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The ABCA4 protein is a phospholipid-retinoid flippase in the outer segments of photoreceptors and the internal membranes of retinal pigment epithelial (RPE) cells. Here, we show that RPE cells derived via induced pluripotent stem-cell from a molecularly and clinically diagnosed STGD1 patient exhibited reduced ABCA4 protein and diminished activity compared to a normal subject. Consequently, STGD1 RPE cells accumulated intracellular autofluorescence-lipofuscin and displayed increased complement C3 activity. The level of C3 inversely correlated with the level of CD46, an early negative regulator of the complement cascade. Persistent complement dysregulation led to deposition of the membrane attack complex on the surface of RPE cells, decrease in transepithelial resistance, and subsequent cell death. These findings are strong evidence of complement-mediated RPE cell damage in STGD1, in the absence of photoreceptors, caused by reduced CD46 regulatory protein.<\/jats:p>","DOI":"10.3390\/cells11213462","type":"journal-article","created":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T03:36:44Z","timestamp":1667360204000},"page":"3462","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Membrane Attack Complex Mediates Retinal Pigment Epithelium Cell Death in Stargardt Macular Degeneration"],"prefix":"10.3390","volume":"11","author":[{"given":"Eunice","family":"Ng","sequence":"first","affiliation":[{"name":"UCLA Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, CA 90095, USA"},{"name":"Molecular Cellular and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nermin","family":"Kady","sequence":"additional","affiliation":[{"name":"UCLA Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, CA 90095, USA"},{"name":"Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Hu","sequence":"additional","affiliation":[{"name":"UCLA Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arpita","family":"Dave","sequence":"additional","affiliation":[{"name":"UCLA Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhichun","family":"Jiang","sequence":"additional","affiliation":[{"name":"UCLA Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Pei","sequence":"additional","affiliation":[{"name":"UCLA Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9498-7982","authenticated-orcid":false,"given":"Michael","family":"Gorin","sequence":"additional","affiliation":[{"name":"UCLA Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0120-4876","authenticated-orcid":false,"given":"Anna","family":"Matynia","sequence":"additional","affiliation":[{"name":"UCLA Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5064-6403","authenticated-orcid":false,"given":"Roxana","family":"Radu","sequence":"additional","affiliation":[{"name":"UCLA Stein Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1126\/science.277.5333.1805","article-title":"Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration","volume":"277","author":"Allikmets","year":"1997","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.1167\/iovs.13-13624","article-title":"Quantitative fundus autofluorescence in recessive Stargardt disease","volume":"55","author":"Burke","year":"2014","journal-title":"Investig. 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