Mapping Structural Distribution and Gating-Property Impacts of Disease-Associated Missense Mutations in Voltage-Gated Sodium Channels.

ABSTRACT: Thousands of voltage-gated sodium (Nav) channel variants contribute to a variety of disorders, including epilepsy, autism, cardiac arrhythmia, and pain disorders. Yet variant effects of more mutations remain unclear. The conventional gain-of-function (GoF) or loss-of-function (LoF) classifications is frequently employed to interpret of variant effects on function and guide precision therapy for sodium channelopathies. Our study challenges this binary classification by analyzing 525 mutations associated with 34 diseases across 366 electrophysiology studies, revealing that diseases with similar phenotypic effects can stem from unique molecular mechanisms. Our results show a high biophysical agreement (86%) between homologous disease-associated variants in different Na_v genes, sign

SUBMITTER: Ahangar AA 

PROVIDER: S-EPMC10541146 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature