An impairment of long distance SOX10 regulatory elements underlies isolated Hirschsprung disease

Hum Mutat. 2014 Mar;35(3):303-7. doi: 10.1002/humu.22499. Epub 2014 Jan 8.


A deletion encompassing several SOX10 enhancers was recently identified in a patient presenting with Waardenburg syndrome type 4 (WS4), which is defined as a combination of Hirschsprung disease (HSCR, intestinal aganglionosis) and WS (deafness and pigmentation defects). The expression patterns of some of the known SOX10 enhancers in animal models led to the speculation that endophenotypes of WS4 may be linked to mutations within some of these sequences. The present study investigated deletions and point mutations within four SOX10 enhancers in 144 unexplained isolated HSCR cases. One deletion and two point mutations affecting binding sites for known neural crest transcription factors were identified. In vitro functional analysis revealed that the first point mutation disrupts autoregulation by SOX10, whereas the second affects AP2a and SOX10 synergistic activity. The present findings suggest that the mutations within SOX10 enhancers contribute to isolated HSCR.

Keywords: Hirschsprung; SOX10; enteric nervous system; neural crest; regulatory elements.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Female
  • Hirschsprung Disease
  • Humans
  • Infant
  • Male
  • Molecular Sequence Data
  • Point Mutation
  • Regulatory Sequences, Nucleic Acid*
  • SOXE Transcription Factors / genetics*
  • Sequence Deletion
  • Transcription Factors / genetics
  • Waardenburg Syndrome / genetics*


  • SOX10 protein, human
  • SOXE Transcription Factors
  • Transcription Factors

Supplementary concepts

  • Waardenburg syndrome, type 4