title: Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence.
abstract: 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.
authors.affiliation: INSERM U-781, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Sabina
authors.initials: S
authors.lastname: Benko
authors.forename: Judy A
authors.initials: JA
authors.lastname: Fantes
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.forename: Dirk-Jan
authors.initials: DJ
authors.lastname: Kleinjan
authors.forename: Sophie
authors.initials: S
authors.lastname: Thomas
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ramsay
authors.forename: Negar
authors.initials: N
authors.lastname: Jamshidi
authors.forename: Abdelkader
authors.initials: A
authors.lastname: Essafi
authors.forename: Simon
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authors.lastname: Heaney
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Gordon
authors.forename: David
authors.initials: D
authors.lastname: McBride
authors.forename: Christelle
authors.initials: C
authors.lastname: Golzio
authors.forename: Malcolm
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authors.lastname: Fisher
authors.forename: Paul
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authors.lastname: Perry
authors.forename: Véronique
authors.initials: V
authors.lastname: Abadie
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
authors.forename: Muriel
authors.initials: M
authors.lastname: Holder-Espinasse
authors.forename: Nicky
authors.initials: N
authors.lastname: Kilpatrick
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Lees
authors.forename: Arnaud
authors.initials: A
authors.lastname: Picard
authors.forename: I Karen
authors.initials: IK
authors.lastname: Temple
authors.forename: Paul
authors.initials: P
authors.lastname: Thomas
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Vazquez
authors.forename: Michel
authors.initials: M
authors.lastname: Vekemans
authors.forename: Hugues
authors.initials: H
authors.lastname: Roest Crollius
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Hastie
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Heather C
authors.initials: HC
authors.lastname: Etchevers
authors.forename: Anna
authors.initials: A
authors.lastname: Pelet
authors.forename: Peter G
authors.initials: PG
authors.lastname: Farlie
authors.forename: David R
authors.initials: DR
authors.lastname: Fitzpatrick
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
mesh_terms: D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D017124:Conserved Sequence; D005190:Family; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010375:Pedigree; D010855:Pierre Robin Syndrome / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000502:physiology; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D055758:SOX9 Transcription Factor / Q000235:genetics*; D020506:Untranslated Regions / Q000235:genetics*
chemical_list: D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D020506:Untranslated Regions