Molecular bases of dominant negative and loss of function mutations at the murine c-kit/white spotting locus: W37, Wv, W41 and W. EMBO J 1990 Jun;9(6):1805-13
Date
06/01/1990Pubmed ID
1693331Pubmed Central ID
PMC551885DOI
10.1002/j.1460-2075.1990.tb08305.xScopus ID
2-s2.0-0025334596 (requires institutional sign-in at Scopus site) 565 CitationsAbstract
The proto-oncogene c-kit encodes a transmembrane tyrosine protein kinase receptor for an unknown ligand and is allelic with the murine white-spotting locus (W). Mutations at the W locus affect various aspects of hematopoiesis, the proliferation and migration of primordial germ cells and melanoblasts during development. The original W mutation and W37 are severe lethal mutations when homozygous. In the heterozygous state the W mutation has a weak phenotype while W37 has dominant characteristics. Wv and W41 are weak W mutations with dominant characteristics. We have characterized the molecular basis of these four W mutations and determined their effects on mast cell differentiation by using a fibroblast/mast cell co-culture assay. We show that W37, Wv and W41 are the result of missense mutations in the kinase domain of the c-kit coding sequence (W37 E----K at position 582; Wv T----M position 660 and W41 V----M position 831), which affect the c-kit associated tyrosine kinase to varying degrees. The c-kit protein products in homozygous mutant mast cells are expressed normally, although the 160 kd cell membrane form of the c-kitW37 protein displays accelerated turnover characteristics. The W mutation is the result of a 78 amino acid deletion which includes the transmembrane domain of the c-kit protein. A 125 kd c-kit protein was detected in homozygous W/W mast cells which lacks kinase activity and is not expressed on the cell surface.(ABSTRACT TRUNCATED AT 250 WORDS)
Author List
Nocka K, Tan JC, Chiu E, Chu TY, Ray P, Traktman P, Besmer PAuthor
Paula Traktman Duncan PhD Emeritus Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AllelesAmino Acid Sequence
Animals
Base Sequence
Cells, Cultured
Chromosome Mapping
Fibroblasts
Mast Cells
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Molecular Sequence Data
Mutation
Phenotype
Pigmentation
Protein-Tyrosine Kinases
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-kit
RNA, Messenger
