ZFIN ID: ZDB-PUB-140618-5
Identification of novel craniofacial regulatory domains located far upstream of SOX9 and disrupted in Pierre Robin sequence
Gordon, C.T., Attanasio, C., Bhatia, S., Benko, S., Ansari, M., Tan, T.Y., Munnich, A., Pennacchio, L.A., Abadie, V., Temple, I.K., Goldenberg, A., van Heyningen, V., Amiel, J., FitzPatrick, D., Kleinjan, D.A., Visel, A., Lyonnet, S.
Date: 2014
Source: Human Mutation   35(8): 1011-20 (Journal)
Registered Authors: Bhatia, Shipra, Gordon, Chris, Lyonnet, Stanislas, van Heyningen, Veronica
Keywords: Pierre Robin, SOX9, campomelic dysplasia, craniofacial, enhancer, long-range regulation
MeSH Terms:
  • Adult
  • Animals
  • Base Sequence
  • Campomelic Dysplasia/genetics*
  • Campomelic Dysplasia/pathology
  • Child
  • Chromosomes, Human, Pair 17
  • Enhancer Elements, Genetic*
  • Female
  • Genetic Loci
  • Humans
  • Male
  • Mandible/abnormalities
  • Mandible/metabolism
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Pierre Robin Syndrome/genetics*
  • Pierre Robin Syndrome/pathology
  • SOX9 Transcription Factor/genetics*
  • Zebrafish
  • p300-CBP Transcription Factors/genetics
  • p300-CBP Transcription Factors/metabolism
PubMed: 24934569 Full text @ Hum. Mutat.
Mutations in the coding sequence of SOX9 cause campomelic dysplasia (CD), a disorder of skeletal development associated with 46,XY disorders of sex development (DSDs). Translocations, deletions and duplications within a ∼2 Mb region upstream of SOX9 can recapitulate the CD-DSD phenotype fully or partially, suggesting the existence of an unusually large cis-regulatory control region. Pierre Robin sequence (PRS) is a craniofacial disorder that is frequently an endophenotype of CD and a locus for isolated PRS at ∼1.2-1.5 Mb upstream of SOX9 has been previously reported. The craniofacial regulatory potential within this locus, and within the greater genomic domain surrounding SOX9, remains poorly defined. We report two novel deletions upstream of SOX9 in families with PRS, allowing refinement of the regions harbouring candidate craniofacial regulatory elements. In parallel, ChIP-Seq for p300 binding sites in mouse craniofacial tissue led to the identification of several novel craniofacial enhancers at the SOX9 locus, which were validated in transgenic reporter mice and zebrafish. Notably, some of the functionally validated elements fall within the PRS deletions. These studies suggest that multiple non-coding elements contribute to the craniofacial regulation of SOX9 expression, and that their disruption results in PRS.