SOX10 MUTATIONS IN PATIENTS WITH WAARDENBURG-HIRSCHSPRUNG-DISEASE

Waardenburg syndrome (WS; deafness with pigmentary abnormalities) and Hirschsprung's disease (HSCR; aganglionic megacolon) are congenital di sorders caused by defective function of the embryonic neural crest(1,2 ). WS and HSCR are associated in patients with Waardenburg-Shah syndro me (WS4), whose symptoms are reminiscent of the white coat-spotting an d aganglionic megacolon displayed by the mouse mutants Dom (Dominant m egacolon), piebald-lethal(s(l)) and lethal spotting (Is). The s(l) and Is phenotypes are caused by mutations in the genes encoding the Endot helin-B receptor (Ednrb) and Endothelin 3 (Edn3), respectively(3,4). T he 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 fr om four families with WS4 have mutations in SOx10, whereas no mutation could be detected in patients with HSCR alone. These mutations are li kely to result in haploinsufficiency of the SOx10 product. Our finding s further define the locus heterogeneity of Waardenburg-Hirschsprung s yndromes. and point to an essential role of SOx10 in the development o f two neural crest-derived human cell lineages.