PPARG F388L, a Transactivation-Deficient Mutant, in Familial Partial Lipodystrophy

Abstract

Autosomal dominant familial partial lipodystrophy (FPLD) due to mutant LMNA encoding nuclear lamin A/C is characterized by adipose tissue repartitioning together with multiple metabolic disturbances, including insulin resistance and dyslipidemia. There is emerging evidence that some rare mutations in peroxisome proliferator-activated receptor-␥ (PPAR-␥), encoded by PPARG, might be associated with human lipodystrophy. We report a three-generation Canadian kindred ascertained based upon partial lipodystrophy, with a normal LMNA gene sequence. Candidate gene sequencing showed that all four affected subjects were heterozygous for a novel T3 A mutation at PPARG nucleotide 1164 in exon 5 that predicted substitution of phenylalanine at codon 388 by leucine (F388L). The mutation was absent from normal family members and normal unrelated subjects, and altered a highly conserved residue within helix 8 of the predicted ligand-binding pocket of PPAR-␥. The mutant receptor had significantly decreased basal transcriptional activity and impaired stimulation by a synthetic ligand. The germline transmission of a transactivation-deficient mutation in PPARG suggests that autosomal dominant partial lipodystrophy is genetically heterogeneous. Our findings are consistent with the idea that mutant PPARG can underlie the partial lipodystrophy phenotype. Diabetes 51: 3586 -3590, 2002

Lessons from human mutations in PPARγ

“…LMNA R482Q was associated with early coronary heart disease, while among the PPARg mutations, only F388L was associated with early coronary heart disease. 17,22 Body mass index was relatively normal, emphasizing that these patients show abnormal fat distribution and not increased fat mass. Elevated TG and lower HDL were ubiquitous among subjects with both molecular types of lipodystrophy.…”

“…We discovered PPARg F388L in a three-generation Canadian lipodystrophy kindred, 22 in whom LMNA sequence was normal. The mutation was absent from 520 normal alleles and co-segregated with the lipodystrophy phenotype.…”

“…Comparisons of fold changes in quantitative traits were against normal matched family controls for LMNA R482Q 16,17 and PPARg F388L 22 and against the normal reference ranges for other subjects. Qualitative assessment of fat distribution indicated differences between the two molecular types of lipodystrophy.…”

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

“…1) (Chan et al, 2010;Zieleniak et al, 2008). Single amino acid mutations within these functional domains result in severe defects in PPAR function that affect lipid metabolism and insulin resistance (Agostini et al, 2006;Barroso et al, 1999;Hegele et al, 2002;Ristow et al, 1998). PPAR heterodimerization with RXRs leads to binding of the peroxisome proliferator response element independent of ligand.…”

Fat poetry: a kingdom for PPARγ

“…In addition, four members of a same family were identified, who suffered from a transactivation deficient mutant PPARg, namely PPARgF388L, which changes a highly conserved residue of helix 8 of the ligand-binding pocket [193]. All four patients were heterozygous carriers and presented partial lipodystrophy as well as hyperinsulinemia.…”