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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    ABSTRACT: Background: Salivary adenoid cystic carcinoma (ACC) is an insidious slow-growing cancer with the propensity to recur and metastasise to distant sites. Basal-like breast carcinoma (BBC) is a molecular subtype that constitutes 15–20% of breast cancers, shares histological similarities and basal cell markers with ACC, lacks expression of ER (oestrogen receptor), PR (progesterone receptor), and HER2 (human epidermal growth factor receptor 2), and, similar to ACC, metastasises predominantly to the lung and brain. Both cancers lack targeted therapies owing to poor understanding of their molecular drivers. Methods: Gene expression profiling, immunohistochemical staining, western blot, RT-PCR, and in silico analysis of massive cancer data sets were used to identify novel markers and potential therapeutic targets for ACC and BBC. For the detection and comparison of gene signatures, we performed co-expression analysis using a recently developed web-based multi-experiment matrix tool for visualisation and rank aggregation. Results: In ACC and BBC we identified characteristic and overlapping SOX10 gene signatures that contained a large set of novel potential molecular markers. SOX10 was validated as a sensitive diagnostic marker for both cancers and its expression was linked to normal and malignant myoepithelial/basal cells. In ACC, BBC, and melanoma (MEL), SOX10 expression strongly co-segregated with the expression of ROPN1B, GPM6B, COL9A3, and MIA. In ACC and breast cancers, SOX10 expression negatively correlated with FOXA1, a cell identity marker and major regulator of the luminal breast subtype. Diagnostic significance of several conserved elements of the SOX10 signature (MIA, TRIM2, ROPN1, and ROPN1B) was validated on BBC cell lines. Conclusion: SOX10 expression in ACC and BBC appears to be a part of a highly coordinated transcriptional programme characteristic for cancers with basal/myoepithelial features. Comparison between ACC/BBC and other cancers, such as neuroblastomaand MEL, reveals potential molecular markers specific for these cancers that are likely linked to their cell identity. SOX10 as a novel diagnostic marker for ACC and BBC provides important molecular insight into their molecular aetiology and cell origin. Given that SOX10 was recently described as a principal driver of MEL, identification of conserved elements of the SOX10 signatures may help in better understanding of SOX10-related signalling and development of novel diagnostic and therapeutic tools.
    British Journal of Cancer 06/2013; 109(2). DOI:10.1038/bjc.2013.326 · 4.82 Impact Factor
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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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    ABSTRACT: The transcription factor SOX10 has essential roles in neural crest-derived cell populations, including myelinating Schwann cells-specialized glial cells responsible for ensheathing axons in the peripheral nervous system. Importantly, SOX10 directly regulates the expression of genes essential for proper myelin function. To date, only a handful of SOX10 target loci have been characterized in Schwann cells. Addressing this lack of knowledge will provide a better understanding of Schwann cell biology and candidate loci for relevant diseases such as demyelinating peripheral neuropathies. We have identified a highly-conserved SOX10 binding site within an alternative promoter at the SH3-domain kinase binding protein 1 (Sh3kbp1) locus. The genomic segment identified at Sh3kbp1 binds to SOX10 and displays strong promoter activity in Schwann cells in vitro and in vivo. Mutation of the SOX10 binding site ablates promoter activity, and ectopic expression of SOX10 in SOX10-negative cells promotes the expression of endogenous Sh3kbp1. Combined, these data reveal Sh3kbp1 as a novel target of SOX10 and raise important questions regarding the function of SH3KBP1 isoforms in Schwann cells.
    Molecular and Cellular Neuroscience 02/2012; 49(2):85-96. DOI:10.1016/j.mcn.2011.10.004 · 3.73 Impact Factor
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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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