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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.