Missense mutations in voltage-gated calcium channels associated with neurodevelopmental and neurodegenerative disorders

Abstract

Missense mutations in the pore-forming α1-subunits of voltage-gated calcium channels (Cav) have been linked to a range of neurodevelopmental and neurodegenerative disorders such as autism, epilepsy, developmental delay and ataxia. Here we prove the pathogenicity of heterozygous variants in L-type Cav1.3 (CACNA1D) and P/Q-type Cav2.1 (CACNA1A) channels identified in patients with neurological pathologies using the whole-cell patch-clamp technique with heterologously expressed channel complexes. Previously, we demonstrated that pathogenic de novo missense mutations in the Cav1.3 channel gating machinery induce typical gating changes compatible with a gain-of-function phenotype.