{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T19:44:32Z","timestamp":1775936672300,"version":"3.50.1"},"posted":{"date-parts":[[2025,3,4]]},"group-title":"Genomics","reference-count":63,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T00:00:00Z","timestamp":1741046400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Rhodopsin (\n                  <jats:italic>RHO<\/jats:italic>\n                  ) 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\n                  <jats:italic>RHO<\/jats:italic>\n                  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\n                  <jats:italic>RHO<\/jats:italic>\n                  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\n                  <jats:italic>RHO<\/jats:italic>\n                  variants with functional evidence supporting pathogenicity. We demonstrate a high concordance between the trafficking scores and ClinVar pathogenicity classifications, highlighting this approach\u2019s 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 a majority of mistrafficking variants. This comprehensive functional map of\n                  <jats:italic>RHO<\/jats:italic>\n                  missense variants provides a valuable resource for pathogenicity assessment, genotype-phenotype correlations, and the development of targeted therapeutic strategies for\n                  <jats:italic>RHO<\/jats:italic>\n                  -adRP, paving the way for improved diagnosis and treatment for patients.\n                <\/jats:p>","DOI":"10.1101\/2025.02.27.640335","type":"posted-content","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T13:05:34Z","timestamp":1741093534000},"source":"Crossref","is-referenced-by-count":2,"title":["A comprehensive map of missense trafficking variants in rhodopsin and their response to pharmacologic correction"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1764-2424","authenticated-orcid":false,"given":"Kannan V.","family":"Manian","sequence":"first","affiliation":[{"name":"Ocular Genomics Institute, Berman-Gund Laboratory for the Study of Retinal Degenerations, Mass Eye and Ear, Harvard Medical School, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9159-7628","authenticated-orcid":false,"given":"Connor H.","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Octant, Inc., Emeryville, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4987-5325","authenticated-orcid":false,"given":"Yan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Ocular Genomics Institute, Berman-Gund Laboratory for the Study of Retinal Degenerations, Mass Eye and Ear, Harvard Medical School, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1098-5395","authenticated-orcid":false,"given":"Nathan","family":"Abell","sequence":"additional","affiliation":[{"name":"Octant, Inc., Emeryville, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoping","family":"Yang","sequence":"additional","affiliation":[{"name":"Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5122-861X","authenticated-orcid":false,"given":"David E.","family":"Root","sequence":"additional","affiliation":[{"name":"Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7285-6973","authenticated-orcid":false,"given":"Matthew L.","family":"Albert","sequence":"additional","affiliation":[{"name":"Octant, Inc., Emeryville, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4257-7145","authenticated-orcid":false,"given":"Jason","family":"Comander","sequence":"additional","affiliation":[{"name":"Ocular Genomics Institute, Berman-Gund Laboratory for the Study of Retinal Degenerations, Mass Eye and Ear, Harvard Medical School, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041112005312000_2025.02.27.640335v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.289.5480.739"},{"key":"2026041112005312000_2025.02.27.640335v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01803-6"},{"key":"2026041112005312000_2025.02.27.640335v1.3","doi-asserted-by":"crossref","unstructured":"Yang, D. , et al. G protein-coupled receptors: structure- and function-based drug discovery. 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