TY - JOUR
T1 - Human piebald trait resulting from a dominant negative mutant allele of the c-kit membrane receptor gene
AU - Fleischman, Roger A.
PY - 1992
Y1 - 1992
N2 - Human piebald trait is an autosomal dominant defect in melanocyte development characterized by patches of hypopigmented skin and hair. Although the molecular basis of pie-baldism 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.
AB - Human piebald trait is an autosomal dominant defect in melanocyte development characterized by patches of hypopigmented skin and hair. Although the molecular basis of pie-baldism 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.
KW - Melanocytes
KW - Pigmentation disorders
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M3 - Article
C2 - 1376329
AN - SCOPUS:0026628784
SN - 0021-9738
VL - 89
SP - 1713
EP - 1717
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 6
ER -