title: A homozygous mutation of prelamin-A preventing its farnesylation and maturation leads to a severe lipodystrophic phenotype: new insights into the pathogenicity of nonfarnesylated prelamin-A.
abstract: BACKGROUND
  Mutations in LMNA, encoding A-type lamins, lead to multiple laminopathies, including lipodystrophies, progeroid syndromes, and cardiomyopathies. Alterations in the prelamin-A posttranslational maturation, resulting in accumulation of farnesylated isoforms, cause human progeroid syndromes. Accumulation of mutant nonfarnesylated prelamin-A leads to cardiomyopathy or progeria in mice, but no data have been provided in humans. OBJECTIVE, DESIGN, SETTING, AND PATIENTS: We searched for LMNA mutations in seven women originating from Reunion Island who were referred for a severe lipodystrophic syndrome. Clinical, molecular, genealogical, and cellular studies were performed in probands and relatives.
  
  
  RESULTS
  The seven probands showed a severe partial lipodystrophic syndrome with diabetes and/or acanthosis nigricans, liver steatosis, hypertriglyceridemia, and low serum leptin and adiponectin levels. Three probands also had severe cardiac rhythm and conduction disturbances. We identified in all probands a homozygous LMNA p.T655fsX49 mutation leading to expression of a mutated prelamin-A with 48 aberrant C-terminal amino acids, preventing its physiological posttranslational farnesylation and maturation. Genealogical and haplotype analyses were consistent with a founder mutation transmitted from a common ancestor in the 17th century. In probands' cultured fibroblasts, mutated prelamin-A was associated with typical laminopathic nuclear dysmorphies, increased oxidative stress, and premature senescence. Heterozygous relatives were asymptomatic or partially affected, in favor of a codominant transmission of the disease with incomplete penetrance in heterozygotes.
  
  
  CONCLUSIONS
  We reveal that a homozygous mutation of prelamin-A preventing its farnesylation leads to a severe lipodystrophic laminopathy in humans, which can be associated with cardiac conduction disturbances, stressing the pathogenicity of nonfarnesylated prelamin-A in human laminopathies.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche S938, Centre de Recherche Saint-Antoine, F-75012 Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Le Dour
authors.forename: Stéphane
authors.initials: S
authors.lastname: Schneebeli
authors.forename: Fawzi
authors.initials: F
authors.lastname: Bakiri
authors.forename: Françoise
authors.initials: F
authors.lastname: Darcel
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Jacquemont
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Maubert
authors.forename: Martine
authors.initials: M
authors.lastname: Auclair
authors.forename: Dorota
authors.initials: D
authors.lastname: Jeziorowska
authors.forename: Yves
authors.initials: Y
authors.lastname: Reznik
authors.forename: Véronique
authors.initials: V
authors.lastname: Béréziat
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Capeau
authors.forename: Olivier
authors.initials: O
authors.lastname: Lascols
authors.forename: Corinne
authors.initials: C
authors.lastname: Vigouroux
mesh_terms: D000052:Acanthosis Nigricans / Q000235:genetics; D052242:Adiponectin / Q000097:blood; D000328:Adult; D001145:Arrhythmias, Cardiac / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000648:ultrastructure; D018703:Founder Effect; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics; D034904:Lamin Type A / Q000235:genetics; D020738:Leptin / Q000097:blood; D008060:Lipodystrophy / Q000097:blood* / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics*; D018384:Oxidative Stress / Q000502:physiology; D010641:Phenotype; D054876:Prenylation / Q000235:genetics*; D011498:Protein Precursors / Q000096:biosynthesis* / Q000235:genetics*; D055815:Young Adult
chemical_list: D052242:Adiponectin; C494847:LMNA protein, human; D034904:Lamin Type A; D020738:Leptin; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A