We have screened the human PPARγ gene in a cohort of subjects with severe insulin resistance and identified defects in nine unrelated families. Heterozygous mutations in affected individuals cosegregate with a phenotype which includes stereotyped (gluteal, limb) partial lipodystrophy, early-onset hypertension, dyslipidaemia and hepatic steatosis. Pathogenesis of the phenotype involves abnormal metabolism of dietary fat intake, with elevated circulating lipids and fat oxidation.
Mutant receptors are functionally impaired and we have delineated three distinct molecular mechanisms: two missense mutants (P467L, V290M) inhibit wild type PPARγ action in a dominant negative manner via enhanced recruitment of corepressor; a loss-of-function, truncation mutant (FSX) in the DNA binding domain, which lacks dominant negative activity, leads to insulin resistance only in combination with a second unrelated gene (PPP1R3) defect; novel mutants in the DNA (C114R, C131Y, C162W) or ligand binding (R357X, fsV315X) domains also limit WT receptor action in a dominant negative manner but may act by sequestering limiting cofactors. PPARγ target gene responses in primary cells from subjects provide ex vivo evidence for differing dominant negative properties of mutant receptors and expression profiling of these cells will further elucidate pathogenetic mechanisms in this disorder.
01 - 05 Apr 2006
European Society of Endocrinology