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Deletion of long-range sequences at Sox10 compromises developmental expression in a mouse model of Waardenburg-Shah (WS4) syndrome


Antonellis, A and Bennett, WR and Menheniott, TR and Prasad, AB and Lee-Lin, SQ and Green, ED and Paisley, D and Kelsh, RN and Pavan, WJ and Ward, A, Deletion of long-range sequences at Sox10 compromises developmental expression in a mouse model of Waardenburg-Shah (WS4) syndrome, Human Molecular Genetics, 15, (2) pp. 259-271. ISSN 0964-6906 (2006) [Refereed Article]

DOI: doi:10.1093/hmg/ddi442


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. Although 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: (i) present a novel hypomorphic SOX10 mutation that results in a WS4-like phenotype in mice; (ii) demonstrate that a 15.9 kb deletion underlies the observed phenotype and likely removes sequences essential for SOX10 expression; (iii) 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.

Item Details

Item Type:Refereed Article
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Developmental genetics (incl. sex determination)
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Bennett, WR (Dr Bill Bennett)
ID Code:63714
Year Published:2006
Web of Science® Times Cited:50
Deposited By:Menzies Institute for Medical Research
Deposited On:2010-05-26
Last Modified:2010-05-26

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