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Familial Partial Lipodystrophy Phenotype Resulting from a Single-Base Mutation in Deoxyribonucleic Acid-Binding Domain of Peroxisome Proliferator-Activated Receptor-

Department of Vascular Medicine (H.M., E.S.) and Radiology (M.M.), Academic Medical Center, 1150 AZ Amsterdam, The Netherlands; Department of Pathology (L.Z., G.L., T.L.), Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, Michigan 48201; Department of Metabolic and Endocrine Diseases (E.H.J., E.K.), University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands; Robarts Research Institute and Schulich School of Medicine (H.C., R.A.H.), London, Ontario, Canada N6A 5K8; and Department of Internal Medicine (C.B.B.), Onze Lieve Vrouwe Gasthuis, 1090 HM Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Houshang Monajemi, Academic Medical Center, Department of Vascular Medicine, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. E-mail: H.monajemi{at}amc.uva.nl; or Robert A. Hegele, Robarts Research Institute, London, Ontario, Canada N6A 5K8. E-mail: hegele{at}robarts.ca.

Context: 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).

Objective: Our objective was to investigate whether the clinical phenotype of this proband is due to mutation(s) in PPAR.

Design: This is a case report.

Patient and Setting: A 31-yr-old female with the clinical phenotype of FPLD3, i.e. lipodystrophy and early childhood diabetes with extreme insulin resistance and hypertriglyceridemia leading to recurrent pancreatitis, was assessed at an academic medical center.

Results: The proband was heterozygous for a novel CT mutation in the PPARG gene that led to the substitution of arginine 194 in PPAR2 isoform, a conserved residue located in the zinc finger structure involved in DNA binding, by tryptophan (R194W). The mutation was absent from the genomes of 100 healthy Caucasians. In vitro analysis of the mutated protein showed that R194W (and R166W in PPAR1 isoform) could not bind to DNA and had no transcriptional activity. Furthermore, R194W had no dominant-negative activity.

Conclusions: The R194W mutation in PPARG disrupts its DNA binding activity and through haploinsufficiency leads to clinical manifestation of FPLD3 and the associated metabolic disturbances.

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