Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1992 Nov;51(5):1058–1065.

Mutations of the KIT (mast/stem cell growth factor receptor) proto-oncogene account for a continuous range of phenotypes in human piebaldism.

R A Spritz 1, S A Holmes 1, R Ramesar 1, J Greenberg 1, D Curtis 1, P Beighton 1
PMCID: PMC1682829  PMID: 1384325

Abstract

Piebaldism is a rare autosomal dominant disorder of pigmentation, characterized by congenital patches of white skin and hair from which melanocytes are absent. We have previously shown that piebaldism can result from missense and frameshift mutations of the KIT proto-oncogene, which encodes the cellular receptor tyrosine kinase for the mast/stem cell growth factor. Here, we report two novel KIT mutations associated with human piebaldism. A proximal frameshift is associated with a mild piebald phenotype, and a splice-junction mutation is associated with a highly variable piebald phenotype. We discuss the apparent relationship between the predicted impact of specific KIT mutations on total KIT-dependent signal transduction and the severity of the resultant piebald phenotypes.

Full text

PDF
1058

Images in this article

1060Figure 2
on p.1060
1061Figure 3
on p.1061
1062Figure 4
on p.1062
1062Figure 5
on p.1062

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Amaya E., Musci T. J., Kirschner M. W. Expression of a dominant negative mutant of the FGF receptor disrupts mesoderm formation in Xenopus embryos. Cell. 1991 Jul 26;66(2):257–270. doi: 10.1016/0092-8674(91)90616-7. [DOI] [PubMed] [Google Scholar]
  2. BREATHNACH A. S., FITZPATRICK T. B., WYLLIE L. M. ELECTRON MICROSCOPY OF MELANOCYTES IN HUMAN PIEBALDISM. J Invest Dermatol. 1965 Jul;45:28–37. doi: 10.1038/jid.1965.87. [DOI] [PubMed] [Google Scholar]
  3. Berdahl L. D., Murray J. C., Besmer P. A HindIII RFLP demonstrated for the kit oncogene on chromosome 4. Nucleic Acids Res. 1988 May 25;16(10):4740–4740. doi: 10.1093/nar/16.10.4740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. COOKE J. V. Familial white skin spotting (piebaldness) ("partial albinism") with white forelock. J Pediatr. 1952 Jul;41(1):1–12. doi: 10.1016/s0022-3476(52)80022-8. [DOI] [PubMed] [Google Scholar]
  5. Curtis D. An SstI RFLP at the C-Kit oncogene locus (KIT). Nucleic Acids Res. 1991 Mar 25;19(6):1352–1352. doi: 10.1093/nar/19.6.1352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fleischman R. A. Human piebald trait resulting from a dominant negative mutant allele of the c-kit membrane receptor gene. J Clin Invest. 1992 Jun;89(6):1713–1717. doi: 10.1172/JCI115772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fleischman R. A., Saltman D. L., Stastny V., Zneimer S. Deletion of the c-kit protooncogene in the human developmental defect piebald trait. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10885–10889. doi: 10.1073/pnas.88.23.10885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Funderburk S. J., Crandall B. F. Dominant piebald trait in a retarded child with a reciprocal translocation and small intercalary deletion. Am J Hum Genet. 1974 Nov;26(6):715–722. [PMC free article] [PubMed] [Google Scholar]
  9. Giebel L. B., Spritz R. A. Mutation of the KIT (mast/stem cell growth factor receptor) protooncogene in human piebaldism. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8696–8699. doi: 10.1073/pnas.88.19.8696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hayashi S., Kunisada T., Ogawa M., Yamaguchi K., Nishikawa S. Exon skipping by mutation of an authentic splice site of c-kit gene in W/W mouse. Nucleic Acids Res. 1991 Mar 25;19(6):1267–1271. doi: 10.1093/nar/19.6.1267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hoo J. J., Haslam R. H., van Orman C. Tentative assignment of piebald trait gene to chromosome band 4q12. Hum Genet. 1986 Jul;73(3):230–231. doi: 10.1007/BF00401233. [DOI] [PubMed] [Google Scholar]
