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SOX10 mutations in patients with Waardenburg-Hirschsprung disease

INSERM U468, Hôpital Henri Mondor, Creteil, France.
Nature Genetics (Impact Factor: 29.65). 03/1998; 18(2):171-3. DOI: 10.1038/ng0298-171
Source: PubMed

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 crest. 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 (ls). The sl and ls phenotypes are caused by mutations in the genes encoding the Endothelin-B receptor (Ednrb) and Endothelin 3 (Edn3), respectively. 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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    • "SOX10 is of particular interest because of its roles as a marker of neural crest stem cells (NCSCs) and in the maintenance and migration of NCSCs (McKeown et al, 2005; Drerup et al, 2009; Miyahara et al, 2011). Remarkably, TrkC and Sox10 may be functionally linked, as inactivating mutations in NTRK3, NTF3, and SOX10 were identified as independent drivers of Hirschsprung disease (Pingault et al, 1998; Ruiz-Ferrer et al, 2008; Fernandez et al, 2009; Sanchez-Mejias et al, 2009), a genetic condition linked to the inability of NCSCs to migrate, differentiate, and develop into the enteric nervous system (Iwashita et al, 2003). "
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    • "All primers sequences are available upon request. The wild-type, E189X, and 847insT SOX10 expression constructs (cloned downstream of a pCMV promoter element)(Inoue et al., 2004; Pingault et al., 1998) were a kind gift of Ken Inoue, Jim Lupski, and Michael Wegner. The pCMV-SOX8 and pCMV- SOX9 expression constructs were a kind gift of Stacie Loftus and Bill Pavan. "
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    • "Some of these findings have helped us to uncover the molecular mechanisms of NC-related diseases, including gene mutation, deletion, and duplication. For example, SOX10 mutation affects normal development of pigment cells and enteric ganglia, which result in hypopigmentation and Hirschsprung disease, respectively (Pingault et al., 1998; Bondurand et al., 1999; Inoue et al., 2002). In addition , a growing body of evidence has also demonstrated that epigenetic mechanisms also play critical roles in NC development. "
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