Human Molecular Genetics Advance Access published online on November 17, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddi017
© 2004 by Oxford University Press
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1 Inserm UR582, Institut de Myologie, GH Pitié-Salpêtrière, 75 013 Paris, France; Inserm IFR14, GH Pitié-Salpêtrière, Paris, France
* To whom correspondence should be addressed. Laminopathies are a group of disorders caused by mutations in the LMNA gene encoding A-type lamins, components of the nuclear lamina. Three of these disorders affect specifically the skeletal and/or cardiac muscles, and their pathogenic mechanisms are still unknown. We chose the LMNA H222P missense mutation identified in a family with autosomal dominant Emery-Dreifuss muscular dystrophy, one of the striated muscle specific laminopathies, to create a faithful mouse model of this type of laminopathy. The mutant mice exhibit overtly normal embryonic development and sexual maturity. At adulthood, male homozygous mice display reduced locomotion activity with abnormal stiff walking posture and all of them die by 9 months of age. As for cardiac phenotype, they develop chamber dilation and hypokinesia with conduction defects. These abnormal skeletal and cardiac features were also observed in the female homozygous mice but with a later onset than in males. Histopathological analysis of the mice revealed muscle degeneration with fibrosis associated with dislocation of heterochromatin and activation of Smad signaling in heart and skeletal muscles. These results demonstrate that LmnaH222P/H222P mice represent a good model for studying laminopathies affecting striated muscles as they develop a dystrophic condition of both skeletal and cardiac muscles similar to the human diseases.
Article
Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies
2 Service des Maladies Cardiovasculaires, Centre Hospitalier Général, 91160 Longjumeau, France
3 Centre d'Immunologie de Marseille-Luminy, Inserm-CNRS-Université de la Méditerranée, Parc Scientifique de Luminy, 13 000 Marseille, France
4 Veterinary Basic Siences, The Royal Veterinary College, London NW1 OTU, UK
5 Inserm IFR14, GH Pitié-Salpêtrière, Paris, France; Service de Cardiologie, GH Pitié-Salpêtrière, 75013 Paris, France
6 Inserm UR582, Institut de Myologie, Bâtiment Babinski, Groupe Hospitalier Pitié-Salpétrière, 47 boulevard de l'Hôpital, 75 651 Paris Cedex 13, France; Inserm IFR14, GH Pitié-Salpêtrière, Paris, France
Gisèle Bonne, E-mail: g.bonne{at}myologie.chups.jussieu.fr
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