title: Clinical and molecular characterization of a severe form of partial lipodystrophy expanding the phenotype of PPARγ deficiency.
abstract: Familial partial lipodystrophy (FPLD) is characterized by abnormal fat distribution and a metabolic syndrome with hypertriglyceridemia. We identified a family with a severe form of FPLD3 with never-reported clinical features and a novel mutation affecting the DNA binding domain of PPARγ (E157D). Apart from the lipodystrophy and severe metabolic syndrome, individuals presented musculoskeletal and hematological issues. E157D heterozygotes had a muscular habitus yet displayed muscle weakness and myopathy. Also, E157D heterozygotes presented multiple cytopenias and a susceptibility to autoimmune disease. In vitro studies showed that the E157D mutation does not decrease the receptor's affinity to classical PPAR response elements or its responsiveness to a PPARγ agonist, yet it severely reduces its target gene transcription. Microarray experiments demonstrated a decreased activation of a wide array of genes, including genes involved in the PPAR response, the immune response, hematopoiesis, and metabolism in muscle. In addition, a subset of genes with cryptic PPAR response elements was activated. In summary, we describe a large family with a novel PPARγ mutation, which extends the clinical phenotype of FPLD3 to include muscular, immune, and hematological features. Together, our results support the role of PPARγ in controlling homeostasis of multiple systems beyond lipid metabolism.
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. pcampeau@bcm.edu
authors: Philippe M
authors: PM
authors: Campeau
authors: Olga
authors: O
authors: Astapova
authors: Rebecca
authors: R
authors: Martins
authors: Jean
authors: J
authors: Bergeron
authors: Patrick
authors: P
authors: Couture
authors: Robert A
authors: RA
authors: Hegele
authors: Todd
authors: T
authors: Leff
authors: Claude
authors: C
authors: Gagné
mesh_terms: D000328:Adult; D000818:Animals; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D052496:Lipodystrophy, Familial Partial / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D041681:NIH 3T3 Cells; D009928:Organ Specificity; D047495:PPAR gamma / Q000172:deficiency* / Q000235:genetics; D010641:Phenotype; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D047495:PPAR gamma