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Pierre Robin sequence may be caused by dysregulation of SOX9 and KCNJ2
  1. Linda P Jakobsen1,
  2. Reinhard Ullmann3,
  3. Steen B Christensen4,
  4. Karl Erik Jensen5,
  5. Kirsten Mølsted6,
  6. Karen F Henriksen2,
  7. Claus Hansen2,
  8. Mary A Knudsen1,
  9. Lars A Larsen2,
  10. Niels Tommerup2,
  11. Zeynep Tümer2
  1. 1Department of Plastic and Reconstructive Surgery and Burns Unit, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
  2. 2Wilhelm Johannsen Centre for Functional Genome Research, Department of Medical Biochemistry and Genetics, Panum Institute, Copenhagen, Denmark
  3. 3Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany
  4. 4Department of Orthopaedic Surgery, Section of Paediatric Orthopaedics, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
  5. 5Department of Diagnostic Radiology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
  6. 6Copenhagen Cleft Palate Centre, Copenhagen, Denmark
  1. Correspondence to:
 Dr L P Jakobsen
 Wilhelm Johannsen Centre for Functional Genome Research, Department of Medical Biochemistry and Genetics, Panum Institute 24.4., Blegdamsvej 3, 2200 Copenhagen N, Denmark; linda{at}imbg.ku.dk

Abstract

Background: The Pierre Robin sequence (PRS), consisting of cleft palate, micrognathia and glossoptosis, can be seen as part of the phenotype in other Mendelian syndromes—for instance, campomelic dysplasia (CD) which is caused by SOX9 mutations—but the aetiology of non-syndromic PRS has not yet been unravelled.

Objective: To gain more insight into the aetiology of PRS by studying patients with PRS using genetic and cytogenetic methods.

Methods: 10 unrelated patients with PRS were investigated by chromosome analyses and bacterial artificial chromosome arrays. A balanced translocation was found in one patient, and the breakpoints were mapped with fluorescence in situ hybridisation and Southern blot analysis. All patients were screened for SOX9 and KCNJ2 mutations, and in five of the patients expression analysis of SOX9 and KCNJ2 was carried out by quantitative real-time PCR.

Results: An abnormal balanced karyotype 46,XX, t(2;17)(q23.3;q24.3) was identified in one patient with PRS and the 17q breakpoint was mapped to 1.13 Mb upstream of the transcription factor SOX9 and 800 kb downstream of the gene KCNJ2. Furthermore, a significantly reduced SOX9 and KCNJ2 mRNA expression was observed in patients with PRS.

Conclusion: Our findings suggest that non-syndromic PRS may be caused by both SOX9 and KCNJ2 dysregulation.

  • BAC, bacterial artificial chromosome
  • CD, campomelic dysplasia
  • CGH, comparative genome hybridisation
  • CL/P cleft lip and/or palate,
  • FISH, fluorescence in situ hybridisation
  • MCNdb, Mendelian Cytogenetics Network database
  • miRNA, microRNA
  • PRS, Pierre Robin sequence
  • QPCR, quantitative real-time PCR
  • SNP, single-nucleotide polymorphism

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Footnotes

  • Competing interests: None.

  • Informed consent was obtained for publication of fig 1.

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