title: 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.
authors.affiliation: Department of Genetics, Division of Radiation and CancerBiology, Stanford University, Stanford, California 94305, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: McGowan
authors.forename: Jun Z
authors.initials: JZ
authors.lastname: Li
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Park
authors.forename: Veronica
authors.initials: V
authors.lastname: Beaudry
authors.forename: Holly K
authors.initials: HK
authors.lastname: Tabor
authors.forename: Amit J
authors.initials: AJ
authors.lastname: Sabnis
authors.forename: Weibin
authors.initials: W
authors.lastname: Zhang
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Martin Hrabé
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
authors.forename: Laura D
authors.initials: LD
authors.lastname: Attardi
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Barsh
mesh_terms: D000818:Animals; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism; D051379:Mice; D009154:Mutation; D038601:Ribosomal Protein S6 / Q000235:genetics / Q000378:metabolism; D012269:Ribosomal Proteins / Q000235:genetics* / Q000378:metabolism; D012880:Skin Pigmentation; D019089:Stem Cell Factor / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D038601:Ribosomal Protein S6; D012269:Ribosomal Proteins; C531064:Rps19 protein, mouse; D019089:Stem Cell Factor; D016159:Tumor Suppressor Protein p53; C040343:ribosomal protein S19; C029611:ribosomal protein S20; C448579:ribosomal protein S6, mouse