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. 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.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Antonellis A,Bennett WR,Menheniott TR,Prasad AB,Lee-Lin SQ,NISC Comparative Sequencing Program.,Green ED,Paisley D,Kelsh RN,Pavan WJ,Ward Adoi
10.1093/hmg/ddi442subject
Has Abstractpub_date
2006-01-15 00:00:00pages
259-71issue
2eissn
0964-6906issn
1460-2083pii
ddi442journal_volume
15pub_type
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