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

作者：Kannan Vrindavan Manian, Connor Ludwig, Yan Zhao, Nathan S. Abell, Robert Warneford-Thomson, Henry Chan, Zachary O. Casey, Xiaoping Yang, David E. Root, Matthew L. Albert, Jason Comander · 发表于：Science Advances · 年份：2026 · DOI：10.1126/sciadv.aef3518 · 被引用次数：3 · 研究领域：Receptor Mechanisms and Signaling、Photoreceptor and optogenetics research、Neuroscience and Neuropharmacology Research

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