title: Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy.
abstract: BACKGROUND
  Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare recessive disease characterized by near absence of adipose tissue, resulting in severe dyslipidemia and insulin resistance. In most reported cases, BSCL is due to alterations in either seipin, of unknown function, or 1-acylglycerol-3-phosphate acyltransferase-beta (AGPAT2), which catalyzes the formation of phosphatidic acid.
  
  
  OBJECTIVE
  We sought to determine the genetic origin of the unexplained cases of BSCL. We thus sequenced CAV1, encoding caveolin-1, as a candidate gene involved in insulin signaling and lipid homeostasis. CAV1 is a key structural component of plasma membrane caveolae, and Cav1-deficient mice display progressive loss of adipose tissue and insulin resistance.
  
  
  METHODS
  We undertook phenotyping studies and molecular screening of CAV1 in four patients with BSCL with no mutation in the genes encoding either seipin or AGPAT2.
  
  
  RESULTS
  A homozygous nonsense mutation (p.Glu38X) was identified in CAV1 in a patient with BSCL born from a consanguineous union. This mutation affects both the alpha- and beta-CAV1 isoforms and ablates CAV1 expression in skin fibroblasts. Detailed magnetic resonance imaging of the proband confirmed near total absence of both sc and visceral adipose tissue, with only vestigial amounts in the dorsal sc regions. In keeping with the lack of adipose tissue, the proband was also severely insulin resistant and dyslipidemic. In addition, the proband had mild hypocalcemia likely due to vitamin D resistance.
  
  
  CONCLUSIONS
  These findings identify CAV1 as a new BSCL-related gene and support a critical role for caveolins in human adipocyte function.
authors.affiliation: Department of Pediatrics, Instituto da Criança, University of Sao Paulo, 05403-900 Sao Paulo, Brazil.
authors.forename: C A
authors.initials: CA
authors.lastname: Kim
authors.forename: Marc
authors.initials: M
authors.lastname: Delépine
authors.forename: Emilie
authors.initials: E
authors.lastname: Boutet
authors.forename: Haquima
authors.initials: H
authors.lastname: El Mourabit
authors.forename: Soazig
authors.initials: S
authors.lastname: Le Lay
authors.forename: Muriel
authors.initials: M
authors.lastname: Meier
authors.forename: Mona
authors.initials: M
authors.lastname: Nemani
authors.forename: Etienne
authors.initials: E
authors.lastname: Bridel
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Leite
authors.forename: Debora R
authors.initials: DR
authors.lastname: Bertola
authors.forename: Robert K
authors.initials: RK
authors.lastname: Semple
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dugail
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Capeau
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Magré
mesh_terms: D017667:Adipocytes / Q000502:physiology; D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D051242:Caveolin 1 / Q000235:genetics* / Q000502:physiology; D018389:Codon, Nonsense; D005260:Female; D006801:Humans; D052497:Lipodystrophy, Congenital Generalized / Q000235:genetics*
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; D018389:Codon, Nonsense