden, Darren J Moore","doi":"10.1093/hmg/ddag103","DOIUrl":"10.1093/hmg/ddag103","url":null,"abstract":"Mutations in the LRRK2 gene are the most frequent cause of familial Parkinson's disease (PD) whereas common variants are associated with an increased risk for sporadic PD. LRRK2 encodes a multi-domain protein displaying two functional enzymatic activities: GTPase and kinase. In addition to familial mutations, several common LRRK2 coding variants have been associated with PD risk in different ethnic populations. Little is known about how these coding variants modulate the risk of developing PD. In this study, we aimed to evaluate the properties of a collection of LRRK2 coding risk variants (A419V, N551K, R1398H, R1628P, M1646T, S1647T, G2385R). With the exception of G2385R, we find that coding risk variants have minimal impact on LRRK2 protein levels, GTP-binding, LRRK2 phosphorylation, and subcellular localization in human cells and primary neurons. G2385R LRRK2 exhibits reduced phosphorylation at Ser910/Ser935 and Ser1292, consistent with diminished kinase activity. Notably, however, LRRK2 variants associated with increased PD risk (R1628P, M1646T, and G2385R) significantly elevate the levels of LRRK2-mediated Rab10 phosphorylation by >two-fold in cells. In contrast, LRRK2 variants associated with reduced PD risk (N551K, R1398H, and N551K-R1398H) do not alter pRab10 levels. The G2385R LRRK2 variant significantly inhibits neurite outgrowth in primary cortical neurons compared to wild-type LRRK2. Our study indicates that LRRK2-dependent Rab phosphorylation represents a relevant readout of PD risk induced by LRRK2 variants and demonstrates that the G2385R variant creates a hyperactive kinase that can impair neuronal integrity at comparable levels to the effects of G2019S LRRK2.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 20","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108763","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

Mutation rate estimates and somatic variants from cancer improve variant interpretation in epilepsy. 突变率估计和来自癌症的体细胞变异改善了癫痫的变异解释。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2026-09-11 DOI: 10.1093/hmg/ddag095

Christian M Boßelmann, Patrick May

引用次数: 0

Multidisciplinary pathogenicity assessment of congenital hypothyroidism-associated SLC5A5 gene variants. 先天性甲状腺功能减退相关SLC5A5基因变异的多学科致病性评估。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2026-09-11 DOI: 10.1093/hmg/ddag105

Sofía Savy, Gerardo Hernán Carro, Mariano Martín, Francisco Andrés Montes, Natalia Silvina Muñoz, Romina Celeste Geysels, Victoria Peyret, Ana María Masini-Repiso, Juan Pablo Nicola

{"title":"Multidisciplinary pathogenicity assessment of congenital hypothyroidism-associated SLC5A5 gene variants.","authors":"Sofía Savy, Gerardo Hernán Carro, Mariano Martín, Francisco Andrés Montes, Natalia Silvina Muñoz, Romina Celeste Geysels, Victoria Peyret, Ana María Masini-Repiso, Juan Pablo Nicola","doi":"10.1093/hmg/ddag105","DOIUrl":"https://doi.org/10.1093/hmg/ddag105","url":null,"abstract":"Next-generation sequencing (NGS) has markedly expanded the mutational spectrum of monogenic congenital hypothyroidism (CH), but has also led to the identification of numerous variants of uncertain significance, limiting the clinical utility of genetic testing. We previously developed an SLC5A5-specific machine learning-based predictor that improved the interpretation of missense variants associated with CH. Here, we systematically evaluated the pathogenicity of all CH-associated SLC5A5 variants reported in the literature using an integrated multidisciplinary framework based on the American College of Medical Genetics and Genomics (ACMG) guidelines. Among the 63 identified SLC5A5 variants, 5% were classified as benign, 16% as likely benign, 15% as of uncertain significance, 37% as likely pathogenic, and 27% as pathogenic. The computational variant effect predictor AlphaMissense was the most appropriate tool for predicting the functional impact of SLC5A5 missense variants. Experimental functional assays assessing the functional impact of SLC5A5 missense variants on radioiodide accumulation were instrumental in reclassifying variants of uncertain significance into clinically actionable categories. Moreover, patients' phenotype revealing reduced to absent thyroid radioiodide accumulation provided valuable phenotypic evidence supporting variant classification, which highlights the diagnostic value of thyroid scintigraphy in CH-associated SLC5A5 variants. Overall, our findings highlight the value of a multidisciplinary pathogenicity evaluation based on the ACMG guidelines, integrating computational predictions, functional assays, and phenotypic data into a standardized and evidence-based framework for the accurate interpretation of SLC5A5 variants, thereby representing a significant advance in the molecular diagnosis of congenital hypothyroidism.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 20","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108740","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

Tissue-specific models of spinal muscular atrophy identify muscle functions required for Drosophila neuromuscular junction architecture. 脊髓性肌萎缩的组织特异性模型确定了果蝇神经肌肉连接结构所需的肌肉功能。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2026-09-11 DOI: 10.1093/hmg/ddag096

Takakazu Yokokura, Hansine Heggeness, Seiko Yoshikawa, Salvatore Alaimo, Thirada Boonrawd, Navpreet Ahluwalia, Thi Thu Van Dihn, Alfredo Ferro, Elizabeth M McNeill, David Van Vactor

{"title":"Tissue-specific models of spinal muscular atrophy identify muscle functions required for Drosophila neuromuscular junction architecture.","authors":"Takakazu Yokokura, Hansine Heggeness, Seiko Yoshikawa, Salvatore Alaimo, Thirada Boonrawd, Navpreet Ahluwalia, Thi Thu Van Dihn, Alfredo Ferro, Elizabeth M McNeill, David Van Vactor","doi":"10.1093/hmg/ddag096","DOIUrl":"https://doi.org/10.1093/hmg/ddag096","url":null,"abstract":"Spinal Muscular Atrophy (SMA) is a neuromuscular disorder associated with motor neuron degeneration, yet the role of the well-conserved Survival of Motor Neuron (SMN) protein in muscle remains insufficiently understood. Using the Drosophila neuromuscular junction (NMJ) as a model, we combined tissue-specific Smn depletion with transcriptomic profiling and prior genetic modifier screens to identify SMN-dependent genes that contribute to synaptic architecture. Functional screening of candidate genes significantly and selectively effected in muscle identified genes whose knockdown phenocopied NMJ morphometry defects characteristic of Smn loss-of-function (LOF), including FER, CAP, HDAC4, Nhe2, and Raskol. Unlike other genes in this group, analysis of postsynaptic architecture using a subsynaptic reticulum (SSR) biomarker disrupted by Smn LOF singled out the conserved tyrosine kinase FER as an SMN-dependent gene in muscle that influences this prominent feature of the NMJ. Analysis of different FER transcripts suggests that elevation of the FERp100 protein isoform in Smn LOF muscle tissue leads to a dominant-negative effect likely to disrupt signaling via the MAPK-family kinase Basket (Bsk) to regulate the downstream phosphatase Puckered (Puc).","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 20","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074497","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