Abstract
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+/Δex41mice. 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.
Highlights
Diseases involving abnormal proliferation of blood vessels in the retina, including diabetic retinopathy and age-related macular degeneration, are common causes of sudden and severe vision loss[1]
We have previously reported that Col4a1Δex[41] causes ocular anterior segment dysgenesis on a B6 background that is suppressed in a 129B6F1 genetic context[13]
In Col4a1+/Δex[41] mice between postnatal day (P) 18 and P21, 6 out of 88 eyes had anterior segment dysgenesis, microphthalmia, corneal abrasions or lens opacities that precluded in vivo retinal imaging (Table 1)
Summary
Diseases involving abnormal proliferation of blood vessels in the retina, including diabetic retinopathy and age-related macular degeneration, are common causes of sudden and severe vision loss[1]. Assembled and modified heterotrimers advance through the secretory pathway to the extracellular space where they polymerize into a network and interact with other extracellular matrix proteins to form basement membranes[5,11,12]. Col4a1+/Δex[41] mice on a C57BL/6J (B6) genetic background have relatively severe ocular pathology including cataracts, anterior segment dysgenesis, optic nerve hypoplasia, and glaucoma[13,16]. We include retinal imaging of an allelic series of genetically matched Col4a1 and Col4a2 mutant mice. We developed a conditional Col4a1 mutation with which to genetically dissect differential cell-type contributions and identify the primary site of pathogenesis for retinopathy. We propose that patients with COL4A1 or COL4A2 mutations may be at risk for developing vision-threatening retinopathy
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