SOX10 mutations in patients with Waardenburg-Hirschsprung disease

ArticleinNature Genetics 18(2):171-3 · March 1998with23 Reads
DOI: 10.1038/ng0298-171 · Source: PubMed
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.
    • "Sox10, a neural crest transcription factor that carries a conserved high-mobility group DNA-binding domain, is critical for the determination, differentiation and maintenance of peripheral glial cells and melanocytes [34]–[37]. Mutations of the Sox10 gene are known to cause degeneration and/or dysfunction of glial cells and melanocytes in a variety of tissues; e.g., Waardenburg syndrome in humans, a rare auditory-pigmentary disorder that generates varying combinations of hearing loss and pigmentation defects [38], [39]. Here, we investigated the potential role of Sox10 in the age-related degeneration of cells in the cochlear lateral wall by examining Sox10 immunostaining patterns in the inner ears of aged CBA/CaJ mice and human temporal bones from older donors. "
    [Show abstract] [Hide abstract] ABSTRACT: Age-related hearing loss (presbycusis) is a common human disorder, affecting one in three Americans aged 60 and over. Previous studies have shown that presbyacusis is associated with a loss of non-sensory cells in the cochlear lateral wall. Sox10 is a transcription factor crucial to the development and maintenance of neural crest-derived cells including some non-sensory cell types in the cochlea. Mutations of the Sox10 gene are known to cause various combinations of hearing loss and pigmentation defects in humans. This study investigated the potential relationship between Sox10 gene expression and pathological changes in the cochlear lateral wall of aged CBA/CaJ mice and human temporal bones from older donors. Cochlear tissues prepared from young adult (1-3 month-old) and aged (2-2.5 year-old) mice, and human temporal bone donors were examined using quantitative immunohistochemical analysis and transmission electron microscopy. Cells expressing Sox10 were present in the stria vascularis, outer sulcus and spiral prominence in mouse and human cochleas. The Sox10+ cell types included marginal and intermediate cells and outer sulcus cells, including those that border the scala media and those extending into root processes (root cells) in the spiral ligament. Quantitative analysis of immunostaining revealed a significant decrease in the number of Sox10+ marginal cells and outer sulcus cells in aged mice. Electron microscopic evaluation revealed degenerative alterations in the surviving Sox10+ cells in aged mice. Strial marginal cells in human cochleas from donors aged 87 and older showed only weak immunostaining for Sox10. Decreases in Sox10 expression levels and a loss of Sox10+ cells in both mouse and human aged ears suggests an important role of Sox10 in the maintenance of structural and functional integrity of the lateral wall. A loss of Sox10+ cells may also be associated with a decline in the repair capabilities of non-sensory cells in the aged ear.
    Full-text · Article · Jun 2014
    • "Of particular importance to neural crest development is also the expression of several transcription factors of highly conserved families, such as Slug/Snail, Sox, Fox, and Pax in the neural folds or in tissues surrounding the sites of neural crest induction. In humans, mutations in PAX3, MITF, SNAI2, and SOX10, have all been directly linked to syndromic neurocristopathies (Dow et al., 1994; Pingault et al., 1998; Watanabe et al., 1998; Sanchez-Martin et al., 2002). Slug/Snail homologues are also expressed in the gastrulating mesoderm, and have been implicated in EMT (Locascio et al., 2002; Wakahashi et al., 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: Neural crest cells (NCCs) are a transient, migratory cell population, which originates during neurulation at the neural folds and contributes to the majority of tissues, including the mesenchymal structures of the craniofacial skeleton. The deregulation of the complex developmental processes that guide migration, proliferation, and differentiation of NCCs may result in a wide range of pathological conditions grouped together as neurocristopathies. Recently, due to their multipotent properties neural crest stem cells have received considerable attention as a possible source for stem cell based regenerative therapies. This exciting prospect underlines the need to further explore the developmental programs that guide NCC differentiation. This review explores the particular importance of ribosome biogenesis defects in this context since a specific interface between ribosomopathies and neurocristopathies exists as evidenced by disorders such as Treacher-Collins-Franceschetti syndrome (TCS) and Diamond-Blackfan anemia (DBA).
    Full-text · Article · Feb 2014
    • "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). "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Jun 2013
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