title: A single-base mutation in the peroxisome proliferator-activated receptor gamma4 promoter associated with altered in vitro expression and partial lipodystrophy.
abstract: Familial partial lipodystrophy (FPLD) results from coding sequence mutations either in LMNA, encoding nuclear lamin A/C, or in PPARG, encoding peroxisome proliferator-activated receptor gamma (PPARgamma). The LMNA form is called FPLD2 (MIM 151660), and the PPARG form is called FPLD3 (MIM 604367). We now report a 21-yr-old female with FPLD and no coding sequence mutations in either LMNA or PPARG. She was heterozygous for a novel A>G mutation at position -14 of intron B upstream of PPARG exon 1 within the promoter of the PPARgamma4 isoform. Her less severely affected father, who had features of the metabolic syndrome and a paucity of limb and gluteal fat, was also heterozygous for -14A>G. This mutation was absent among 600 alleles from normal Caucasians. A minimal promoter sequence bearing the mutation had significantly reduced promoter activity when used to drive reporter expression in in vitro expression in two cell lines, compared with the wild-type sequence. This is the first report of a human mutation in the promoter of a PPARgamma isoform. Because the mutation affects PPARgamma4 expression and is associated with FPLD, this implies that PPARgamma4 might be important for fat depot distribution and metabolism in vivo.
authors.affiliation: Robarts Research Institute, Division of Endocrinology, University of Western Ontario, London, Ontario, Canada N6A 5K8.
authors.forename: Khalid
authors.initials: K
authors.lastname: Al-Shali
authors.forename: Henian
authors.initials: H
authors.lastname: Cao
authors.forename: Nine
authors.initials: N
authors.lastname: Knoers
authors.forename: Ad R
authors.initials: AR
authors.lastname: Hermus
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Tack
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
mesh_terms: D041721:3T3-L1 Cells; D000328:Adult; D000818:Animals; D003923:Diabetes Mellitus, Lipoatrophic / Q000235:genetics*; D005260:Female; D006801:Humans; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics*; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms
chemical_list: D047495:PPAR gamma; D020033:Protein Isoforms