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Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects

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.

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Figure 1: Dsk3 and Dsk4 pigmentary phenotype.
Figure 2: Positional cloning of Dsk mutations.
Figure 3: Tissue-specific modulation of Rps6 gene dosage.
Figure 4: Gene expression and Kit signaling in Rps mutants.
Figure 5: p53 is sufficient and necessary to induce dark skin.
Figure 6: Effect of Rps19Dsk3 on bone marrow.
Figure 7: Pathophysiology of mutations affecting ribosomal proteins (Rp).

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Gene Expression Omnibus

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Acknowledgements

We thank G. Thomas (University of Cincinnati) and S. Volarevic (University of Cincinnati) for Rps6lox mice, I. Jackson (MRC Human Genetics Unit) and M. Shin (Fox Chase Cancer Center) for Dct-lacZ mice, S. Artandi (Stanford University) and J. Jorcano (Epithelial Biomedicine Division CIEMAT) for Tg.K5Cre mice, A. Alizadeh (Stanford University) for Tg.MitfCre mice and T. Jacks (Massachusetts Institute of Technology) for Trp53KO mice. We thank P. Khavari and U. Francke for their careful review of the work, H. Manuel for technical support and B. Glader for advice regarding Diamond-Blackfan anemia. K.A.M. and C.Y.P. are supported by Mentored Clinical Scientist Development Investigator Awards from the National Institutes of Health. G.S.B. is supported by a Research Project Grant from the National Institutes of Health. Part of this work was supported by a grant from the German Human Genome Project (DHGP) and the National Genome Research Network (NGFN 01GR0430) to M.H.d.A.

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Correspondence to Gregory S Barsh.

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McGowan, K., Li, J., Park, C. et al. Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects. Nat Genet 40, 963–970 (2008). https://doi.org/10.1038/ng.188

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