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In the eye, these include anterior segment dysgenesis, optic nerve hypoplasia and retinal vascular tortuosity. Here we investigate the retinal pathology in mice carrying dominant-negative <jats:italic>Col4a1<\/jats:italic> mutations. To this end, we examined retinas longitudinally <jats:italic>in vivo<\/jats:italic> using fluorescein angiography, funduscopy and optical coherence tomography. We assessed retinal function by electroretinography and studied the retinal ultrastructural pathology. Retinal examinations revealed serous chorioretinopathy, retinal hemorrhages, fibrosis or signs of pathogenic angiogenesis with chorioretinal anastomosis in up to approximately 90% of <jats:italic>Col4a1<\/jats:italic> mutant eyes depending on age and the specific mutation. To identify the cell-type responsible for pathogenesis we generated a conditional <jats:italic>Col4a1<\/jats:italic> mutation and determined that primary vascular defects underlie <jats:italic>Col4a1<\/jats:italic>-associated retinopathy. We also found focal activation of M\u00fcller cells and increased expression of pro-angiogenic factors in retinas from <jats:italic>Col4a1<\/jats:italic><jats:sup>+\/\u0394<jats:italic>ex41<\/jats:italic><\/jats:sup>mice. Together, our findings suggest that patients with <jats:italic>COL4A1<\/jats:italic> and <jats:italic>COL4A2<\/jats:italic> mutations may be at elevated risk of retinal hemorrhages and that retinal examinations may be useful for identifying patients with <jats:italic>COL4A1<\/jats:italic> and <jats:italic>COL4A2<\/jats:italic> mutations who are also at elevated risk of hemorrhagic strokes.<\/jats:p>","DOI":"10.1038\/srep18602","type":"journal-article","created":{"date-parts":[[2016,1,27]],"date-time":"2016-01-27T10:12:28Z","timestamp":1453889548000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Col4a1 mutations cause progressive retinal neovascular defects and retinopathy"],"prefix":"10.1038","volume":"6","author":[{"given":"Marcel V.","family":"Alavi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mao","family":"Mao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bradley T.","family":"Pawlikowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manana","family":"Kvezereli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacque L.","family":"Duncan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard T.","family":"Libby","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon W. M.","family":"John","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas B.","family":"Gould","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,1,27]]},"reference":[{"key":"BFsrep18602_CR1","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/s00109-013-0993-5","volume":"91","author":"PA Campochiaro","year":"2013","unstructured":"Campochiaro, P. A. Ocular neovascularization. J Mol Med (Berl) 91, 311\u2013321 (2013).","journal-title":"J Mol Med (Berl)"},{"key":"BFsrep18602_CR2","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1126\/science.1109418","volume":"308","author":"DB Gould","year":"2005","unstructured":"Gould, D. B. et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. 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