Characterization of Three Distinct Loss-of-Function Cav2.3 Variants
Abstract
De novo variants in CACNA1E, the gene encoding the Cav2.3 voltage-gated calcium channel, are often associated with severe neurodevelopmental disorders, including developmental and epileptic encephalopathy. All reported variants up to date have exhibited gain-of-function effects on their biophysical properties. Here, we functionally characterize three pathogenic CACNA1E variants: H151L, M163T, and R1182C, using electrophysiology and structural modeling. M163T and R1182C exhibit depolarizing shifts in the voltage-dependence of activation, whereas R1182C also shows a reduced peak current density. H151L selectively slows recovery from inactivation. Our findings provide the first mechanistic evidence linking loss-of-function Cav2.3 pathogenic variants to variable neurological phenotypes, expanding the clinical spectrum of CACNA1E channelopathies.
Fields of Study & Subjects
Ion channel regulation and function
Cardiac electrophysiology and arrhythmias
Phosphodiesterase function and regulation
Publication details
- Journal / source
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Volume
- 27
- Issue
- 9
- Pages
- 4103–4103
- Publication date
- 3 May 2026
- Language
- EN