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SOX10 mutations in patients with Waardenburg-Hirschsprung disease

Abstract

Waardenburg syndrome (WS; deafness with pigmentary abnormalities) and Hirschsprung's disease (HSCR; aganglionic megacolon) are congenital disorders caused by defective function of the embryonic neural crest1,2. WS and HSCR are associated in patients with Waardenburg-Shah syndrome (WS4), whose symptoms are reminiscent of the white coat-spotting and aganglionic megacolon displayed by the mouse mutants Dom (Dominant megacolon), piebald-lethal (sl) and lethal spotting (Is). The sl and Is phenotypes are caused by mutations in the genes encoding the Endothelin-B receptor (Ednrb) and Endothelin 3 (Edn3), respectively3,4. The identification of Sox10 as the gene mutated in Dom mice (B.H. et al., manuscript submitted) prompted us to analyse the role of its human homologue SOx10 in neural crest defects. Here we show that patients from four families with WS4 have mutations in SOx10, whereas no mutation could be detected in patients with HSCR alone. These mutations are likely to result in haploinsufficiency of the SOx10 product. Our findings further define the locus heterogeneity of Waardenburg-Hirschsprung syndromes, and point to an essential role of SOx10 in the development of two neural crest-derived human cell lineages.

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References

  1. Badner, J., Sieber, W., Garver, K. & Chakravarti, A. A genetic study of Hirschsprung disease. Am. J. Hum. Genet. 46, 568–580 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Read, A.P. & Newton, V.E. Waardenburg syndrome. J. Med. Genet. 34, 656–665 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hosoda, K. et al. Targeted and natural (piebald-lthal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. cell 79, 1267–1276 (1994).

    Article  CAS  PubMed  Google Scholar 

  4. Baynash, A. et al. Interaction of Endothelin-3 with Endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 79, 1277–1285 (1994).

    Article  CAS  PubMed  Google Scholar 

  5. Steel, K. & Barkway, C. Another role for melanocytes; their importance for normal stria vascularis development in the mammalian inner ear. Development 107, 453–463 (1989).

    CAS  PubMed  Google Scholar 

  6. Tassabehji, M. et al. Waardenburg's syndrome patients havemutations in the human homologue of the Pax-3 paired box gene. Nature 355, 635–636 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Baldwin, C.T., Hoth, C.F., Amos, J.A. Amos, J.A., da-Silva, E.O. & Milunsky, A. An exonic mutation in the HuP2 paired domain gene causes Waardenburg syndrome. Nature 355, 637–638 (1992).

    Article  CAS  PubMed  Google Scholar 

  8. Hoth, C. et al. Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type 1. Am. J. Hum. Genet. 52, 455–462 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Tassabehji, M., Newton, V.E. & Read, A.P. Waardenburg syndrome type 2 is caused by mutations in the human microphthalmia (MITF) gene. Nature Genet. 8, 251–255 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Chakravarti, A. Endothelin receptor-mediated signaling in Hirschsprung disease. Hum. Mol. Genet. 5, 303–307 (1996).

    CAS  PubMed  Google Scholar 

  11. Hofstra, R.M.W., Osinga, J. & Buys, C.H.C.M. Mutations in Hirschsprung disease: when does a mutation contribute to the phenotype. Eur. J. Hum. Genet. 5, 180–185 (1997).

    CAS  PubMed  Google Scholar 

  12. Omenn, G.S. & McKusick, V.A. The association of Waardenburg syndrome and Hirschsprung megacolon. Am. J. Med. Genet. 3, 217–223 (1979).

    Article  CAS  PubMed  Google Scholar 

  13. Fried, K. & Beer, S. Waardenburg and Hirschsprung's disease in the same patient. Clin. Genet. 18, 91–92 (1980).

    CAS  PubMed  Google Scholar 

  14. Shah, K.N. et al. White forelock, pigmentary disorder of irides, and long segment Hirschsprung megacolon. Am. J. Med. Genet. 99, 432–435 (1981).

    CAS  Google Scholar 

  15. Ambani, L.M. Waardenburg and Hirschsprung syndromes. J. Pediatr. 102, 802 (1983).

    Article  CAS  PubMed  Google Scholar 

  16. Meire, F., Standeart, L., De Laey, J.J. & Zeng, L.H. Waardenburg syndrome, nature Hirschsprung megacolon, and Marcus Gunn ptosis. Am. J. Med. Genet. 27, 683–686 (1987).

    Article  CAS  PubMed  Google Scholar 

  17. Puffenberger, E.G. et al. A missense mutation of the Endothelin-B receptor gene in multigenic Hirschsprung's disease. Cell 79, 1257–1266 (1994).

    Article  CAS  PubMed  Google Scholar 

  18. Edery, P. et al. Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung phenotype (Shah-Waardenburg syndrome). Nature Genet. 12, 442–444 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Hofstra, R. et al. A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). Nature Genet. 12, 445–447 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Kulhbrodt, K., Herbarth, B., Sock, E., Hermans-Bormeyer, I. & Wegner, M., O, a novel transcriptional modulator in glial cells. J. Neurosd. 18 (1) 237–250 (1998).

    Article  Google Scholar 

  21. Pingault, V. et al. Human homology and candidate genes for the dominant megacolon locus, a mouse model of Hirschsprung disease. Genomics 39, 86–89 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Van Houte, L.P.A. et al. Solution structure of the sequence-specific HMG Box of the Lymphocyte Transcriptional Activator Sox-4. J. Biol. Chem. 270, 30516–30524 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Weir, H.M., Kraulis, P.J., Raine, A.R.C., Laue, E.D. & Thomas, J.O. Structure of the HMG box motif in the B-domain of HMG1. EMBO J. 12, 1311–1319 (1993).

    Article  CAS  PubMed  Google Scholar 

  24. Werner, M., Huth, J., Gronenborn, A. & Clore, G. Molecular basis of human 46 X,Y sex reversal revealed from the three-dimensional solution structure of the human SRY-DNA complex. Cell 81, 705–714 (1995).

    Article  CAS  PubMed  Google Scholar 

  25. Fisher, E. & Scambler, P. Human haploinsufficiency - one for sorrow, two for joy. Nature Genet. 7, 5–7 (1994).

    Article  CAS  PubMed  Google Scholar 

  26. Romeo, G. & McKusick, V. Phenotypic diversity, allelic series and modifier genes. Nature Genet. 7, 451–453 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. Pavan, W.J., Mac, S., Cheng, M. & Tilghman, S.M. Quantitative trait loci that modify the severity of spotting in piebald Mice. Genome Res. 5, 29–41 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. Lane, P.W. & Liu, H.M. Association of megacolon with a new dominant spotting gene (Dom) in the mouse. J. Hereof. 75, 435–439 (1984).

    Article  CAS  Google Scholar 

  29. Kapur, R.P. et al. Abnormal microenvironmental signals underlie intestinal aganglionosis in Dominant megacolon mutant mice. Dev. Biol. 174, 360–369 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Puliti, A., Poirier, V., Goossens, M. & Simonneau, M. Neuronal defects in genotyped dominant megacolon (Dom) mouse embryos, a model for Hirschsprung disease. NeuroReport 7, 489–492 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Southard-Smith, E.M., Kos, L. & Pavan, W.J. SoxlO mutation disrupts neural crest development in Dom Hirschsprung mouse model. Nature Genet. 18, 60–64 (1998).

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Michel Goossens.

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Pingault, V., Bondurand, N., Kuhlbrodt, K. et al. SOX10 mutations in patients with Waardenburg-Hirschsprung disease. Nat Genet 18, 171–173 (1998). https://doi.org/10.1038/ng0298-171

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