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This version published online on February 13, 2007
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-1807
A more recent version of this article appeared on May 1, 2007
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Submitted on August 17, 2006
Accepted on February 7, 2007

Familial partial lipodystrophy phenotype resulting from a single-base mutation in DNA binding domain of peroxisome proliferator-activated receptor gamma

Houshang Monajemi*, Lin Zhang, Gang Li, Ellen H. Jeninga, Henian Cao, Mario Maas, C. B. Brouwer, Eric Kalkhoven, Erik Stroes, Robert A. Hegele, and Todd Leff

Department of vascular medicine, and radiology, Academic Medical Center, Amsterdam, The Netherlands; Department of Pathology, Center for Integrative Metabolic & Endocrine Research, Wayne State University School of Medicine, Detroit, Michigan, USA; Department of Metabolic and Endocrine Diseases, UMC Utrecht, The Netherlands; Robarts Research Institute and Schulich School of Medicine, London, Ontario, Canada; Department of Internal Medicine, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands

* To whom correspondence should be addressed. E-mail: H.monajemi{at}amc.uva.nl.

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 gamma (PPAR{gamma}). The LMNA form is called FPLD2 (MIM 151660) and the PPARG form is called FPLD3 (MIM 604367).

Objective: To investigate whether the clinical phenotype of this proband is due to mutation(s) in PPAR{gamma}.

Design: Case report

Setting: Academic medical center

Patient: 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.

Results: The proband was heterozygous for a novel C > T mutation in PPARG gene that led to the substitution of arginine 194 in PPAR{gamma}2 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 PPAR{gamma}1 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.
Key words: FPLD • lipodystrophy • PPAR{gamma} • haploinsufficiency • dominant negative




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