Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects

Greg Barsh and colleagues show that two loci for dark skin in mice result from mutations in Rps19 and Rps20 , encoding the ribosomal proteins S19 and S20. They further show that the dark skin phenotype and other pleiotropic effects of these mutations, including reduced erythrocyte count and body size, are mediated through stabilization of p53. Mutations in genes encoding ribosomal proteins cause the Minute phenotype in Drosophila and mice, and Diamond-Blackfan syndrome in humans. Here we report two mouse dark skin ( Dsk ) loci caused by mutations in Rps19 (ribosomal protein S19) and Rps20 (ribosomal protein S20). We identify a common pathophysiologic program in which p53 stabilization stimulates Kit ligand expression, and, consequently, epidermal melanocytosis via a paracrine mechanism. Accumulation of p53 also causes reduced body size and erythrocyte count. These results provide a mechanistic explanation for the diverse collection of phenotypes that accompany reduced dosage of genes encoding ribosomal proteins, and have implications for understanding normal human variation and human disease.