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Mao Mao, Marion Jeanne, Tanav Popli, Kendall Hoff, Saunak Sen, Douglas B Gould; Identification of genetic modifier underlying COL4A1-related anterior segment dysgenesis in mice. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3662.
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© ARVO (1962-2015); The Authors (2016-present)
Anterior segment dysgenesis (ASD) describes a spectrum of congenital disorders affecting anterior structures of the eye that can lead to glaucoma. ASD phenotypes are variable between patients, and mutations in different genes, allelic heterogeneity, or genetic modifiers can all contribute to the phenotypic variability. Previously we showed that mice with a mutation in the gene encoding collagen type IV alpha1 (COL4A1) develop multi-system disorders including ASD, myopathy and hemorrhagic stroke on the C57BL/6J background. When the mutation was crossed to the CAST/EiJ background, the phenotypes were largely suppressed. This project aims to investigate new mechanisms of ASD by identifying modifiers that ameliorate pathology caused by Col4a1 mutations.
We performed a quantitative trait locus (QTL) mapping analysis in the F2 progeny of C57BL/6J and CAST/EiJ mice with the Col4a1 mutation to identify modifier loci for ASD. We did slit-lamp examinations to assess the extent of ASD and scored the severity. We genotyped 192 mice at 646 markers and performed a genome scan to identify QTL. Genome-wide significance was established using permutation testing. To test if the loci for ASD also modify other phenotypes, we also performed QTL mapping for myopathy. We then generated congenic strains to validate the loci. We also assessed levels of intracerebral hemorrhages on these congenic strains to test if the loci for ASD also modify hemorrhagic stroke.
We identified a 21Mbp modifier locus on chromosome 1 (LOD score = 11.20) for ASD. The same locus was also identified as the only modifier locus for myopathy (LOD score = 5.61). Congenic mice in which the CAST/EiJ chromosomal region containing the modifier locus had been crossed to the C57BL/6J background developed milder ASD and myopathy than their non-congenic C57BL/6J littermates. However, levels of intracerebral hemorrhages were similar between the two strains.
Our results suggest that there is a single modifier locus for Col4a1-related ASD and myopathy on CAST/EiJ Chromosome 1. The suppressor of ASD and myopathy does not ameliorate hemorrhage stroke, suggesting the modifier can be tissue-specific and different mechanisms are involved. Identification of the modifier gene could reveal novel mechanisms for ASD etiology.
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