KIT – Piebaldism

Piebaldism is an autosomal dominant pigmentary disorder characterized by congenital depigmented skin patches and a white forelock due to the absence of melanocytes. The KIT gene encodes a transmembrane receptor tyrosine kinase essential for melanoblast proliferation, migration, and survival. Heterozygous loss-of-function or dominant-negative mutations in KIT disrupt melanocyte development, leading to the classic piebald phenotype.

Genetic evidence for KIT involvement in piebaldism includes over 28 unrelated probands bearing heterozygous pathogenic variants (PMID:7529964). Reported mutations span missense substitutions in the tyrosine kinase domain, splicing defects, and in-frame deletions. A prototypical example is c.1990G>A (p.Gly664Arg) which was absent in controls and co-segregated with the phenotype in the index family (PMID:1717985).

Segregation analyses demonstrate that KIT variants co-segregate with piebaldism in multiple multi-generation kindreds, including complete linkage in at least four affected relatives in the original pedigree (PMID:1717985). This consistent inheritance pattern underscores the high penetrance of KIT mutations.

Functional studies in murine models of the W locus, allelic with KIT, recapitulate dominant white spotting and melanocyte defects (PMID:1690623; PMID:1688471). In vitro assays reveal that kinase-domain missense mutations impair KIT autophosphorylation and downstream signaling pathways critical for melanoblast survival (PMID:1370874).

Mechanistically, pathogenic KIT variants cluster in the tyrosine kinase domains and act via haploinsufficiency or dominant-negative interference, leading to arrested melanoblast migration. This aligns with the absence of melanocytes in depigmented patches and forelock regions.

In summary, definitive genetic and functional data support KIT as the causal gene for autosomal dominant piebaldism. Molecular testing of KIT is clinically useful for diagnosis, genetic counseling, and prenatal planning in affected families.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1991 • Mutation of the KIT (mast/stem cell growth factor receptor) protooncogene in human piebaldism. PMID:1717985
• American journal of human genetics • 1995 • Novel mutations and deletions of the KIT (steel factor receptor) gene in human piebaldism. PMID:7529964
• Ciba Foundation symposium • 1990 • The mouse W/c-kit locus. PMID:1690623
• Science (New York, N.Y.) • 1990 • The dominant W42 spotting phenotype results from a missense mutation in the c-kit receptor kinase. PMID:1688471
• American journal of human genetics • 1992 • Dominant negative and loss of function mutations of the c-kit (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism. PMID:1370874

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