Abstract:

Author summary Birt-Hogg-Dubé (BHD) syndrome is a dominantly inherited genetic disease characterized by predisposition to fibrofolliculomas, lung cysts, and renal cancer. The disease is linked to germline variants in the folliculin (FLCN) tumor suppressor gene. Here, we present a combined computational and experimental study, focusing on rare BHD-linked missense and single amino acid deletion variants. Our data show that many disease-causing FLCN variants lead to structural destabilization and rapid proteasomal degradation of the FLCN protein. The reduced level of FLCN, in turn, leads to degradation of the FLCN binding partners FNIP1 and FNIP2. Additional results show that the turnover of FLCN is regulated by the deubiquitylating enzyme Ubp15/USP7 and molecular chaperones. We propose that for some missense variants, stabilization and resulting restoration of function may hold therapeutic potential, and that our computational saturation scan encompassing both missense variants and single site deletions in FLCN may allow classification of rare FLCN variants of uncertain clinical significance.