Ca_v1.4 congenital stationary night blindness is associated with an increased rate of proteasomal degradation.

ABSTRACT: Pathogenic, generally loss-of-function, variants in CACNA1F, encoding the Ca_v1.4α₁ calcium channel, underlie congenital stationary night blindness type 2 (CSNB2), a rare inherited retinal disorder associated with visual disability. To establish the underlying pathomechanism, we investigated 10 clinically derived CACNA1F missense variants located across pore-forming domains, connecting loops, and the carboxy-tail domain of the Ca_v1.4α subunit. Homology modeling showed that all variants cause steric clashes; informatics analysis correctly predicted pathogenicity for 7/10 variants. In vitro analyses demonstrated that all variants cause a decrease in current, global expression, and protein stability and act through a loss-of-function mechan

SUBMITTER: Sadeh TT 

PROVIDER: S-EPMC10188973 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature