title: Deletion of the c-kit protooncogene in the human developmental defect piebald trait.
abstract: The protooncogene c-kit is critical for development of hematopoietic stem cells, germ cells, and melanoblasts in the mouse. Homozygous mutations of this gene in the mouse cause anemia, infertility, and albinism, whereas heterozygous mutant mice usually exhibit only a white forehead blaze and depigmentation of the ventral body, tail, and feet. The heterozygous mouse phenotype is very similar to human piebald trait, which is characterized by a congenital white hair forelock and ventral and extremity depigmentation. To investigate the possibility that alterations in the human c-kit gene may be a cause of piebald trait, DNA from seven unrelated affected individuals was examined by Southern blot analysis. One subject, although cytogenetically normal, has a heterozygous deletion of the c-kit protooncogene. This deletion encompasses the entire coding region for c-kit and also involves the closely linked gene for platelet-derived growth factor receptor alpha. Fluorescence in situ hybridization of genomic c-kit probes to metaphase chromosomes independently confirmed the deletion in this case. These findings provide molecular evidence mapping piebald trait to the c-kit locus on chromosome 4. Although we cannot exclude the involvement of other closely linked genes, the demonstration of a genomic c-kit deletion in one subject with piebald trait and the marked concordance of the human and mouse phenotypes provide strong evidence for the role of c-kit in the development of human melanocytes and in the pathogenesis of piebald trait.
authors.affiliation: Department of Medicine, University of Texas Southwestern Medical Center, Dallas 75235.
authors.forename: R A
authors.initials: RA
authors.lastname: Fleischman
authors.forename: D L
authors.initials: DL
authors.lastname: Saltman
authors.forename: V
authors.initials: V
authors.lastname: Stastny
authors.forename: S
authors.initials: S
authors.lastname: Zneimer
mesh_terms: D000818:Animals; D015139:Blotting, Southern; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002872:Chromosome Deletion; D002894:Chromosomes, Human, Pair 4; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D006580:Genetic Carrier Screening; D005838:Genotype; D006133:Growth Substances / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007376:Interleukin-2 / Q000235:genetics; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009363:Neoplasm Proteins / Q000235:genetics; D009693:Nucleic Acid Hybridization; D016116:Piebaldism / Q000235:genetics*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit; D011519:Proto-Oncogenes; D011956:Receptors, Cell Surface / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor; D015183:Restriction Mapping
chemical_list: C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D007376:Interleukin-2; D009363:Neoplasm Proteins; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D004247:DNA; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor