DESCRIZIONE DI UN CASO DI SEVERA INSULINO-RESISTENZA E LIPODISTROFIA PARZIALE, CAUSATO DA UNA MUTAZIONE A CARICO DEL PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPAR-GAMMA): CARATTERIZZAZIONE CLINICA E MOLECOLARE.

Mutations affecting ligand or DNA binding functions of PPARγ are associated with lipodystrophic insulin resistance. In the present study, we describe a 31 yr old female, heterozygous for a novel, mutation of PPARγ. Clinical features included hirsutism, polycystic ovarian syndrome, dyslipidaemia and hypertension. Hyperinsulinaemia during an OGTT and HOMA-IR 11.1% confirmed severe insulin resistance. She had distal limb and gluteal lipodystrophy with reduced subcutaneous adipose tissue (SCAT) but preserved visceral adipose tissue (VAT), with SCAT/VAT ratio of 0.619 (NR 0.19±0.084) and hepatic steatosis on MRS (Intrahepatic lipid 26.8% NR<5). In functional studies, the mutant receptor was more transcriptionally impaired with lower-affinity ligand (PGJ2) than synthetic agonist (rosiglitazone). Electrophoretic mobility shift assays (EMSA) with hFABP4 PPARE showed absent DNA binding. Modelling based on the PPARγ–RXR heterodimer structure, indicates that this mutation involve a conserved aminoacid, which forms part of the extended DNA binding domain in the hinge region of the receptor. This residue interacts with bases in the minor groove upstream of the PPARE, and this substitution is predicted to destabilize such contacts. This mutation represents a novel mechanism whereby loss of receptor interaction with DNA is associated with human metabolic disease.