Annexin A6 modifies muscular dystrophy by mediating sarcolemmal repair

KA Swaggart, AR Demonbreun… - Proceedings of the …, 2014 - National Acad Sciences
KA Swaggart, AR Demonbreun, AH Vo, KE Swanson, EY Kim, JP Fahrenbach
Proceedings of the National Academy of Sciences, 2014National Acad Sciences
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 …
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.
National Acad Sciences