Ocular Dysgenesis and Glaucoma

Mutations in type IV collagen alpha 1 (Col4a1) were originally identified because they cause highly penetrant ocular anterior segment dysgenesis (ASD) and elevated intraocular pressure (IOP) in mice. Human patients have also been identified with ASD and early onset glaucoma as a result of COL4A1 mutations. Subsequently, we discovered that the mutations can also cause optic nerve hypoplasia. The penetrance and severity of anterior and posterior ocular dysgenesis are both genetically rescued by changing the genetic context. Postdoctoral fellow Dr. Mao Mao is using modifier crosses and a conditional Col4a1 mutation to understand when, where and how mutations in Col4a1 cause anterior and posterior ocular dysgenesis.

Independently, we are also seeking to further understand ocular development and disease by identifying new genes and mechanisms that underlie anterior segment dysgenesis. Dr. Meredith Protas is analyzing whole–genome sequence from patients diagnosed with Axenfeld –Rieger syndrome that do not have mutations in previously identified genes. Using this approach we expect to identify novel genes and cellular pathways that are necessary for normal ocular development and that, when perturbed, cause ocular dysgenesis in human patients.


Depending on genetic context, Col4a1 mutant mice have retinopathy including loss of retinal-pigmented epithelium (RPE) and photoreceptor cells. COL4A1 is part of an elaborate extracellular matrix between the RPE and choroid called Bruch’s membrane. The outer two layers of Bruch’s membrane are basement membranes, which contain COL4A1 protein that is secreted either from the RPE (in the inner layer of Bruch’s membrane) or from the choroidal vascular endothelial cells (in the outer layer of Bruch’s membrane). Aspects of the retinopathy in Col4a1 mutant mice model Age-related macular degeneration, which is thought to result from a smoldering innate immune response to products of oxidative damage. Dr. Marcel Alavi is using genetic interactions and a conditional mutation to test the hypothesis that Col4a1 mutations cause retinopathy by causing ER stress and oxidative stress in the outer retina.

    Cerebral small vessel disease and hemorrhagic strokes

COL4A1 and COL4A2 mutations are a common cause of porencephaly – a rare and devastating disease characterized by cerebral white matter lesions and cystic cerebral cavities that often communicate with the lateral ventricles. Mutations in patients and mutant mice also cause highly penetrant cerebral small vessel disease that leads to multi-focal and recurrent intracerebral hemorrhages. In both cases, the eventual cerebrovascular complications likely arise from abnormalities in cerebral angiogenesis during development. We are working to understand the pathways by which COL4A1 and COL4A2 participate in normal cerebral angiogenesis.

    Walker–Warburg Syndrome and Muscle–Eye–Brain Disease

WWS and MEB are part of a spectrum of disease characterized by congenital muscular dystrophy, ocular dysgenesis and cerebral cortical lamination defects. The pleiotropic spectrum of Col4a1 pathology includes these hallmarks. In addition to ocular dysgenesis (described above) Dr. Cassandre Labelle–Dumais is using cell biology, allelic series and genetic modifiers to understand how Col4a1 and Col4a2 mutations influence cerebral cortical development and myopathy respectively.

Slit lamp examination of eyes from Col4a1+/+ (left column) and Col4a1 mutant/+ (right column) mice shows that the Col4a1 mutation causes anterior segment dysgenesis characterized by abnormal iris vasculature, open pupil, pigment dispersion, cataract (upper panel) and enlarged anterior chamber (lower panel).

Image of a retina (taken with a Micron III fundus camera) from a mouse with a mutation in Col4a1. The bright spot in the image is a large retinal lesion. Lesions such as these are often seen in patients with retinopathies such as Age-related macular degeneration.

Col4a1 Mut/+

Mutations in Col4a1 cause cerebrovascular diseases such as intracerebral hemorrhages (asterisks on the Magnetic Resonance Image (MRI) of the brain, left panel) and angiogenesis abnormalities (vascular tortuosity in the retina, center panel). We are investigating the mechanisms underlying these pathologies by studying the vascular basement membrane and the association of the different cell types that constitute the neurovascular unit (right panel).

In mice with mutations in Col4a1 or Col4a2 we identify breaches in the pial basement membrane (arrow and asterisk) that contribute to neuronal lamination defects and neural ectopias (arrow). These cerebral cortical lamination defects are also detected in patients with Walker–Warburg Syndrome and Muscle–Eye–Brain disease.