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Lamin A/C–mediated neuromuscular junction defects in Emery-Dreifuss muscular dystrophy

¹ National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
² Institut National de la Santé et de la Recherche Médicale, Unite Mixte de Recherche U582, Institut de Myologie, Paris F-75013, France
³ Université Pierre et Marie Curie, University Paris 06, Unite Mixte de Recherche S582, Institut Federatif de Recherche 14, Paris F-75013, France
⁴ School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
⁵ Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC 20010
⁶ Institute of Medical Biology, Immunos, Singapore City 138668, Singapore
⁷ Assistance Publique, Hôpitaux de Paris, Groupe Hospitalier Pitié Salpêtrière, Unité Fonctionnelle de Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris F-75013, France

Correspondence to Tom Misteli: mistelit{at}mail.nih.gov

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.

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