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Annexin A6 modifies muscular dystrophy by mediating sarcolemmal repair.

  • Author(s): 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
  • et al.

Published Web Location

http://www.pnas.org/content/111/16/6004.long
No data is associated with this publication.
Abstract

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.

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