Studies of Rhbdf1 and Rhbdf2 GOF mutant mice (Fig. 2D, E)—Rhbdf1viable (Hosur et al. 2020), curly bare (Rhbdf2cub), uncovered (Rhbdf2uncv), and CRISPR/Cas9-mediated genetically engineered mouse model of tylosis with esophageal cancer (Rhbdf2TOC)—suggest that RHBDF1 and RHBDF2 have distinct functions, and thereby distinct physiological targets. This evidence concerns the gene RHBDF1 and Non-epidermolytic palmoplantar keratoderma.