Strain-Dependent Anterior Segment Dysgenesis and Progression to Glaucoma inCol4a1Mutant Mice

Abstract

Citation: Mao M, Smith RS, Alavi MV, et al. Strain-dependent anterior segment dysgenesis and progression to glaucoma in Col4a1 mutant mice. Invest Ophthalmol Vis Sci. 2015;56:6823-6831. DOI:10.1167/iovs.15-17527 PURPOSE. Mutations in the gene encoding collagen type IV alpha 1 (COL4A1) cause multisystem disorders including anterior segment dysgenesis (ASD) and optic nerve hypoplasia. The penetrance and severity of individual phenotypes depends on genetic context. Here, we tested the effects of a Col4a1 mutation in two different genetic backgrounds to compare how genetic context influences ocular dysgenesis, IOP, and progression to glaucoma.METHODS. Col4a1 mutant mice maintained on a C57BL/6J background were crossed to either 129S6/SvEvTac or CAST/EiJ and the F1 progeny were analyzed by slit-lamp biomicroscopy and optical coherence tomography. We also measured IOPs and compared tissue sections of eyes and optic nerves.RESULTS. We found that the CAST/EiJ inbred strain has a relatively uniform and profound suppression on the effects of Col4a1 mutation and that mutant CASTB6F1 mice were generally only very mildly affected. In contrast, mutant 129B6F1 mice had more variable and severe ASD and IOP dysregulation that were associated with glaucomatous signs including lost or damaged retinal ganglion cell axons and excavation of the optic nerve head.CONCLUSIONS. Ocular defects in Col4a1 mutant mice model ASD and glaucoma that are observed in a subset of patients with COL4A1 mutations. We demonstrate that different inbred strains of mice give graded severities of ASD and we detected elevated IOP and glaucomatous damage in 129B6F1, but not CASTB6F1 mice that carried a Col4a1 mutation. These data demonstrate that genetic context differences are one factor that may contribute to the variable penetrance and severity of ASD and glaucoma in patients with COL4A1 mutations.

Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations

“…Soon after, heterozygous, semi-dominant pathogenic COL4A1 and COL4A2 mutations were identified in humans and in multiple mouse lines that model the pathology in patients 15–17 . Consistent with the broad distribution of α1(IV) 2 α2(IV) heterotrimers in nearly all basement membranes, COL4A1 and COL4A2 mutations cause multisystem disorders with abnormalities in the vasculature, brain, eyes, kidneys and muscles being the most commonly reported to date 18–20 . Cerebrovascular disease (CVD) is one of the most notable consequences of COL4A1 and COL4A2 mutations and comprises a growing constellation of clinical manifestations including porencephaly, small-vessel disease, leukoencephalopathy, intracranial aneurysms and recurrent intracerebral hemorrhages (ICH).…”

“…Because of procedural differences between research groups, notably the focus and depth of analysis, it is difficult to directly compare graded levels of relative severities for each mutation. Importantly, the genetic context in which the mutations are studied also has a significant effect on the penetrance and/or severity of pathology 18, 80, 101, 111 . For example, Col4a1 mutant mice maintained on a pure C57BL/6J background have severe ocular dysgenesis, myopathy and ICH that are all suppressed in mutant mice that were crossed for a single generation to the CAST/EiJ inbred strain 15, 18, 80, 101, 111 .…”

“…Importantly, the genetic context in which the mutations are studied also has a significant effect on the penetrance and/or severity of pathology 18, 80, 101, 111 . For example, Col4a1 mutant mice maintained on a pure C57BL/6J background have severe ocular dysgenesis, myopathy and ICH that are all suppressed in mutant mice that were crossed for a single generation to the CAST/EiJ inbred strain 15, 18, 80, 101, 111 . Notably, the 129SvEvTac inbred strain also suppressed anterior segment dysgenesis, but not ICH, indicating that genetic context can have differential effects on distinct phenotypes and suggesting heterogeneity in the pathogenic mechanisms underlying different Col4a1 -related phenotypes 101 .…”

Col4a1 mutations cause progressive retinal neovascular defects and retinopathy

“…Col4a1 +/Δ ex41 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 . Dysgenesis and cataracts in Col4a1 +/Δ ex41 mice on a B6 background make it difficult to image and study retinal phenotypes, however, these defects are genetically modified when crossed once (F1) to 129S6/SvEvTac (129) mice 13 16 . Most Col4a1 +/Δ ex41 129B6F1 mice have only mild anterior segment dysgenesis allowing visualization of the retinas in vivo .…”

The Progress of BMP4 on the Role of Ocular Development and Eye Diseases

“…Fluorescein angiography showed the presence of leakage in the vitreous body fluorescein small vascular tortuous dense network of vitreous body vascular anomalies lead to the lens and retina adhesion aggravate retinal detachment, thus obtains the BMP4 on the development of normal lens plays an important role. Maruyama et al (2006) Investigated the expression of BMP4 in the developing retina (Mao et al, 2015). In E19, a very strong BMP4 Immunoreactivity (IR) was found in the nerve fiber layer.…”