title: A Novel Lamin A Mutant Responsible for Congenital Muscular Dystrophy Causes Distinct Abnormalities of the Cell Nucleus.
abstract: 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.
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative (BFA), CNRS UMR 8251, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Barateau
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative (BFA), CNRS UMR 8251, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vadrot
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative (BFA), CNRS UMR 8251, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Vicart
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative (BFA), CNRS UMR 8251, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Ana
authors.initials: A
authors.lastname: Ferreiro
authors.affiliation: Centre de Référence des Maladies Neuromusculaires de l'Est Parisien, Secteur Pédiatrique, Hôpital d'Enfants Armand Trousseau, Paris, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Mayer
authors.affiliation: Centre de Référence Déficiences Intellectuelles, Département de Génétique et INSERM U975, Groupe hospitalier Pitié-Salpétrière, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Héron
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 6, Inserm UMR_S938, Centre de Recherche Saint-Antoine, Institute of Cardiometabolism and Nutrition (ICAN), AP-HP, Hôpital Saint-Antoine, Laboratoire Commun de Biologie et Génétique Moléculaires et Service d'Endocrinologie Diabétologie et Endocrinologie de la Reproduction, Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Vigouroux
authors.affiliation: Unité de Biologie Fonctionnelle et Adaptative (BFA), CNRS UMR 8251, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Brigitte
authors.identifier: http://orcid.org/0000-0002-0249-0088
authors.initials: B
authors.lastname: Buendia
mesh_terms: D000107:Acetylation; D000293:Adolescent; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D016922:Cellular Senescence; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D008060:Lipodystrophy / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009136:Muscular Dystrophies / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D012867:Skin / Q000378:metabolism / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; C494847:LMNA protein, human; D034904:Lamin Type A; D008565:Membrane Proteins; C093413:lamina-associated polypeptide 2