Novel CACNA1A Variant p.Cys256Phe Disrupts Disulfide Bonds and Causes Spinocerebellar Ataxia.

Background Spinocerebellar ataxia (SCA) is a progressive, autosomal dominant neurodegenerative disorder typically associated with CAG repeat expansions. Objective We assessed the pathogenicity of the novel, heterozygous missense variant p.Cys256Phe (C256F) in the pore-forming α1-subunit of the Cav2.1 Ca2+ channel found in a 63-year-old woman with SCA with no CAG repeat expansion. Methods We examined the effect of the C256F variant on channel function using whole-cell patch-clamp recordings in transfected tsA-201 cells. Results The maximum Ca2+ current density was significantly reduced in the mutant compared to wild-type, which could not be explained by lower expression levels of mutant Cav2.1 α1- protein. Together with a significant increase in current inactivation, this is consistent with a loss of channel function. Molecular modeling predicted disruption of a conserved disulfide bond through the C256F variant. Conclusions Our results support the pathogenicity of the C256F variant for the SCA phenotype and provide further insight into Cav2.1 structure and function.