Structural and functional characterization of an achromatopsia-associated mutation in a phototransduction channel.
Commun Biol
; 5(1): 190, 2022 03 01.
Article
em En
| MEDLINE
| ID: mdl-35233102
ABSTRACT
Numerous missense mutations in cyclic nucleotide-gated (CNG) channels cause achromatopsia and retinitis pigmentosa, but the underlying pathogenic mechanisms are often unclear. We investigated the structural basis and molecular/cellular effects of R410W, an achromatopsia-associated, presumed loss-of-function mutation in human CNGA3. Cryo-EM structures of the Caenorhabditis elegans TAX-4 CNG channel carrying the analogous mutation, R421W, show that most apo channels are open. R421, located in the gating ring, interacts with the S4 segment in the closed state. R421W disrupts this interaction, destabilizes the closed state, and stabilizes the open state. CNGA3_R410W/CNGB3 and TAX4_R421W channels are spontaneously active without cGMP and induce cell death, suggesting cone degeneration triggered by spontaneous CNG channel activity as a possible cause of achromatopsia. Our study sheds new light on CNG channel allosteric gating, provides an impetus for a reevaluation of reported loss-of-function CNG channel missense disease mutations, and has implications for mutation-specific treatment of retinopathy.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Defeitos da Visão Cromática
/
Canais de Cátion Regulados por Nucleotídeos Cíclicos
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Commun Biol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos