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

Nat Genet. 2009 Mar;41(3):359-64. doi: 10.1038/ng.329. Epub 2009 Feb 22.


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 approximately 1.5 Mb centromeric and approximately 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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Chromosome Mapping
  • Chromosomes, Human, Pair 17
  • Conserved Sequence
  • Family
  • Gene Expression Regulation, Developmental
  • Humans
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Pedigree
  • Pierre Robin Syndrome / genetics*
  • Polymorphism, Genetic / physiology
  • Regulatory Elements, Transcriptional / genetics
  • SOX9 Transcription Factor / genetics*
  • Untranslated Regions / genetics*


  • SOX9 Transcription Factor
  • SOX9 protein, human
  • Untranslated Regions

Associated data

  • GENBANK/AC007642
  • GENBANK/AC009126
  • GENBANK/AC092662
  • GENBANK/AC098485
  • GENBANK/BC021285
  • GENBANK/BC052274
  • OMIM/114290
  • OMIM/142983
  • OMIM/170390
  • OMIM/261800
  • OMIM/600681
  • OMIM/608160
  • RefSeq/NC_000002
  • RefSeq/NC_000005
  • RefSeq/NC_000017
  • RefSeq/NC_000077
  • RefSeq/NC_006591
  • RefSeq/NC_007873
  • RefSeq/NM_000346
  • RefSeq/NM_000891
  • RefSeq/NM_002758
  • RefSeq/NM_011448
  • RefSeq/NM_018658
  • RefSeq/NM_170741
  • RefSeq/NM_170742