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 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.

Distinct role for c-kit receptor tyrosine kinase and SgIGSF adhesion molecule in attachment of mast cells to fibroblasts

“…55 The mutant allele W 42 is a point mutation in the kinase domain. 56 The extracellular domain of KIT encoded by the W 42 allele expresses normally on the cell surface but this mutant KIT is incapable of transducing intracellular signals. The adhesion of W/W 42 CMCs to NIH/3T3 fibroblasts was better than that of W/W CMCs.…”

Heterozygous Kit Mutants with Little or No Apparent Anemia Exhibit Large Defects in Overall Hematopoietic Stem Cell Function

“…In this study we define 3 Kit heterozygous alleles -W- 42 Figure 2), and each differs in its effect on hematopoiesis, pigmentation and fertility (Table 1) [20][21][22][23]. The residues altered by the W-v and W-41 alleles are highly conserved among several receptor tyrosine kinases, while that of the W-42 allele is conserved in all tyrosine and serinethreonine kinases [20,23]. Our results demonstrate large HSC functional defects in heterozygous Kit mutants with little or no apparent anemia and variations, among the mutants, in effects specific to the CMP, LT-and ST-stages of HSC differentiation.…”

“…Stem cell factor (SCF), also called KIT ligand or mast cell growth factor, encoded by the Steel locus (Sl), is the ligand specific to Kit [17][18][19]. Kit has a large number of mutant alleles [5][6][9][10][20][21][22][23], causing phenotypes that vary in severity; in most cases, the molecular lesions have been identified [20][21][22][23][24][25]. Kit has also been linked to a wide variety of cancers [4,[26][27][28][29][30].…”

Detection of c-kit exons 11- and 17-activating mutations in testicular seminomas by high-resolution melting amplicon analysis

“…1,2 A functional c-kit gene is necessary for proper development and migration of the interstitial cells of Cajal, blood cell progenitors, mast cells, melanocytes, as well as for normal spermatogenesis. [3][4][5][6] It is becoming apparent that many human malignancies that develop from cells with KIT-expressing lineages contain activating mutations in the c-kit gene. 7,8 The c-kit-activating mutations appear restricted to those in exons 9, 11, 13 and 17 and consist of in-frame deletions and insertions as well as point mutations.…”