  12. Jimbow K., Fitzpatrick T. B., Szabo G., Hori Y. Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis, nevus depigmentosus, and piebaldism. J Invest Dermatol. 1975 Jan;64(1):50–62. doi: 10.1111/1523-1747.ep12540914. [DOI] [PubMed] [Google Scholar]
  13. Kashles O., Yarden Y., Fischer R., Ullrich A., Schlessinger J. A dominant negative mutation suppresses the function of normal epidermal growth factor receptors by heterodimerization. Mol Cell Biol. 1991 Mar;11(3):1454–1463. doi: 10.1128/mcb.11.3.1454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lacassie Y., Thurmon T. F., Tracy M. C., Pelias M. Z. Piebald trait in a retarded child with interstitial deletion of chromosome 4. Am J Hum Genet. 1977 Nov;29(6):641–642. [PMC free article] [PubMed] [Google Scholar]
  15. Lathrop G. M., Lalouel J. M. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet. 1984 Mar;36(2):460–465. [PMC free article] [PubMed] [Google Scholar]
  16. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  17. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Smith E. A., Seldin M. F., Martinez L., Watson M. L., Choudhury G. G., Lalley P. A., Pierce J., Aaronson S., Barker J., Naylor S. L. Mouse platelet-derived growth factor receptor alpha gene is deleted in W19H and patch mutations on chromosome 5. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4811–4815. doi: 10.1073/pnas.88.11.4811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  20. Spritz R. A., Giebel L. B., Holmes S. A. Dominant negative and loss of function mutations of the c-kit (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism. Am J Hum Genet. 1992 Feb;50(2):261–269. [PMC free article] [PubMed] [Google Scholar]
  21. Stephenson D. A., Mercola M., Anderson E., Wang C. Y., Stiles C. D., Bowen-Pope D. F., Chapman V. M. Platelet-derived growth factor receptor alpha-subunit gene (Pdgfra) is deleted in the mouse patch (Ph) mutation. Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):6–10. doi: 10.1073/pnas.88.1.6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ueno H., Colbert H., Escobedo J. A., Williams L. T. Inhibition of PDGF beta receptor signal transduction by coexpression of a truncated receptor. Science. 1991 May 10;252(5007):844–848. doi: 10.1126/science.1851331. [DOI] [PubMed] [Google Scholar]
  23. Ueno H., Gunn M., Dell K., Tseng A., Jr, Williams L. A truncated form of fibroblast growth factor receptor 1 inhibits signal transduction by multiple types of fibroblast growth factor receptor. J Biol Chem. 1992 Jan 25;267(3):1470–1476. [PubMed] [Google Scholar]
  24. Ullrich A., Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990 Apr 20;61(2):203–212. doi: 10.1016/0092-8674(90)90801-k. [DOI] [PubMed] [Google Scholar]
  25. Vandenplas S., Wiid I., Grobler-Rabie A., Brebner K., Ricketts M., Wållis G., Bester A., Boyd C., Måthew C. Blot hybridisation analysis of genomic DNA. J Med Genet. 1984 Jun;21(3):164–172. doi: 10.1136/jmg.21.3.164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Winship I., Young K., Martell R., Ramesar R., Curtis D., Beighton P. Piebaldism: an autonomous autosomal dominant entity. Clin Genet. 1991 May;39(5):330–337. doi: 10.1111/j.1399-0004.1991.tb03039.x. [DOI] [PubMed] [Google Scholar]
  27. Yamamoto Y., Nishimoto H., Ikemoto S. Interstitial deletion of the proximal long arm of chromosome 4 associated with father-child incompatibility within the Gc-system: probable reduced gene dosage effect and partial piebald trait. Am J Med Genet. 1989 Apr;32(4):520–523. doi: 10.1002/ajmg.1320320419. [DOI] [PubMed] [Google Scholar]
  28. Yarden Y., Kuang W. J., Yang-Feng T., Coussens L., Munemitsu S., Dull T. J., Chen E., Schlessinger J., Francke U., Ullrich A. Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J. 1987 Nov;6(11):3341–3351. doi: 10.1002/j.1460-2075.1987.tb02655.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Yarden Y., Ullrich A. Growth factor receptor tyrosine kinases. Annu Rev Biochem. 1988;57:443–478. doi: 10.1146/annurev.bi.57.070188.002303. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES