Résumé :
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Lamin A and C, encoded by LMNA gene, localize at the inner face of the nuclear membrane and interact with multiple proteins and DNA. Mutations reported all along the LMNA gene are responsible for multiple diseases including Emery-Dreifuss muscular dystrophy (EDMD). Among them, the deletion of the lysine 32 leads to a severe phenotype with the first clinical signs appearing before the age of 2 and a loss of ambulation before the age of 10. Homozygous knock-in mice reproducing this mutation show a pronounced reduction of lamin A/C protein levels. At birth, they are undistinguishable from their wild type littermates but they rapidly develop an overall growth retardation in weight and size and die around 15 days of life. Histological analysis of mutant muscles shows a reduction of fibre cross section area, an increased proportion of fibres with central nuclei and embryonic myosin heavy chains expression compared to wild type littermates resembling a maturation defect. Culture of mutant myoblasts shows no reduction of myoblasts proliferation but a delayed differentiation with major nuclear abnormalities: several nuclear proteins interacting with lamin A/C are mislocalized, the chromatin is abnormally distributed and the nuclear shape is severely altered. In conclusion, these preliminary data suggest that KI-LmnadelK32 mice rapidly develop severe and progressive signs of muscular dystrophy probably due to improper post-natal muscular differentiation.
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