title: New PPARG mutation leads to lipodystrophy and loss of protein function that is partially restored by a synthetic ligand.
abstract: OBJECTIVE
  Familial partial lipodystrophy caused by mutations in the PPARG gene is characterised by altered distribution of subcutaneous fat, muscular hypertrophy and symptoms of metabolic syndrome. PPARG encodes peroxisome proliferator-activated receptor (PPAR)gamma, a nuclear hormone receptor playing a crucial role in lipid and glucose metabolism and in several other cellular regulatory processes.
  
  
  METHODS
  PPARG was screened for mutations by direct sequencing in two patients with lipodystrophy, one unaffected family member and 124 controls. Body composition was examined in affected patients, and they were investigated for abnormalities in laboratory results. Functional analysis of the mutant protein was assessed by determining transcriptional activity and possible interference with the wild-type protein.
  
  
  RESULTS
  In two patients with familial partial lipodystrophy, we identified a nucleotide substitution in the PPARG gene. This mutation results in the substitution of aspartate by asparagine at residue 424 (D424N) in the ligand-binding domain of PPARgamma. The unaffected family member and all 124 controls did not carry this mutation. D424N PPARgamma had a significantly lower ability than wild-type PPARgamma to activate a PPARgamma-stimulated reporter gene, but did not exert a negative effect on the wild-type protein. Partial activation of D424N PPARgamma was achieved in the presence of the agonist rosiglitazone.
  
  
  CONCLUSIONS
  We report a new PPARG mutation, D424N, which is located in the ligand-binding domain of the protein and leads to familial partial lipodystrophy. D424N PPARgamma exhibited a loss of function, which was partially restored by adding the PPARgamma agonist rosiglitazone, suggesting possible treatment potential of this agent.
authors.affiliation: Departments of Medicine and of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Angelika
authors.initials: A
authors.lastname: Lüdtke
authors.forename: Janine
authors.initials: J
authors.lastname: Buettner
authors.forename: Hartmut H-J
authors.initials: HH
authors.lastname: Schmidt
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Worman
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D052496:Lipodystrophy, Familial Partial / Q000188:drug therapy / Q000235:genetics*; D024821:Metabolic Syndrome / Q000235:genetics; D020125:Mutation, Missense; D047495:PPAR gamma / Q000819:agonists / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone