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Updated: Aug 8, 2026
Cell Population Analyses During Skin Carcinogenesis
Published on: August 21, 2013
Dominant negative and loss of function mutations of the c-kit (mast/stem cell growth factor receptor) proto-oncogene
R A Spritz1, L B Giebel, S A Holmes
1Department of Medical Genetics, University of Wisconsin, Madison.
Abstract:
Piebaldism is an autosomal dominant disorder of melanocyte development and is characterized by congenital white patches of skin and hair from which melanocytes are completely absent. A similar disorder of the mouse, "dominant white spotting" (W), results from mutations of the c-kit proto-oncogene, which encodes the cellular tyrosine kinase receptor for the mast/stem cell growth factor. We have identified c-kit gene mutations in three patients with piebaldism. A missense substitution (Phe----Leu) at codon 584, within the tyrosine kinase domain, is associated with a severe piebald phenotype, whereas two different frameshifts, within codons 561 and 642, are both associated with a variable and relatively mild piebald phenotype. This is consistent with a possible "dominant negative" effect of missense c-kit polypeptides on the function of the dimeric receptor.
Insights
Mutations in the c-kit gene cause piebaldism, a disorder affecting melanocyte development. Different c-kit gene mutations result in varying degrees of skin and hair white spotting, impacting pigment cell function.
Area of Science:
- Genetics
- Dermatology
- Molecular Biology
Background:
- Piebaldism is an autosomal dominant disorder affecting melanocyte development.
- It is characterized by congenital white patches of skin and hair due to absent melanocytes.
- The mouse "dominant white spotting" (W) disorder is linked to c-kit proto-oncogene mutations.
Purpose of the Study:
- To investigate the role of the c-kit gene in human piebaldism.
- To identify specific c-kit gene mutations associated with piebaldism phenotypes.
Main Methods:
- Genetic analysis of three patients with piebaldism.
- Identification and characterization of mutations in the c-kit gene.
Main Results:
- c-kit gene mutations were identified in all three patients.
- A missense mutation (Phe584Leu) correlated with severe piebaldism.
- Two frameshift mutations (codons 561 and 642) correlated with variable, milder phenotypes.
Conclusions:
- c-kit gene mutations are causative in human piebaldism.
- The type and location of c-kit mutations influence disease severity.
- Missense c-kit mutations may exert a dominant negative effect on receptor function.
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