Identification of novel craniofacial regulatory domains located far upstream of SOX9 and disrupted in Pierre Robin sequence

Christopher T Gordon, Catia Attanasio, Shipra Bhatia, Sabina Benko, Morad Ansari, Tiong Y Tan, Arnold Munnich, Len A Pennacchio, Véronique Abadie, I Karen Temple, Alice Goldenberg, Veronica van Heyningen, Jeanne Amiel, David FitzPatrick, Dirk A Kleinjan, Axel Visel, Stanislas Lyonnet

Research output: Contribution to journalArticlepeer-review


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 harboring 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 noncoding elements contribute to the craniofacial regulation of SOX9 expression, and that their disruption results in PRS.

Original languageEnglish
Pages (from-to)1011-20
Number of pages10
JournalHuman Mutation
Issue number8
Publication statusPublished - Aug 2014


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