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Mao Mao, Debbie Kuo, Cassandre Labelle-Dumais, Marion Jeanne, Jack Favor, Douglas B. Gould; Allelic influence of Col4a1 and Col4a2 in anterior segment dysgenesis in mice. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4923.
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© ARVO (1962-2015); The Authors (2016-present)
Anterior segment dysgenesis (ASD) is a spectrum of congenital disorders affecting anterior structures of the eye that can lead to glaucoma. ASD can be variable between patients and mutations in different genes, allelic heterogeneity, or genetic modifiers can all contribute to the phenotypic variability. Mutations in COL4A1 (type IV collagen alpha 1) were recently identified to cause ASD in some patients. COL4A1 and its binding partner COL4A2 are major components of basement membranes. COL4A1 and COL4A2 form heterotrimers in the endoplasmic reticulum before being secreted into the extracellular space where they form a network. Most COL4A1 mutations occur in the triple helix-forming domain that is crucial heterotrimer for assembly. These mutations typically impair proper heterotrimer formation leading to ER retention and intracellular accumulation at the expense of secretion. Not all patients with COL4A1 mutations have ASD and allelic heterogeneity is one possible explanation for the reduced penetrance. Therefore, the purpose of this study was to understand the contribution of different alleles to the spectrum of ASD pathology using mouse models.
Seven different Col4a1 mutations and one Col4a2 mutation were bred into the C57BL/6J genetic background. All mutations except one are missense mutations within the triple helix domain. Clinical analysis of anterior segments was performed to assess the ASD phenotype. Histological analysis of the optic nerves was performed to test the severity of optic nerve hypoplasia. In addition, intracellular accumulation and extracellular secretion of COL4A1 or COL4A2 were analyzed by Western blot.
All mutations caused ASD including cloudy corneas, abnormal iris vasculature, iridocorneal adhesions, pigment dispersion, cataract and enlarged anterior chamber. However, the strains differed in phenotypic expressivity, penetrance and severity. Four mutations caused optic nerve hypoplasia. Molecular analysis revealed three classes of mutations. Most mutations showed increased intracellular accumulation and impaired secretion. However, one mutation showed secretion deficits without significant accumulation, and another mutation was not significantly different from wildtype for accumulation or secretion.
Our results demonstrate phenotypic and molecular heterogeneity among Col4a1 and Col4a2 mutations. Whether the phenotypic heterogeneity reflects a mechanistic heterogeneity remains to be tested.
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