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Human Molecular Genetics Advance Access published online on December 5, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi442
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Published by Oxford University Press 2005. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oupjournals.org
Received October 12, 2005
Accepted November 25, 2005

Article

Deletion of Long-Range Sequences at Sox10 Compromises Developmental Expression in a Mouse Model of Waardenburg-Shah (WS4) Syndrome

Anthony Antonellis 1 *, William R. Bennett 2 *, Trevelyan R. Menheniott 2, Arjun B. Prasad 3, Shih-Queen Lee-Lin 1, NISC Comparative Sequencing Program 4, Eric D. Green 5, Derek Paisley 2, Robert N. Kelsh 2, William J. Pavan 6 *, and Andrew Ward 2

1 Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
2 Developmental Biology Programme and Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
3 Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA; Graduate Genetics Program, The George Washington University, Washington, DC 20052, USA
4 NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
5 Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA; NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
6 Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, 49 Convent Dr., Bldg. 49, Rm. 4A82, Bethesda, MD 20892, USA

* To whom correspondence should be addressed.
William J. Pavan, E-mail: bpavan{at}nhgri.nih.gov


  Abstract

The transcription factor SOX10 is mutated in the human neurocristopathy Waardenburg-Shah syndrome (WS4), which is characterized by enteric aganglionosis and pigmentation defects. SOX10 directly regulates genes expressed in neural crest lineages, including the enteric ganglia and melanocytes. While some SOX10 target genes have been reported, the mechanisms by which SOX10 expression is regulated remain elusive. Here, we describe a transgene-insertion mutant mouse line (Hry) that displays partial enteric aganglionosis, a loss of melanocytes, and decreased Sox10 expression in homozygous embryos. Mutation analysis of Sox10 coding sequences was negative, suggesting that non-coding regulatory sequences are disrupted. To isolate the Hry molecular defect, Sox10 genomic sequences were collected from multiple species, comparative sequence analysis was performed, and software was designed (ExactPlus) to identify identical sequences shared among species. Mutation analysis of conserved sequences revealed a 15.9-kb deletion located 47.3 kb upstream of Sox10 in Hry mice. ExactPlus revealed three clusters of highly conserved sequences within the deletion, one of which shows strong enhancer potential in cultured melanocytes. These studies: (1) present a novel hypomorphic Sox10 mutation that results in a WS4-like phenotype in mice; (2) demonstrate that a 15.9-kb deletion underlies the observed phenotype and likely removes sequences essential for Sox10 expression; and (3) combine a novel in silico method for comparative sequence analysis with in vitro functional assays to identify candidate regulatory sequences deleted in this strain. These studies will direct further analyses of Sox10 regulation and provide candidate sequences for mutation detection in WS4 patients lacking a SOX10 coding mutation.


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T. Werner, A. Hammer, M. Wahlbuhl, M. R. Bosl, and M. Wegner
Multiple conserved regulatory elements with overlapping functions determine Sox10 expression in mouse embryogenesis
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[Abstract] [Full Text] [PDF]


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