Molecular bases of dominant negative and loss of function mutations at the murine c-kit/white spotting locus: W37, Wv, W41 and W.

Abstract

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)

A Role of Mast Cell Glycosaminoglycans for the Immunological Expulsion of Intestinal Nematode, Strongyloides venezuelensis

“…The roles of mast cells were further examined with mast cell-deficient W/W v mice. W/W v mice have mutations in c-kit protein, in which W and W v are a missense mutation in the kinase domain and a deletion mutation in transmembrane domain, respectively (20). Because c-kit protein is the receptor for c-kit ligand/stem cell factor (21), which induces development of both connective tissue type and mucosal mast cells (22,23), W/W v mice virtually lack mast cells (24).…”

Synergistic effects on erythropoiesis, thrombopoiesis, and stem cell competitiveness in mice deficient in thrombopoietin and steel factor receptors

“…[16][17][18] The Kit Wv allele contains a missense mutation of 2007CϾT (Thr to Met), in the kinase domain-encoding sequence that results in partial loss of function. 19 In vitro, SF, acting in synergy with early-acting factors such as IL-11 and Flt3L, can support modest expansion of pluripotent HSCs. 12 Tpo is a member of the 4 ␣-helical hematopoietin family and binds to the c-Mpl receptor.…”

Transforming growth factor-β regulates Kit ligand expression in rat ovarian surface epithelial cells

“…The Kit x/v mutation is a substituted amino acid in the Kit receptor kinase domain resulting in reduced kinase activity (Nocka et al, 1990;Reith et al, 1990). In Kit x/v mice, the surface epithelium of neonatal animals exhibited foci of crowded OSE cells up to several layers thick compared to non-mutant animals of the same strain (Murphy, 1972).…”