A Novel Lamin A Mutant Responsible for Congenital Muscular Dystrophy Causes Distinct Abnormalities of the Cell Nucleus

• Published in: PloS one 2017-01, Vol.12 (1), p.e0169189-e0169189
• Main Authors: Barateau, Alice, Vadrot, Nathalie, Vicart, Patrick, Ferreiro, Ana, Mayer, Michèle, Héron, Delphine, Vigouroux, Corinne, Buendia, Brigitte
• Format: Article
• Language: English
• Subjects: Abnormalities; Acetylation; Actin; Adolescent; Aging; Analysis; Animals; Biology and Life Sciences; Cardiomyopathy; Cell culture; Cell Nucleus - metabolism; Cell Nucleus - pathology; Cellular Senescence; Chromatin; Coding; Cytoskeleton; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drugs; Dystrophy; Female; Fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Filaments; Gene Expression; Gene mutation; Genetic aspects; Genomes; Histones - genetics; Histones - metabolism; Honeycomb construction; Humans; Intermediate filament proteins; Lamin Type A - genetics; Lamin Type A - metabolism; Lamins; Life Sciences; Lipodystrophy; Lipodystrophy - complications; Lipodystrophy - genetics; Lipodystrophy - metabolism; Lipodystrophy - pathology; Medicine and Health Sciences; Membrane proteins; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Microtubules; Muscular Dystrophies - complications; Muscular Dystrophies - genetics; Muscular Dystrophies - metabolism; Muscular Dystrophies - pathology; Muscular dystrophy; Mutation; Myoblasts; Myoblasts - metabolism; Myoblasts - pathology; Nuclear structure; Nuclei; Nuclei (cytology); Primary Cell Culture; Progeria; Proteins; Research and Analysis Methods; Risk factors; Senescence; Signal transduction; Skin; Skin - metabolism; Skin - pathology; Structure-function relationships
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0169189

A-type lamins, the intermediate filament proteins participating in nuclear structure and function, are encoded by LMNA. LMNA mutations can lead to laminopathies such as lipodystrophies, premature aging syndromes (progeria) and muscular dystrophies. Here, we identified a novel heterozygous LMNA p.R388P de novo mutation in a patient with a non-previously described severe phenotype comprising congenital muscular dystrophy (L-CMD) and lipodystrophy. In culture, the patient's skin fibroblasts entered prematurely into senescence, and some nuclei showed a lamina honeycomb pattern. C2C12 myoblasts were transfected with a construct carrying the patient's mutation; R388P-lamin A (LA) predominantly accumulated within the nucleoplasm and was depleted at the nuclear periphery, altering the anchorage of the inner nuclear membrane protein emerin and the nucleoplasmic protein LAP2-alpha. The mutant LA triggered a frequent and severe nuclear dysmorphy that occurred independently of prelamin A processing, as well as increased histone H3K9 acetylation. Nuclear dysmorphy was not significantly improved when transfected cells were treated with drugs disrupting microtubules or actin filaments or modifying the global histone acetylation pattern. Therefore, releasing any force exerted at the nuclear envelope by the cytoskeleton or chromatin did not rescue nuclear shape, in contrast to what was previously shown in Hutchinson-Gilford progeria due to other LMNA mutations. Our results point to the specific cytotoxic effect of the R388P-lamin A mutant, which is clinically related to a rare and severe multisystemic laminopathy phenotype.