A comprehensive map of missense trafficking variants in rhodopsin and their response to pharmacologic correction.

Authors

Kannan V Manian, Connor H Ludwig, Yan Zhao, Nathan S Abell, Robert Warneford-Thomson, Henry Chan, Zachary O Casey, Xiaoping Yang, David E Root, Matthew L Albert, Jason Comander

Published in

Science advances. Volume 12. Issue 31. Pages eaef3518. Jul 31, 2026. Epub Jul 29, 2026.

Abstract

Rhodopsin (RHO) missense variants are a leading cause of autosomal dominant retinitis pigmentosa (adRP), a progressive retinal degeneration. Interpreting RHO variant pathogenicity is challenging, and understanding their disease mechanisms is essential for developing therapeutics. We present a high-resolution map of RHO missense variant trafficking using deep mutational scanning approaches, including a surface abundance immunoassay and a complementary membrane proximity assay. This comprehensive, reproducible dataset encompassed all 6612 possible missense variants. Over 700 variants had pathogenic trafficking scores, substantially expanding the number of RHO variants with functional data. Trafficking scores correlated with the magnitude of ER stress markers and ClinVar pathogenicity classifications. Data also identified structurally clustered mutational intolerance around the intradiscal beta-plug region. Treatment with the chaperone YC-001 restored surface trafficking in most mistrafficking variants. This functional map of RHO variants provides a valuable resource for pathogenicity assessment, genotype-phenotype correlations, and the development of targeted therapeutic strategies for RHO-adRP.

PMID:
42525778
Bibliographic data and abstract were imported from PubMed on 30 Jul 2026.

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