Cav1.4 congenital stationary night blindness is associated with an increased rate of proteasomal degradation

Frontiers in Cell and Developmental Biology

Cell and Developmental Biology

Tal T. Sadeh¹  Forbes Manson¹  Graeme C. Black²  Richard A. Baines³ 

[1] Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom;Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom;Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Manchester University NHS Foundation Trust, St Mary’s Hospital, Manchester, United Kingdom;Division of Neuroscience, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom;

关键词: Ca1.4;    CACNA1;    voltage-gated calcium channel;    variant pathogenicity;    proteasome inhibitor;    bortezomib;   

DOI  :  10.3389/fcell.2023.1161548

 received in 2023-02-08, accepted in 2023-04-17,  发布年份 2023

来源: Frontiers

【 摘 要 】

Pathogenic, generally loss-of-function, variants in CACNA1F, encoding the Cav1.4α1 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 Cav1.4α 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 mechanism and suggested that the mutant Cav1.4α proteins were degraded by the proteasome. We showed that the reduced current for these variants could be significantly increased through treatment with clinical proteasome inhibitors. In addition to facilitating clinical interpretation, these studies suggest that proteasomal inhibition represents an avenue of potential therapeutic intervention for CSNB2.

【 授权许可】

Unknown   
Copyright © 2023 Sadeh, Baines, Black and Manson.