Human Molecular Genetics Advance Access published online on June 13, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm137
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Activation of MAPK in hearts of Emd null mice: similarities between mouse models of X-linked and autosomal dominant Emery-Dreifuss muscular dystrophy
1 Departments of Medicine and of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, USA 2 Department of Biomedical Informatics, College of Physicians and Surgeons, Columbia University, New York, USA 3 Institut National de la Santé et de la Recherche Médicale, U582, Institut de Myologie, Paris, France 4 Université Pierre et Marie Curie-Paris 6, Faculté de médecine, Paris, France 5 AP-HP, Groupe hospitalier Pitié-Salpêtrière, U.F. Myogénétique et Cardiogénétique, service de Biochimie Métabolique, Paris, France 6 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
* Correspondence: Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, 10 Floor, Room 508, New York, NY 10032, USA; Phone: 212-305-8156, Fax: 212-305-6443, Email: hjw14{at}columbia.edu
Received April 25, 2007; Revised May 16, 2007; Accepted May 18, 2007
Emery-Dreifuss muscular dystrophy (EDMD) is an inherited disorder characterized by slowly progressive skeletal muscle weakness in a humero-peroneal distribution, early contractures and prominent cardiomyopathy with conduction block. Mutations in EMD, encoding emerin, and LMNA, encoding A-type lamins, respectively cause X-linked and autosomal dominant EDMD. Emerin and A-type lamins are proteins of the inner membrane of the nuclear envelope. Whereas the genetic cause of EDMD has been described and the proteins well characterized, little is known on how abnormalities in nuclear envelope proteins cause skeletal muscle disease. In this study, we analyzed genome-wide expression profiles in hearts from Emd knock-out mice, a model of X-linked EDMD, using Affymetrix GeneChips. This analysis showed a molecular signature similar to that we previously described in hearts from Lmna H222P knock-in mice, a model of autosomal dominant EDMD. There was a common activation of the ERK1/2 branch of the mitogen-activated protein kinase (MAPK) pathway in both murine models, as well as activation of downstream targets implicated in the pathogenesis of cardiomyopathy. Activation of MAPK signaling appears to be a cornerstone in the development of heart disease in both X-linked and autosomal dominant EDMD.
# Present Address: UBC Bioinformatics Centre, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
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