Lamin A/C-mediated neuromuscular junction defects in Emery-Dreifuss muscular dystrophy.
The LMNA gene encodes lamins A and C, two intermediate filament-type proteins that are important determinants of interphase nuclear architecture. Mutations in LMNA lead to a wide spectrum of human diseases including autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD), which affects skeletal and cardiac muscle. The cellular mechanisms by which mutations in LMNA cause disease have been elusive. Here, we demonstrate that defects in neuromuscular junctions (NMJs) are part of the disease mechanism in AD-EDMD. Two AD-EDMD mouse models show innervation defects including misexpression of electrical activity-dependent genes and altered epigenetic chromatin modifications. Synaptic nuclei are not properly recruited to the NMJ because of mislocalization of nuclear envelope components. AD-EDMD patients with LMNA mutations show the same cellular defects as the AD-EDMD mouse models. These results suggest that lamin A/C-mediated NMJ defects contribute to the AD-EDMD disease phenotype and provide insights into the cellular and molecular mechanisms for the muscle-specific phenotype of AD-EDMD.
Méjat
Alexandre
A
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Decostre
Valérie
V
Li
Juan
J
Renou
Laure
L
Kesari
Akanchha
A
Hantaï
Daniel
D
Stewart
Colin L
CL
Xiao
Xiao
X
Hoffman
Eric
E
Bonne
Gisèle
G
Misteli
Tom
T
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009121:Muscle Denervation; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000294:innervation / Q000648:ultrastructure; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009469:Neuromuscular Junction / Q000473:pathology*; D021381:Protein Transport
C494847:LMNA protein, human; D034904:Lamin Type A