Nature Genetics
18, 171 - 173 (1998)
doi:10.1038/ng0298-171
SOX10 mutations in patients with Waardenburg-Hirschsprung diseaseVéronique Pingault1, Nadège Bondurand1, Kirsten Kuhlbrodt2, Derk E. Goerich2, Marie-Odette Préhu1, Aldamaria Puliti1, 5, Beate Herbarth2, Irm Hermans-Borgmeyer2, Eric Legius3, Gert Matthijs3, Jeanne Amiel4, Stanislas Lyonnet4, Isabella Ceccherini5, Giovanni Romeo5, Jill Clayton Smith6, Andrew P. Read6, Michael Wegner2
& Michel Goossens1, 7
1INSERM U468, Hopital Henri Mondor, 94010 Creteil, France.
2Zentrum für Molekulare Neurobiologie, Universität Hamburg, Martinistr. 52,20246 Hamburg, Germany.
3 Center for Human Genetics, University of Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
4INSERM U393, Hôpital des Enfants-Malades, 75743 Paris, France.
5Lab. Genetica Molecolare, Istituto G. Gaslini, 16148 Genoa, Italy.
6University Department of Medical Genetics, St Mary's Hospital, Manchester Ml3 OJH, UK.
7e-mail: goossens@im3.inserm.fr 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.
REFERENCES
- Badner, J., Sieber, W., Garver, K. & Chakravarti, A. A genetic study of Hirschsprung disease. Am. J. Hum. Genet. 46, 568−580 (1990). | PubMed | ISI | ChemPort |
- Read, A.P. & Newton, V.E. Waardenburg syndrome. J. Med. Genet. 34, 656−665 (1997). | PubMed | ISI | ChemPort |
- 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 | PubMed | ISI | ChemPort |
- 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 | PubMed | ISI | ChemPort |
- 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). | PubMed | ISI | ChemPort |
- 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 | PubMed | ISI | ChemPort |
- 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 | PubMed | ISI | ChemPort |
- 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). | PubMed | ISI | ChemPort |
- 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). | PubMed | ISI | ChemPort |
- Chakravarti, A. Endothelin receptor-mediated signaling in Hirschsprung disease. Hum. Mol. Genet. 5, 303−307 (1996). | PubMed | ISI | ChemPort |
- 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). | PubMed | ISI | ChemPort |
- Omenn, G.S. & McKusick, V.A. The association of Waardenburg syndrome and Hirschsprung megacolon. Am. J. Med. Genet. 3, 217−223 (1979). | PubMed | ISI | ChemPort |
- Fried, K. & Beer, S. Waardenburg and Hirschsprung's disease in the same patient. Clin. Genet. 18, 91−92 (1980). | PubMed | ISI | ChemPort |
- Shah, K.N. et al. White forelock, pigmentary disorder of irides, and long segment Hirschsprung megacolon. Am. J. Med. Genet. 99, 432−435 (1981). | ChemPort |
- Ambani, L.M. Waardenburg and Hirschsprung syndromes. J. Pediatr. 102, 802 (1983). | PubMed | ChemPort |
- 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). | PubMed | ISI | ChemPort |
- 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 | PubMed | ISI | ChemPort |
- Edery, P. et al. Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung phenotype (Shah-Waardenburg syndrome). Nature Genet. 12, 442−444 (1996). | PubMed | ISI | ChemPort |
- 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). | PubMed | ISI | ChemPort |
- 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).
- 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 | PubMed | ChemPort |
- 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 | PubMed | ChemPort |
- 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). | PubMed | ISI | ChemPort |
- 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). | PubMed | ISI | ChemPort |
- Fisher, E. & Scambler, P. Human haploinsufficiency - one for sorrow, two for joy. Nature Genet. 7, 5−7 (1994). | PubMed | ISI | ChemPort |
- Romeo, G. & McKusick, V. Phenotypic diversity, allelic series and modifier genes. Nature Genet. 7, 451−453 (1994). | PubMed | ISI | ChemPort |
- 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). | PubMed | ISI | ChemPort |
- 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). | ChemPort |
- Kapur, R.P. et al. Abnormal microenvironmental signals underlie intestinal aganglionosis in Dominant megacolon mutant mice. Dev. Biol. 174, 360−369 (1996). | Article | PubMed | ISI | ChemPort |
- 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). | PubMed | ISI | ChemPort |
- 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 | PubMed | ISI | ChemPort |
|
