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 alpha 1-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 alpha 1- 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.

Automated summary

The novel C256F variant in the Cav2.1 Ca2+ channel alpha 1-subunit is found to have pathogenicity in SCA, affecting channel function and contributing to the disease phenotype.