A comprehensive map of missense trafficking variants in rhodopsin and their response to pharmacologic correction DOI Creative Commons
Kannan V. Manian, Connor H. Ludwig, Yan Zhao

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 4, 2025

Abstract Rhodopsin ( RHO ) missense variants are a leading cause of autosomal dominant retinitis pigmentosa (adRP), progressive retinal degeneration with no currently approved therapies. Interpreting the pathogenicity growing number identified is major clinical challenge, and understanding their disease mechanisms essential for developing effective Here, we present high-resolution map variant trafficking using two complementary deep mutational scanning (DMS) approaches based on surface abundance immunoassay membrane proximity assay. We generated comprehensive dataset encompassing all 6,612 possible single-residue variants, revealing strong correlation between methods. Over 700 were pathogenic scores, significantly expanding functional evidence supporting pathogenicity. demonstrate high concordance scores ClinVar classifications, highlighting this approach’s utility in resolving uncertain significance (VUS). The data also structurally clustered trafficking-deficient predominantly within N-terminal region second extracellular loop, above extracellular/intradiscal beta-plug region. Furthermore, evaluated efficacy non-retinoid pharmacological chaperone YC-001, observing significant rescue defects majority mistrafficking variants. This provides valuable resource assessment, genotype-phenotype correlations, development targeted therapeutic strategies -adRP, paving way improved diagnosis treatment patients.

Язык: Английский

A comprehensive map of missense trafficking variants in rhodopsin and their response to pharmacologic correction DOI Creative Commons
Kannan V. Manian, Connor H. Ludwig, Yan Zhao

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 4, 2025

Abstract Rhodopsin ( RHO ) missense variants are a leading cause of autosomal dominant retinitis pigmentosa (adRP), progressive retinal degeneration with no currently approved therapies. Interpreting the pathogenicity growing number identified is major clinical challenge, and understanding their disease mechanisms essential for developing effective Here, we present high-resolution map variant trafficking using two complementary deep mutational scanning (DMS) approaches based on surface abundance immunoassay membrane proximity assay. We generated comprehensive dataset encompassing all 6,612 possible single-residue variants, revealing strong correlation between methods. Over 700 were pathogenic scores, significantly expanding functional evidence supporting pathogenicity. demonstrate high concordance scores ClinVar classifications, highlighting this approach’s utility in resolving uncertain significance (VUS). The data also structurally clustered trafficking-deficient predominantly within N-terminal region second extracellular loop, above extracellular/intradiscal beta-plug region. Furthermore, evaluated efficacy non-retinoid pharmacological chaperone YC-001, observing significant rescue defects majority mistrafficking variants. This provides valuable resource assessment, genotype-phenotype correlations, development targeted therapeutic strategies -adRP, paving way improved diagnosis treatment patients.

Язык: Английский

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