Novel CACNA1A Variant p.Cys256Phe Disrupts Disulfide Bonds and Causes Spinocerebellar Ataxia.
Mov Disord
; 37(2): 401-404, 2022 02.
Article
in En
| MEDLINE
| ID: mdl-34647648
ABSTRACT
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Calcium Channels
/
Spinocerebellar Ataxias
Type of study:
Etiology_studies
/
Prognostic_studies
Limits:
Female
/
Humans
/
Middle aged
Language:
En
Journal:
Mov Disord
Journal subject:
NEUROLOGIA
Year:
2022
Type:
Article
Affiliation country:
Austria