Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence

Sabina Benko, Judy A. Fantes, Jeanne Amiel, Dirk Jan Kleinjan, Sophie Thomas, Jacqueline Ramsay, Negar Jamshidi, Abdelkader Essafi, Simon Heaney, Christopher T. Gordon, David McBride, Christelle Golzio, Malcolm Fisher, Paul Perry, Véronique Abadie, Carmen Ayuso, Muriel Holder-Espinasse, Nicky Kilpatrick, Melissa M. Lees, Arnaud PicardI. Karen Temple, Paul Thomas, Marie Paule Vazquez, Michel Vekemans, Hugues Roest Crollius, Nicholas D. Hastie, Arnold Munnich, Heather C. Etchevers, Anna Pelet, Peter G. Farlie, David R. Fitzpatrick, Stanislas Lyonnet

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271 Citations (Scopus)


Pierre Robin sequence (PRS) is an important subgroup of cleft palate. We report several lines of evidence for the existence of a 17q24 locus underlying PRS, including linkage analysis results, a clustering of translocation breakpoints 1.06-1.23 Mb upstream of SOX9, and microdeletions both ∼1.5 Mb centromeric and ∼1.5 Mb telomeric of SOX9. We have also identified a heterozygous point mutation in an evolutionarily conserved region of DNA with in vitro and in vivo features of a developmental enhancer. This enhancer is centromeric to the breakpoint cluster and maps within one of the microdeletion regions. The mutation abrogates the in vitro enhancer function and alters binding of the transcription factor MSX1 as compared to the wild-type sequence. In the developing mouse mandible, the 3-Mb region bounded by the microdeletions shows a regionally specific chromatin decompaction in cells expressing Sox9. Some cases of PRS may thus result from developmental misexpression of SOX9 due to disruption of very-long-range cis-regulatory elements.

Original languageEnglish
Pages (from-to)359-364
Number of pages6
JournalNature Genetics
Issue number3
Publication statusPublished or Issued - Mar 2009

ASJC Scopus subject areas

  • Genetics

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