The Dominant W 42 Spotting Phenotype Results from a Missense Mutation in the c- kit Receptor Kinase

Abstract

The murine white spotting locus ( W ) is allelic with the proto-oncogene c- kit , which encodes a transmembrane tyrosine protein kinase receptor for an unknown ligand. Mutations at the W locus affect various aspects of hematopoiesis and the proliferation and migration of primordial germ cells and melanoblasts during development to varying degrees of severity. The W 42 mutation has a particularly severe effect in both the homozygous and the heterozygous states. The molecular basis of the W 42 mutation was determined. The c- kit protein products in homozygous mutant mast cells were expressed normally but displayed a defective tyrosine kinase activity in vitro. Nucleotide sequence analysis of mutant complementary DNAs revealed a missense mutation that replaces aspartic acid with asparagine at position 790 in the c- kit protein product. Aspartic acid-790 is a conserved residue in all protein kinases. These results provide an explanation for the dominant nature of the W 42 mutation and provide insight into the mechanism of c- kit -mediated signal transduction.