Dominant negative and loss of function mutations of the c-kit (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism.
Piebaldism is an autosomal dominant disorder of melanocyte development and is characterized by congenital white patches of skin and hair from which melanocytes are completely absent. A similar disorder of the mouse, "dominant white spotting" (W), results from mutations of the c-kit proto-oncogene, which encodes the cellular tyrosine kinase receptor for the mast/stem cell growth factor. We have identified c-kit gene mutations in three patients with piebaldism. A missense substitution (Phe----Leu) at codon 584, within the tyrosine kinase domain, is associated with a severe piebald phenotype, whereas two different frameshifts, within codons 561 and 642, are both associated with a variable and relatively mild piebald phenotype. This is consistent with a possible "dominant negative" effect of missense c-kit polypeptides on the function of the dimeric receptor.
Spritz
R A
RA
Department of Medical Genetics, University of Wisconsin, Madison.
Giebel
L B
LB
Holmes
S A
SA
D000595:Amino Acid Sequence; D001483:Base Sequence; D015139:Blotting, Southern; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D016116:Piebaldism / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit; D011519:Proto-Oncogenes
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019009:Proto-Oncogene Proteins c-kit