Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects.
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.
McGowan
Kelly A
KA
Department of Genetics, Division of Radiation and CancerBiology, Stanford University, Stanford, California 94305, USA.
Li
Jun Z
JZ
Park
Christopher Y
CY
Beaudry
Veronica
V
Tabor
Holly K
HK
Sabnis
Amit J
AJ
Zhang
Weibin
W
Fuchs
Helmut
H
de Angelis
Martin Hrabé
MH
Myers
Richard M
RM
Attardi
Laura D
LD
Barsh
Gregory S
GS
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*
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