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Pathogenic Mechanisms of Two Novel Variants in the GJB1 Gene
Fenliang Xiao1,2,3, Miaojing Xu1, Wei Li1
1Department of Neurology Nanfang Hospital Southern Medical University Guangzhou Guangdong China fimmu.com.
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.