title: Identification of a novel point mutation of mouse proto-oncogene c-kit through N-ethyl-N-nitrosourea mutagenesis.
abstract: Manipulation of the mouse genome has emerged as an important approach for studying gene function and establishing human disease models. In this study, the mouse mutants were generated through N-ethyl-N-nitrosourea (ENU)-induced mutagenesis in C57BL/6J mice. The screening for dominant mutations yielded several mice with fur color abnormalities. One of them causes a phenotype similar to that shown by dominant-white spotting (W) allele mutants. This strain was named Wads because the homozygous mutant mice are white color, anemic, deaf, and sterile. The new mutation was mapped to 42 cM on chromosome five, where proto-oncogene c-kit resides. Sequence analysis of c-kit cDNA from Wads(m/m) revealed a unique T-to-C transition mutation that resulted in Phe-to-Ser substitution at amino acid 856 within a highly conserved tyrosine kinase domain. Compared with other c-kit mutants, Wads may present a novel loss-of-function or hypomorphic mutation. In addition to the examination of adult phenotypes in hearing loss, anemia, and mast cell deficiency, we also detected some early developmental defects during germ cell differentiation in the testis and ovary of neonatal Wads(m/m) mice. Therefore, the Wads mutant may serve as a new disease model of human piebaldism, anemia, deafness, sterility, and mast cell diseases.
authors.affiliation: Model Animal Research Center, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210089, People's Republic of China.
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Ruan
authors.forename: Nian
authors.initials: N
authors.lastname: Zhang
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D002875:Chromosomes; D003001:Cloning, Molecular; D005038:Ethylnitrosourea / Q000494:pharmacology*; D005260:Female; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009153:Mutagens / Q000494:pharmacology*; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D017434:Protein Structure, Tertiary; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000378:metabolism
chemical_list: C000715470:MAS1 protein, human; D009153:Mutagens; D000090063:Proto-Oncogene Mas; D012694:Serine; D019009:Proto-Oncogene Proteins c-kit; D005038:Ethylnitrosourea
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