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

Houshang Monajemi, Lin Zhang, Gang Li, Ellen H. Jeninga, Henian Cao, Mario Maas, C. B. Brouwer, Eric Kalkhoven, Erik Stroes, Robert A. Hegele, Todd Leff
2007 Journal of Clinical Endocrinology and Metabolism  
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
more » ... 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 C3 T mutation in the PPARG gene that led to the substitution of arginine 194 in PPAR␥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␥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. (J Clin Endocrinol Metab 92: 1606 -1612, 2007) The study was approved by the University of Western Ontario Ethics Review Panel (protocol 07920E), and the subject gave informed consent to participate. First
doi:10.1210/jc.2006-1807 pmid:17299075 fatcat:fpwaxrsjqzd6bp2h2kmqxq5qim