title: Expression of a mutant lamin A that causes Emery-Dreifuss muscular dystrophy inhibits in vitro differentiation of C2C12 myoblasts.
abstract: Autosomal dominantly inherited missense mutations in lamins A and C cause several tissue-specific diseases, including Emery-Dreifuss muscular dystrophy (EDMD) and Dunnigan-type familial partial lipodystrophy (FPLD). Here we analyze myoblast-to-myotube differentiation in C2C12 clones overexpressing lamin A mutated at arginine 453 (R453W), one of the most frequent mutations in EDMD. In contrast with clones expressing wild-type lamin A, these clones differentiate poorly or not at all, do not exit the cell cycle properly, and are extensively committed to apoptosis. These disorders are correlated with low levels of expression of transcription factor myogenin and with the persistence of a large pool of hyperphosphorylated retinoblastoma protein. Since clones mutated at arginine 482 (a site responsible for FPLD) differentiate normally, we conclude that C2C12 clones expressing R453W-mutated lamin A represent a good cellular model to study the pathophysiology of EDMD. Our hypothesis is that lamin A mutated at arginine 453 fails to build a functional scaffold and/or to maintain the chromatin compartmentation required for differentiation of myoblasts into myocytes.
authors.affiliation: Département de Biologie Cellulaire, Institut Jacques Monod, CNRS, Universités Paris 6 & 7, 75251 Paris cedex 05, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Favreau
authors.forename: Dominique
authors.initials: D
authors.lastname: Higuet
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Courvalin
authors.forename: Brigitte
authors.initials: B
authors.lastname: Buendia
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D002453:Cell Cycle; D002454:Cell Differentiation; D002460:Cell Line; D018507:Gene Expression Regulation, Developmental; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D024510:Muscle Development; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism; D009928:Organ Specificity; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism
chemical_list: D015415:Biomarkers; D034904:Lamin Type A; D018809:Proliferating Cell Nuclear Antigen; D016160:Retinoblastoma Protein