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Annexin A6 modifies muscular dystrophy by mediating sarcolemmal repair
- Swaggart, Kayleigh A., Demonbreun, Alexis R., Vo, Andy H., Swanson, Kaitlin E., Kim, Ellis Y., Fahrenbach, John P., Holley-Cuthrell, Jenan, Eskin, Ascia, Chen, Zugen, Squire, Kevin, Heydemann, Ahlke, Palmer, Abraham A., Nelson, Stanley F., McNally, Elizabeth M.
- Proceedings of the National Academy of Sciences of the United States of America 2014 v.111 no.16 pp. 6004-6009
- RNA, animal models, cardiomyopathy, exons, heart, image analysis, loci, modifiers (genes), muscular dystrophy, mutation, phenotypic variation, quantitative trait loci, sequence analysis
- Many monogenic disorders, including the muscular dystrophies, display phenotypic variability despite the same disease-causing mutation. To identify genetic modifiers of muscular dystrophy and its associated cardiomyopathy, we used quantitative trait locus mapping and whole genome sequencing in a mouse model. This approach uncovered a modifier locus on chromosome 11 associated with sarcolemmal membrane damage and heart mass. Whole genome and RNA sequencing identified Anxa6 , encoding annexin A6, as a modifier gene. A synonymous variant in exon 11 creates a cryptic splice donor, resulting in a truncated annexin A6 protein called ANXA6N32. Live cell imaging showed that annexin A6 orchestrates a repair zone and cap at the site of membrane disruption. In contrast, ANXA6N32 dramatically disrupted the annexin A6-rich cap and the associated repair zone, permitting membrane leak. Anxa6 is a modifier of muscular dystrophy and membrane repair after injury.