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Mutations in collagen, type IV, alpha 1 (COL4A1), a major component of basement membranes, cause multisystem disorders in humans and mice. 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  Col4a1  mutations. To this end, we examined retinas longitudinally  in vivo  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  Col4a1  mutant eyes depending on age and the specific mutation. To identify the cell-type responsible for pathogenesis we generated a conditional  Col4a1  mutation and determined that primary vascular defects underlie  Col4a1 -associated retinopathy. We also found focal activation of Müller cells and increased expression of pro-angiogenic factors in retinas from  Col4a1  +/Δ ex41  mice. Together, our findings suggest that patients with  COL4A1  and  COL4A2  mutations may be at elevated risk of retinal hemorrhages and that retinal examinations may be useful for identifying patients with  COL4A1  and  COL4A2  mutations who are also at elevated risk of hemorrhagic strokes.

Col4a1 mutations cause progressive retinal neovascular defects and retinopathy