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Proc Natl Acad Sci U S A. 2014 Apr 22;111(16):6004-9. doi: 10.1073/pnas.1324242111. Epub 2014 Apr 9.

Annexin A6 modifies muscular dystrophy by mediating sarcolemmal repair.

Author information

1
Department of Human Genetics, Department of Medicine, Committee on Development, Regeneration and Stem Cell Biology, Department of Pathology, Molecular Pathogenesis and Molecular Medicine and Department of Psychiatry, University of Chicago, Chicago, IL 60637.

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.

KEYWORDS:

dystrophin; muscle; plasma membrane

PMID:
24717843
PMCID:
PMC4000833
DOI:
10.1073/pnas.1324242111
[Indexed for MEDLINE]
Free PMC Article
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