title: A mutation in the c-fos gene associated with congenital generalized lipodystrophy.
abstract: BACKGROUND
  Congenital generalized lipodystrophy (CGL) or Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare genetic syndrome characterized by the absence of adipose tissue. As CGL is thought to be related to malfunctions in adipocyte development, genes involved in the mechanisms of adipocyte biology and maintenance or differentiation of adipocytes, especially transcription factors are candidates. Several genes (BSCL1-4) were found to be associated to the syndrome but not all CGL patients carry mutations in these genes.
  
  
  RESULTS
  In a patient with CGL and insulin resistance we investigated the known candidate genes but the patient did not carry a relevant mutation. Analyses of the insulin activated signal transduction pathways in isolated fibroblasts of the patient revealed a postreceptor defect altering expression of the immediate early gene c-fos. Sequence analyses revealed a novel homozygous point mutation (c.-439, T→A) in the patients' c-fos promoter. The point mutation was located upstream of the well characterized promoter elements in a region with no homology to any known cis-elements. The identified mutation was not detected in a total of n=319 non lipodystrophic probands. In vitro analyses revealed that the mutation facilitates the formation of a novel and specific protein/DNA complex. Using mass spectrometry we identified the proteins of this novel complex. Cellular investigations demonstrate that the wild type c-fos promoter can reconstitute the signaling defect in the patient, excluding further upstream signaling alterations, and vice versa the investigations with the c-fos promoter containing the identified mutation generally reduce basal and inducible c-fos transcription activity. As a consequence of the identified point mutation gene expression including c-Fos targeted genes is significantly altered, shown exemplified in cells of the patient.
  
  
  CONCLUSIONS
  The immediate-early gene c-fos is one essential transcription factor to initiate adipocyte differentiation. According to the role of c-fos in adipocyte differentiation our findings of a mutation that initiates a repression mechanism at c-fos promoter features the hypothesis that diminished c-fos expression might play a role in CGL by interfering with adipocyte development.
authors.affiliation: Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at the Heinrich-Heine-University Duesseldorf, Leibniz Center for Diabetes Research, Duesseldorf, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Knebel
authors.forename: Jorg
authors.initials: J
authors.lastname: Kotzka
authors.forename: Stefan
authors.initials: S
authors.lastname: Lehr
authors.forename: Sonja
authors.initials: S
authors.lastname: Hartwig
authors.forename: Haluk
authors.initials: H
authors.lastname: Avci
authors.forename: Sylvia
authors.initials: S
authors.lastname: Jacob
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nitzgen
authors.forename: Martina
authors.initials: M
authors.lastname: Schiller
authors.forename: Winfried
authors.initials: W
authors.lastname: März
authors.forename: Michael M
authors.initials: MM
authors.lastname: Hoffmann
authors.forename: Eva
authors.initials: E
authors.lastname: Seemanova
authors.forename: Jutta
authors.initials: J
authors.lastname: Haas
authors.forename: Dirk
authors.initials: D
authors.lastname: Muller-Wieland
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000502:physiology; D000328:Adult; D002454:Cell Differentiation; D005260:Female; D015870:Gene Expression; D017781:Genes, Immediate-Early; D016762:Genes, fos / Q000235:genetics* / Q000502:physiology; D006801:Humans; D052497:Lipodystrophy, Congenital Generalized / Q000235:genetics*; D017354:Point Mutation
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