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Genetics, Vol. 169, 819-831, February 2005, Copyright © 2005
doi:10.1534/genetics.104.027177
Identification of a Novel Point Mutation of Mouse Proto-Oncogene c-kit Through N-Ethyl-N-nitrosourea Mutagenesis
Hai-Bin Ruan*,
Nian Zhang*,
and
Xiang Gao*,
,1
* Model Animal Research Center, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China 210089
Model Organism Division, E-Institute of Shanghai Unviersity, Shanghai, China
Van Andel Research Institute, Grand Rapids, Michigan 49503
1 Corresponding author: Model Animal Research Center, Nanjing University, 308 Xuefu Rd., Pukou District, Nanjing 210089, People's Republic of China.
E-mail: gaoxiang{at}nju.edu.cn
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 Wadsm/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 Wadsm/m mice. Therefore, the Wads mutant may serve as a new disease model of human piebaldism, anemia, deafness, sterility, and mast cell diseases.
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