Mutations in PTRF encoding cavin-1 are responsible for congenital generalized lipodystrophy type 4 (CGL4) characterized by lipoatrophy, insulin resistance, dyslipidemia, and muscular dystrophy. Cavin-1 cooperates with caveolins to form the plasma membrane caveolae, which are involved in cellular trafficking and signalling and in lipid turnover.

We sought to identify PTRF mutations in patients with CGL and to determine their impact on insulin sensitivity, adipose differentiation, and cellular autophagy.

We performed phenotyping studies and molecular screening of PTRF in two unrelated families with CGL. Cellular studies were conducted in cultured skin fibroblasts from the two probands and from control subjects, and in murine 3T3-F442A preadipocytes. Knockdown of cavin-1 or ATG5 was obtained by small interfering RNA-mediated silencing.

We identified two new PTRF homozygous mutations (p.Asp59Val or p.Gln157Hisfs*52) in four patients with CGL4 presenting with generalized lipoatrophy and associated metabolic abnormalities. In probands' fibroblasts, cavin-1 expression was undetectable and caveolin-1 and -2 barely expressed. Ultrastructural analysis revealed a loss of membrane caveolae and the presence of numerous cytoplasmic autophagosomes. Patients' cells also showed increased autophagic flux and blunted insulin signaling. These results were reproduced by PTRF knockdown in control fibroblasts and in 3T3-F442A preadipocytes. Cavin-1 deficiency also impaired 3T3-F442A adipocyte differentiation. Suppression of autophagy by small interfering RNA-mediated silencing of ATG5 improved insulin sensitivity and adipocyte differentiation.

This study showed that cavin-1 deficiency resulted in maladaptative autophagy that contributed to insulin resistance and altered adipocyte differentiation. These new pathophysiological mechanisms could open new therapeutic perspectives for adipose tissue diseases including CGL4.