A Single-Base Mutation in the Peroxisome Proliferator-Activated Receptor γ4 Promoter Associated with Altered in Vitro Expression and Partial Lipodystrophy

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 γ (PPARγ). 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 PPARγ4 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 PPARγ isoform. Because the mutation affects PPARγ4 expression and is associated with FPLD, this implies that PPARγ4 might be important for fat depot distribution and metabolism in vivo.