The dominant W42 spotting phenotype results from a missense mutation in the c-kit receptor kinase.
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 W42 mutation has a particularly severe effect in both the homozygous and the heterozygous states. The molecular basis of the W42 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 W42 mutation and provide insight into the mechanism of c-kit-mediated signal transduction.
Molecular Biology Program, Sloan Kettering Institute, New York, NY 10021.
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Traktman
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Besmer
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D015870:Gene Expression; D006720:Homozygote; D008099:Liver / Q000032:analysis / Q000166:cytology / Q000196:embryology; D008407:Mast Cells / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit; D012313:RNA / Q000032:analysis; D011956:Receptors, Cell Surface / Q000235:genetics; D015398:Signal Transduction
D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D012313:RNA; D004247:DNA; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit