Functional characterization of a novel de novo CACNA1C pathogenic variant in a patient with neurodevelopmental disorder.

ABSTRACT: Mutations in CACNA1C, the gene encoding Ca_v1.2 voltage-gated calcium channels, are associated with a spectrum of disorders, including Timothy syndrome and other neurodevelopmental and cardiac conditions. In this study, we report a child with a de novo heterozygous missense variant (c.1973T > C; L658P) in CACNA1C, presenting with refractory epilepsy, global developmental delay, hypotonia, and multiple systemic abnormalities, but without overt cardiac dysfunction. Electrophysiological analysis of the recombinant Ca_v1.2 L658P variant revealed profound gating alterations, most notably a significant hyperpolarizing shift in the voltage dependence of activation and inactivation. Additionally, molecular modeling suggested that the L658P mutation disrupts interactions within

SUBMITTER: Stringer RN 

PROVIDER: S-EPMC11934713 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature