Article abstract
Nature Genetics 40, 963 - 970 (2008)
Published online: 20 July 2008 | doi:10.1038/ng.188
Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects
Kelly A McGowan1, Jun Z Li1,2,7, Christopher Y Park3, Veronica Beaudry4, Holly K Tabor1,2,7, Amit J Sabnis1,7, Weibin Zhang1, Helmut Fuchs5, Martin Hrabé de Angelis5, Richard M Myers1,2,7, Laura D Attardi1,4 & Gregory S Barsh1,6
Abstract
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.
- Department of Genetics, Stanford University, Stanford, California 94305, USA.
- Stanford Human Genome Center, Stanford University, Stanford, California 94305, USA.
- Department of Pathology, Stanford University, Stanford, California 94305, USA.
- Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University, Stanford, California 94305, USA.
- Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Institute of Experimental Genetics, Neuherberg D-85764, Germany.
- Department of Pediatrics, Stanford University, Stanford, California 94305, USA.
- Present addresses: Department of Human Genetics, School of Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA (J.Z.L.), Center for Biomedical Ethics, Stanford University, Stanford, California 94305, USA (H.K.T.), University of California, San Francisco, School of Medicine, San Francisco, California 94143, USA (A.J.S.) and HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35486, USA (R.M.M.).
Correspondence to: Gregory S Barsh1,6 e-mail: gbarsh@stanford.edu
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