title: High prevalence of laminopathies among patients with metabolic syndrome.
abstract: Constitutional laminopathies, such as the Dunnigan familial partial lipodystrophy, are severe diseases caused by mutations in A-type lamins and share several features with metabolic syndrome (MS). In this study, we hypothesized that MS may be, in some cases, a mild form of laminopathies and use the abnormal cell nucleus phenotype observed in these diseases as a primary screening test in patients suffering from common MS. Nuclear shape and lamin A nucleoplasmic distribution abnormalities were systematically searched in lymphoblastoid cells of 87 consecutive patients with MS. In parallel, five genes encoding either the A-type lamins or the enzymes of the lamin A maturation pathway were systematically sequenced (LMNA, ZMPSTE24, ICMT, FNTA and FNTB). We identified 10 MS patients presenting abnormal nuclear shape and disturbed lamin A/C nuclear distribution. These patients were not clinically different from those without nuclear abnormalities except that they were younger, and had higher triglyceridemia and SGPT levels. Three of them carry a heterozygous mutation in LMNA or in ZMPSTE24, a gene encoding one of the lamin A processing enzymes. All three mutations are novel missense mutations predicted to be damaging. Both lymphoblastoid cells and skin fibroblasts from the patient carrying the mutation in ZMPSTE24, showed accumulation of lamin A precursor, indicating an alteration of the lamin A processing, confirmed by functional study. Together, these results show for the first time, that a significant proportion of MS patients exhibits laminopathies and suggest that systematic investigation of lamin A and its partners should be performed at the diagnosis of this syndrome.
authors: INSERM UMR_S626, Université de la Méditerranée, Marseille, France.
authors: Anne
authors: A
authors: Dutour
authors: Patrice
authors: P
authors: Roll
authors: Bénédicte
authors: B
authors: Gaborit
authors: Sébastien
authors: S
authors: Courrier
authors: Marie-Christine
authors: MC
authors: Alessi
authors: David-Alexandre
authors: DA
authors: Tregouet
authors: Fabien
authors: F
authors: Angelis
authors: Andrée
authors: A
authors: Robaglia-Schlupp
authors: Nathalie
authors: N
authors: Lesavre
authors: Pierre
authors: P
authors: Cau
authors: Nicolas
authors: N
authors: Lévy
authors: Catherine
authors: C
authors: Badens
authors: Pierre-Emmanuel
authors: PE
authors: Morange
mesh_terms: D000328:Adult; D015331:Cohort Studies; D005260:Female; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D020125:Mutation, Missense
chemical_list: D034904:Lamin Type A; D008565:Membrane Proteins; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human