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A Single-Base Mutation in the Peroxisome Proliferator-Activated Receptor 4 Promoter Associated with Altered in Vitro Expression and Partial Lipodystrophy

Robarts Research Institute (K.A.-S., H.C., R.A.H.) and Division of Endocrinology (K.A.-S., R.A.H.), University of Western Ontario, London, Ontario, Canada N6A 5K8; and Departments of Human Genetics (N.K.), Endocrinology (A.R.H.), and General Internal Medicine (C.J.T.), University Medical Centre, 6500 HB Nijmegen, The Netherlands

Address all correspondence and requests for reprints to: Robert A. Hegele, M.D., F.R.C.P.(C), F.A.C.P., Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 406–100 Perth Drive, London, Ontario, Canada N6A 5K8. E-mail: robert.hegele{at}rri.on.ca.

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 (PPAR). 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 PPAR4 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 PPAR isoform. Because the mutation affects PPAR4 expression and is associated with FPLD, this implies that PPAR4 might be important for fat depot distribution and metabolism in vivo.

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