Southard-Smith, E.M. et al. The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome. Genome Res. 9, 215-225

Case Western Reserve University, Cleveland, Ohio, United States
Genome Research (Impact Factor: 14.63). 04/1999; 9(3):215-25.
Source: PubMed


Hirschsprung disease (HSCR) is a multigenic neurocristopathy clinically recognized by aganglionosis of the distal gastrointestinal tract. Patients presenting with aganglionosis in association with hypopigmentation are classified as Waardenburg syndrome type 4 (Waardenburg-Shah, WS4). Variability in the disease phenotype of WS4 patients with equivalent mutations suggests the influence of genetic modifier loci in this disorder. Sox10(Dom)/+ mice exhibit variability of aganglionosis and hypopigmentation influenced by genetic background similar to that observed in WS4 patients. We have constructed Sox10(Dom)/+ congenic lines to segregate loci that modify the neural crest defects in these mice. Consistent with previous studies, increased lethality of Sox10(Dom)/+ animals resulted from a C57BL/6J locus(i). However, we also observed an increase in hypopigmentation in conjunction with a C3HeB/FeJLe-a/a locus(i). Linkage analysis localized a hypopigmentation modifier of the Dom phenotype to mouse chromosome 10 in close proximity to a previously reported modifier of hypopigmentation for the endothelin receptor B mouse model of WS4. To evaluate further the role of SOX10 in development and disease, we have performed comparative genomic analyses. An essential role for this gene in neural crest development is supported by zoo blot hybridizations that reveal extensive conservation throughout vertebrate evolution and by similar Northern blot expression profiles between mouse and man. Comparative sequence analysis of the mouse and human SOX10 gene have defined the exon-intron boundaries of SOX10 and facilitated mutation analysis leading to the identification of two new SOX10 mutations in individuals with WS4. Structural analysis of the HMG DNA-binding domain was performed to evaluate the effect of human mutations in this region.

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    • "HSCR is observed in about 1/5000 live birth and is more frequent in males than in females (4∶1), a difference most prominent in S-HSCR [6]. Several genes have been implicated in the development of HSCR, including the RET proto-oncogene [7]–[9], endothelin receptor B gene (EDNRB) [10]–[17], endothelin-3 gene (EDN3) [18], [19], glial-cell-line-derived neurotrophic factor (GDNF) [20]–[22], SOX10 [23], [24], NRTN [25], ECE1 [26], ZFHX1B [27], PHOX2B [28], KIAA1279 [29], TCF4 [26]. However, mutations in these genes explain only a minority of cases and the vast majority (80%) of HSCR heritability remains unknown [30]. "
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    ABSTRACT: Hirschsprung disease (HSCR) exhibits complex genetics with incomplete penetrance and variable severity thought to result as a consequence of multiple gene interactions that modulate the ability of enteric neural crest cells to populate the developing gut. As reported previously, when the same null mutation of the Ednrb gene, Ednrb(sl), was introgressed into the F344 strain, almost 60% of F344-Ednrb(sl/sl) pups did not show any symptoms of aganglionosis, appearing healthy and normally fertile. These findings strongly suggested that the severity of HSCR was affected by strain-specific genetic factor (s). In this study, the genetic basis of such large strain differences in the severity of aganglionosis in the rat model was studied by whole-genome scanning for quantitative trait loci (QTLs) using an intercross of (AGH-Ednrb(sl)×F344-Ednrb(sl)) F(1) with the varying severity of aganglionosis. Genome linkage analysis identified one significant QTL on chromosome 2 for the severity of aganglionosis. Our QTL analyses using rat models of HSCR revealed that multiple genetic factors regulated the severity of aganglionosis. Moreover, a known HSCR susceptibility gene, Gdnf, was found in QTL that suggested a novel non-coding sequence mutation in GDNF that modifies the penetrance and severity of the aganglionosis phenotype in EDNRB-deficient rats. A further identification and analysis of responsible genes located on the identified QTL could lead to the richer understanding of the genetic basis of HSCR development.
    Full-text · Article · Nov 2011 · PLoS ONE
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    • "Alterations that affect these enhancers such as spontaneously occurring deletions in the distal upstream region or immediately in front of the promoter have been shown to disturb neural crest development in mouse and chicken (17,23). Considering that heterozygous mutations in the SOX10 coding region also lead to neural crest defects (so-called neurocristopathies) in humans including Waardenburg syndrome (in which melanocyte development is disturbed) and Hirschsprung disease (in which enteric nervous system development remains incomplete) (10,24,25), it seems plausible that cases with unclear molecular origin may result from such SOX10 enhancer mutations that may cause or predispose to disease. "
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    ABSTRACT: The Sox10 transcription factor is a central regulator of vertebrate neural crest and nervous system development. Its expression is likely controlled by multiple enhancer elements, among them U3 (alternatively known as MCS4). Here we analyze U3 activity to obtain deeper insights into Sox10 function and expression in the neural crest and its derivatives. U3 activity strongly depends on the presence of Sox10 that regulates its own expression as commonly observed for important developmental regulators. Sox10 bound directly as monomer to at least three sites in U3, whereas a fourth site preferred dimers. Deletion of these sites efficiently reduced U3 activity in transfected cells and transgenic mice. In stimulating the U3 enhancer, Sox10 synergized with many other transcription factors present in neural crest and developing peripheral nervous system including Pax3, FoxD3, AP2α, Krox20 and Sox2. In case of FoxD3, synergism involved Sox10-dependent recruitment to the U3 enhancer, while Sox10 and AP2α each had to bind to the regulatory region. Our study points to the importance of autoregulatory activity and synergistic interactions for maintenance of Sox10 expression and functional activity of Sox10 in the neural crest regulatory network.
    Full-text · Article · Sep 2011 · Nucleic Acids Research
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    • "This congenital disorder is observed in about 1/5000 live births, although significant differences in incidence exist between ethnic groups [5]. Several susceptibility genes have been identified for HSCR, namely the RET proto-oncogene [6]–[8], endothelin receptor B gene (EDNRB) [9]–[16], endothelin-3 gene (EDN3) [17], [18], GDNF gene [19]–[21], and SOX10 gene [22], [23], which play important roles in the formation of the enteric nervous system (ENS). "
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    ABSTRACT: Hirschsprung disease (HSCR) is thought to result as a consequence of multiple gene interactions that modulate the ability of enteric neural crest cells to populate the developing gut. However, it remains unknown whether the single complete deletion of important HSCR-associated genes is sufficient to result in HSCR disease. In this study, we found that the null mutation of the Ednrb gene, thought indispensable for enteric neuron development, is insufficient to result in HSCR disease when bred onto a different genetic background in rats carrying Ednrb(sl) mutations. Moreover, we found that this mutation results in serious congenital sensorineural deafness, and these strains may be used as ideal models of Waardenburg Syndrome Type 4 (WS4). Furthermore, we evaluated how the same changed genetic background modifies three features of WS4 syndrome, aganglionosis, hearing loss, and pigment disorder in these congenic strains. We found that the same genetic background markedly changed the aganglionosis, but resulted in only slight changes to hearing loss and pigment disorder. This provided the important evidence, in support of previous studies, that different lineages of neural crest-derived cells migrating along with various pathways are regulated by different signal molecules. This study will help us to better understand complicated diseases such as HSCR and WS4 syndrome.
    Full-text · Article · Sep 2011 · PLoS ONE
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