Pathogenic Mechanisms of Two Novel Variants in the GJB1 Gene

IF 1.8 2区医学 Q2 GENETICS & HEREDITY

Human Mutation Pub Date : 2026-10-09 DOI:10.1155/humu/7388252

Fenliang Xiao, Miaojing Xu, Wei Li, Zijian Xu, Haishan Jiang, Shaogang Qu

{"title":"Pathogenic Mechanisms of Two Novel Variants in the GJB1 Gene","authors":"Fenliang Xiao, Miaojing Xu, Wei Li, Zijian Xu, Haishan Jiang, Shaogang Qu","doi":"10.1155/humu/7388252","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <h3> Background and Aims</h3>\n \n <p>Charcot–Marie–Tooth disease X-linked Type 1 (CMTX1), caused by <i>GJB1</i> mutations, presents diagnostic challenges due to phenotypic heterogeneity and novel variants. This study reviews clinical data from 2021–2024 and investigates the mechanisms of two novel <i>GJB1</i> variants.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We retrospectively analyzed eight male patients, evaluating clinical signs, electrophysiology, and sural nerve biopsies. Pathogenicity of novel variants was assessed via bioinformatics, ChimeraX molecular modeling, and HeLa cell models focusing on protein localization and channel function (scratch-loading/DAPI assays).</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Patients showed typical distal muscle atrophy and intermediate conduction velocities; three exhibited rare CNS white matter abnormalities. Two novel variants were identified: c.130dupT and c.124A > G. c.130dupT led to a complete “loss of expression” of the full-length Cx32 protein. c.124A > G resulted in significant cytoplasmic protein retention (<i>p</i> < 0.05). Molecular modeling revealed a physical constriction (1.229 Å) in the channel bottleneck and an increased electrostatic barrier. Functional assays confirmed significant impairment in both gap junction and hemichannel activity (<i>p</i> < 0.01).</p>\n </section>\n \n <section>\n \n <h3> Interpretation</h3>\n \n <p>This study identifies two previously unreported <i>GJB1</i> variants and elucidates their distinct pathogenic mechanisms: c.130dupT acts through loss of expression, whereas c.124A > G causes functional defect via structural channel constriction. These findings expand the genetic spectrum of CMTX1 and provide a basis for precise molecular diagnosis.</p>\n </section>\n </div>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2026 1","pages":""},"PeriodicalIF":1.8000,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/7388252","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Human Mutation","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1155/humu/7388252","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}

引用次数: 0

Abstract

Background and Aims

Charcot–Marie–Tooth disease X-linked Type 1 (CMTX1), caused by GJB1 mutations, presents diagnostic challenges due to phenotypic heterogeneity and novel variants. This study reviews clinical data from 2021–2024 and investigates the mechanisms of two novel GJB1 variants.

Methods

We retrospectively analyzed eight male patients, evaluating clinical signs, electrophysiology, and sural nerve biopsies. Pathogenicity of novel variants was assessed via bioinformatics, ChimeraX molecular modeling, and HeLa cell models focusing on protein localization and channel function (scratch-loading/DAPI assays).

Results

Patients showed typical distal muscle atrophy and intermediate conduction velocities; three exhibited rare CNS white matter abnormalities. Two novel variants were identified: c.130dupT and c.124A > G. c.130dupT led to a complete “loss of expression” of the full-length Cx32 protein. c.124A > G resulted in significant cytoplasmic protein retention (p < 0.05). Molecular modeling revealed a physical constriction (1.229 Å) in the channel bottleneck and an increased electrostatic barrier. Functional assays confirmed significant impairment in both gap junction and hemichannel activity (p < 0.01).

Interpretation

This study identifies two previously unreported GJB1 variants and elucidates their distinct pathogenic mechanisms: c.130dupT acts through loss of expression, whereas c.124A > G causes functional defect via structural channel constriction. These findings expand the genetic spectrum of CMTX1 and provide a basis for precise molecular diagnosis.

查看原文本刊更多论文

GJB1基因两种新变异的致病机制

背景和目的由GJB1突变引起的x连锁1型（CMTX1），由于表型异质性和新的变异，提出了诊断挑战。本研究回顾了2021-2024年的临床数据，并探讨了两种新型GJB1变异的机制。方法回顾性分析8例男性患者的临床症状、电生理和腓肠神经活检。通过生物信息学、ChimeraX分子模型和以蛋白质定位和通道功能为重点的HeLa细胞模型（刮擦加载/DAPI测定）评估新变异的致病性。结果患者表现为典型的远端肌萎缩，传导速度中等；3例出现罕见的中枢神经系统白质异常。鉴定出两种新的变异：c.130dupT和c.124A >； G。c.130dupT导致全长Cx32蛋白完全“失表达”。c.124A >； G导致显著的细胞质蛋白滞留（p < 0.05）。分子模型揭示了通道瓶颈处的物理收缩（1.229 Å）和静电屏障的增加。功能分析证实了间隙连接和半通道活性的显著损伤（p < 0.01）。本研究确定了两种以前未报道的GJB1变异，并阐明了它们不同的致病机制：c.130dupT通过表达缺失起作用，而c.124A >； G通过结构通道狭窄导致功能缺陷。这些发现扩大了CMTX1的遗传谱，为精确的分子诊断提供了基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Human Mutation 医学-遗传学

CiteScore

8.40

自引率

5.10%

发文量

190

审稿时长

2 months

期刊介绍： Human Mutation is a peer-reviewed journal that offers publication of original Research Articles, Methods, Mutation Updates, Reviews, Database Articles, Rapid Communications, and Letters on broad aspects of mutation research in humans. Reports of novel DNA variations and their phenotypic consequences, reports of SNPs demonstrated as valuable for genomic analysis, descriptions of new molecular detection methods, and novel approaches to clinical diagnosis are welcomed. Novel reports of gene organization at the genomic level, reported in the context of mutation investigation, may be considered. The journal provides a unique forum for the exchange of ideas, methods, and applications of interest to molecular, human, and medical geneticists in academic, industrial, and clinical research settings worldwide.