Article Text

other Versions

PDF
Original article
Mutations in the T (brachyury) gene cause a novel syndrome consisting of sacral agenesis, abnormal ossification of the vertebral bodies and a persistent notochordal canal
  1. A V Postma1,2,
  2. M Alders2,
  3. M Sylva1,
  4. C M Bilardo3,4,
  5. E Pajkrt3,
  6. R R van Rijn5,
  7. S Schulte-Merker6,
  8. S Bulk7,
  9. S Stefanovic1,
  10. A Ilgun1,
  11. P Barnett1,
  12. M M A M Mannens2,
  13. A F M Moorman1,
  14. R J Oostra1,
  15. M C van Maarle2
  1. 1Department of Anatomy, Embryology & Physiology,Academic Medical Centre, Amsterdam, The Netherlands
  2. 2Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands
  3. 3Department of Obstetrics and Gynaecology, Academic Medical Centre, Amsterdam, The Netherlands
  4. 4Department of Obstetrics and Gynaecology, University Medical Centre, Groningen, The Netherlands
  5. 5Department of Radiology, Academic Medical Centre, Amsterdam, The Netherlands
  6. 6Hubrecht Institute, KNAW and University Medical Centre Utrecht, Utrecht, The Netherlands
  7. 7Department of Medical Genetics, University Medical Center Utrecht, The Netherlands
  1. Correspondence to Professor R J Oostra, Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, Amsterdam 1105 AZ, The Netherlands; r.j.oostra{at}amc.nl

Abstract

Background The T gene (brachyury gene) is the founding member of the T-box family of transcription factors and is vital for the formation and differentiation of the mesoderm and the axial development of all vertebrates.

Results We report here on four patients from three consanguineous families exhibiting sacral agenesis, a persistent notochordal canal and abnormal ossification of the vertebral bodies, and the identification and characterisation of their underlying genetic defect. Given the consanguineous nature and the similarity of the phenotypes between the three families, we performed homozygosity mapping and identified a common 4.1 Mb homozygous region on chromosome 6q27, containing T, brachyury homologue (mouse) or T. Sequencing of T in the affected individuals led to the identification of a homozygous missense mutation, p.H171R, in the highly conserved T-box. The homozygous mutation results in diminished DNA binding, increased cell growth, and interferes with the normal expression of genes involved in ossification, notochord maintenance and axial mesoderm development.

Conclusions We have identified a shared homozygous mutation in three families in T and linked it to a novel syndrome consisting of sacral agenesis, a persistent notochordal canal and abnormal ossification of the vertebral bodies. We suggest that screening for the ossification of the vertebrae is warranted in patients with sacral agenesis to evaluate the possible causal involvement of T.

  • Clinical Genetics
  • Developmental
  • Genome-Wide
  • Linkage

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.