Annexin A6 modifies muscular dystrophy by mediating sarcolemmal repair.
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.
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.
Kayleigh A
KA
Swaggart
Alexis R
AR
Demonbreun
Andy H
AH
Vo
Kaitlin E
KE
Swanson
Ellis Y
EY
Kim
John P
JP
Fahrenbach
Jenan
J
Holley-Cuthrell
Ascia
A
Eskin
Zugen
Z
Chen
Kevin
K
Squire
Ahlke
A
Heydemann
Abraham A
AA
Palmer
Stanley F
SF
Nelson
Elizabeth M
EM
McNally
D000009:Abdominal Muscles / Q000473:pathology; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D017317:Annexin A6 / Q000235:genetics / Q000378:metabolism*; D033481:Chromosomes, Mammalian / Q000235:genetics; D004198:Disease Susceptibility; D060045:Genes, Modifier; D014644:Genetic Variation; D006352:Heart Ventricles / Q000473:pathology; D042541:Intracellular Space / Q000378:metabolism; D008566:Membranes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000473:pathology*; D009929:Organ Size; D021381:Protein Transport; D040641:Quantitative Trait Loci / Q000235:genetics; D012508:Sarcolemma / Q000378:metabolism* / Q000473:pathology*; D014945:Wound Healing / Q000235:genetics
D017317:Annexin A6
dystrophin; muscle; plasma membrane