Allelic heterogeneity contributes to variability in ocular dysgenesis, myopathy and brain malformations caused byCol4a1 and Col4a2mutations

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Collagen type IV alpha 1 and 2 (COL4A1 and COL4A2) are present in nearly all basement membranes.COL4A1andCOL4A2mutations are pleiotropic, affecting multiple organ systems to differing degrees, and both genetic-context and environmental factors influence this variable expressivity. Here, we report important phenotypic and molecular differences in an allelic series ofCol4a1andCol4a2mutant mice that are on a uniform genetic background. We evaluated three organs commonly affected byCOL4A1andCOL4A2mutations and discovered allelic heterogeneity in the penetrance and severity of ocular dysgenesis, myopathy and brain malformations. Similarly, we show allelic heterogeneity in COL4A1 and COL4A2 biosynthesis. While most mutations that we examined caused increased intracellular and decreased extracellular COL4A1 and COL4A2, we identified three mutations with distinct biosynthetic signatures. Reduced temperature or presence of 4-phenylbutyrate ameliorated biosynthetic defects in primary cell lines derived from mutant mice. Together, our data demonstrate the effects and clinical implications of allelic heterogeneity inCol4a1- andCol4a2-related diseases. Understanding allelic differences will be valuable for increasing prognostic accuracy and for the development of therapeutic interventions that consider the nature of the molecular cause in patients withCOL4A1andCOL4A2mutations.

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