The novel loss of function Ile354Val mutation in PPARG causes familial partial lipodystrophy.

AIMS: Familial partial lipodystrophy (FPLD) is a rare autosomal dominant disorder, mostly due to mutations in lamin A (LMNA) or in peroxisome proliferator-activated receptor gamma (PPARG) genes. In the present study, we aimed to identify and functionally characterize the genetic defect underlying FPLD in an Italian family presenting with several affected individuals in three consecutive generations. METHODS: Mutational screening by direct Sanger sequencing has been carried out on both LMNA and PPARG genes. In silico analyses and functional in vitro studies on transfected cell lines have been also performed to evaluate the biological impact of the identified mutation. RESULTS: We identified a novel PPARG missense mutation (i.e., PPARγ2 Ile354Val) segregating with FPLD in the study family. In silico analyses and in vitro experiments showed that probably altering the PPARγ2 ligand binding domain conformation, the Ile354Val aminoacid change leads to a significant reduction (i.e., ~ 30-35%) of transcriptional activity in the mutant receptor, with no evidences of a dominant negative effect on the wild-type receptor. CONCLUSIONS: Our present data extend the spectrum of PPARG mutations responsible for FPLD3 and reinforce the notion that even loss of function mutations affecting transcriptional activity to an extent lower than that observed in the case of haploinsufficiency are able to cause a severe FPLD3 phenotype.

Very severely obese patients have a high prevalence of type 2 diabetes mellitus and cardiovascular disease.

The prevalence of very severe obesity has increased progressively and faster than other classes of obesity over the last years. It is unclear whether the prevalence of obesity-related complications and health risks increases progressively or reaches a plateau above a certain degree of obesity. The aim of our study was to investigate whether the severity of obesity was correlated with the prevalence of type 2 diabetes mellitus (T2DM), impaired fasting glucose, impaired glucose tolerance (IGT), metabolic syndrome (MS), and cardiovascular diseases (CVDs) in a large cohort of patients with different degrees of obesity. A cross-sectional study was conducted in 938 obese patients without a previous diagnosis of diabetes. Patients were assigned to different categories of obesity: mild-moderate obesity (BMI 30-39.9 kg/m(2)), morbid obesity (BMI 40-49.9 kg/m(2)), and super-obesity (SO, BMI ≥50 kg/m(2)). The prevalence of IGF, IGT, screen-detected T2DM, MS, and CVD was higher in SO patients than in the other groups. Interestingly, the association between SO and either MS or CVD was independent of glucose tolerance status, indicating that factors other than glucose metabolism also favor cardio-metabolic complications in obese patients. In patients without screen-detected T2DM (n = 807), insulin sensitivity and secretion OGTT-derived indexes indicated that SO patients had the worst glucose homeostasis relative to the other categories of obesity, which was indicated by the most reduced disposition index in these patients, a predictor of future T2DM. In conclusion, SO patients have an extremely high prevalence of glucose metabolism deterioration, and cardio-metabolic complications are more prevalent in these patients compared to less obese patients.