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Human piebald trait resulting from a dominant negative mutant allele of the c-kit membrane receptor gene.

Abstract
Human piebald trait is an autosomal dominant defect in melanocyte development characterized by patches of hypopigmented skin and hair. Although the molecular basis of piebaldism has been unclear, a phenotypically similar "dominant spotting" of mice is caused by mutations in the murine c-kit protooncogene. In this regard, one piebald case with a point mutation and another with a deletion of c-kit have been reported, although a polymorphism or the involvement of a closely linked gene could not be excluded. To confirm the hypothesis that piebaldism results from mutations in the human gene, c-kit exons were amplified by polymerase chain reaction from the DNA of 10 affected subjects and screened for nucleotide changes by single-stranded conformation polymorphism analysis. In one subject with a variant single-stranded conformation polymorphism pattern for the first exon encoding the kinase domain, DNA sequencing demonstrated a missense mutation (Glu583----Lys). This mutation is identical to the mouse W37 mutation which abolishes autophosphorylation of the protein product and causes more extensive depigmentation than "null" mutations. In accord with this "dominant negative" effect, the identical mutation in this human kindred is associated with unusually extensive depigmentation. Thus, the finding of a piebald subject with a mutation that impairs receptor activity strongly implicates the c-kit gene in the molecular pathogenesis of this human developmental defect.
AuthorsR A Fleischman
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 89 Issue 6 Pg. 1713-7 (Jun 1992) ISSN: 0021-9738 [Print] United States
PMID1376329 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Proto-Oncogene Proteins
  • Receptors, Cell Surface
  • DNA
  • Proto-Oncogene Proteins c-kit
Topics
  • Alleles
  • Amino Acid Sequence
  • Base Sequence
  • DNA
  • Genes, Dominant
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Phenotype
  • Piebaldism (genetics)
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins (genetics)
  • Proto-Oncogene Proteins c-kit
  • Receptors, Cell Surface (genetics)
  • Sequence Homology, Nucleic Acid

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