{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T11:19:43Z","timestamp":1788866383928,"version":"build-2803163510"},"reference-count":46,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T00:00:00Z","timestamp":1718755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute of the National Institutes of Health","doi-asserted-by":"publisher","award":["1K08EY032991"],"award-info":[{"award-number":["1K08EY032991"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute of the National Institutes of Health","doi-asserted-by":"publisher","award":["P30EY007003"],"award-info":[{"award-number":["P30EY007003"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Choroideremia Research Foundation","award":["1K08EY032991"],"award-info":[{"award-number":["1K08EY032991"]}]},{"name":"Choroideremia Research Foundation","award":["P30EY007003"],"award-info":[{"award-number":["P30EY007003"]}]},{"name":"Choroideremia Research Foundation Canada","award":["1K08EY032991"],"award-info":[{"award-number":["1K08EY032991"]}]},{"name":"Choroideremia Research Foundation Canada","award":["P30EY007003"],"award-info":[{"award-number":["P30EY007003"]}]},{"name":"Research to Prevent Blindness","award":["1K08EY032991"],"award-info":[{"award-number":["1K08EY032991"]}]},{"name":"Research to Prevent Blindness","award":["P30EY007003"],"award-info":[{"award-number":["P30EY007003"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cells"],"abstract":"<jats:p>Choroideremia is an X-linked chorioretinal dystrophy caused by mutations in CHM, encoding Rab escort protein 1 (REP-1), leading to under-prenylation of Rab GTPases (Rabs). Despite ubiquitous expression of CHM, the phenotype is limited to degeneration of the retina, retinal pigment epithelium (RPE), and choroid, with evidence for primary pathology in RPE cells. However, the spectrum of under-prenylated Rabs in RPE cells and how they contribute to RPE dysfunction remain unknown. A CRISPR\/Cas-9-edited CHM\u2212\/\u2212 iPSC-RPE model was generated with isogenic control cells. Unprenylated Rabs were biotinylated in vitro and identified by tandem mass tag (TMT) spectrometry. Rab12 was one of the least prenylated and has an established role in suppressing mTORC1 signaling and promoting autophagy. CHM\u2212\/\u2212 iPSC-RPE cells demonstrated increased mTORC1 signaling and reduced autophagic flux, consistent with Rab12 dysfunction. Autophagic flux was rescued in CHM\u2212\/\u2212 cells by transduction with gene replacement (ShH10-CMV-CHM) and was reduced in control cells by siRNA knockdown of Rab12. This study supports Rab12 under-prenylation as an important cause of RPE cell dysfunction in choroideremia and highlights increased mTORC1 and reduced autophagy as potential disease pathways for further investigation.<\/jats:p>","DOI":"10.3390\/cells13121068","type":"journal-article","created":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T11:47:17Z","timestamp":1718797637000},"page":"1068","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Reduced Retinal Pigment Epithelial Autophagy Due to Loss of Rab12 Prenylation in a Human iPSC-RPE Model of Choroideremia"],"prefix":"10.3390","volume":"13","author":[{"given":"Maide \u00d6.","family":"Raeker","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirosha D.","family":"Perera","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athanasios J.","family":"Karoukis","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kecia L.","family":"Feathers","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin R.","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"KCL Center for Cell and Gene Therapy, London WC2R 2LS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra A.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Michigan, Ann Arbor, MI 48105, USA"},{"name":"Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9737-054X","authenticated-orcid":false,"given":"Abigail T.","family":"Fahim","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"OCT377","DOI":"10.1167\/iovs.15-18421","article-title":"Visual Function and Central Retinal Structure in Choroideremia","volume":"57","author":"Heon","year":"2016","journal-title":"Investig. 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