• A Corrigendum to this article was published on 26 September 2013

This article has been updated

Abstract

Craniosynostosis, the premature fusion of the cranial sutures, is a heterogeneous disorder with a prevalence of 1 in 2,200 (refs. 1,2). A specific genetic etiology can be identified in 21% of cases3, including mutations of TWIST1, which encodes a class II basic helix-loop-helix (bHLH) transcription factor, and causes Saethre-Chotzen syndrome, typically associated with coronal synostosis4,5,6. Using exome sequencing, we identified 38 heterozygous TCF12 mutations in 347 samples from unrelated individuals with craniosynostosis. The mutations predominantly occurred in individuals with coronal synostosis and accounted for 32% and 10% of subjects with bilateral and unilateral pathology, respectively. TCF12 encodes one of three class I E proteins that heterodimerize with class II bHLH proteins such as TWIST1. We show that TCF12 and TWIST1 act synergistically in a transactivation assay and that mice doubly heterozygous for loss-of-function mutations in Tcf12 and Twist1 have severe coronal synostosis. Hence, the dosage of TCF12-TWIST1 heterodimers is critical for normal coronal suture development.

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Change history

  • 05 September 2013

    In the version of this article initially published, numbering and spacing for the exon structure of TCF12 in Figure 2a was incorrect. The error has been corrected in the HTML and PDF versions of the article.

Accessions

Primary accessions

NCBI Reference Sequence

Referenced accessions

Protein Data Bank

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Acknowledgements

We thank all the families for their participation, S. Butler for cell culture, J. Frankland and T. Rostron for DNA sequencing, S. Knight for coordinating array–comparative genomic hybridization (aCGH), L. Gregory and the High-Throughput Genomics core at the Wellcome Trust Centre for Human Genetics for exome sequencing, R. Evans for review of anesthetic records, W. Baggley for clinical photography, A. van den Ouweland for genetic testing, E.-M. Füchtbauer (Aarhus University) for constructs and Y. Zhuang (Duke University) for the gift of the Tcf12flox mutant. This work was funded by the National Institute for Health Research (NIHR) Biomedical Research Centre Oxford (V.P.S. and R.J.C.), the Oxford University Clinical Academic Graduate School and the Oxfordshire Health Services Research Committee (V.P.S.), the Oxford Craniofacial Unit Charitable Fund (V.P.S.), the Thames Valley Comprehensive Local Research Network (J.M.P.), The Dutch Center for Translational Molecular Medicine (P.J.v.d.S.), the Carolien Bijl Foundation (J.A.C.G.), the US National Institutes of Health (NIH; R01DE016320 and R01DE019650 to R.E.M.) and the Wellcome Trust (093329 to S.R.F.T. and A.O.M.W.).

Author information

Author notes

    • Vikram P Sharma
    • , Aimée L Fenwick
    • , Mia S Brockop
    •  & Stephen R F Twigg

    These authors contributed equally to this work.

    • Robert E Maxson
    • , Stephen R F Twigg
    •  & Andrew O M Wilkie

    These authors jointly directed this work.

Affiliations

  1. Clinical Genetics Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

    • Vikram P Sharma
    • , Aimée L Fenwick
    • , Julie M Phipps
    • , Stephen R F Twigg
    •  & Andrew O M Wilkie
  2. Craniofacial Unit, Oxford University Hospitals National Health Service (NHS) Trust, Oxford, UK.

    • Vikram P Sharma
    • , David Johnson
    • , Steven A Wall
    •  & Andrew O M Wilkie
  3. Department of Biochemistry and Molecular Biology, University of Southern California/Norris Cancer Center, Los Angeles, California, USA.

    • Mia S Brockop
    •  & Robert E Maxson
  4. Université Paris–Sud, Orsay, France.

    • Mia S Brockop
  5. Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

    • Simon J McGowan
  6. Department of Plastic and Reconstructive Surgery, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.

    • Jacqueline A C Goos
    •  & Irene M J Mathijssen
  7. Department of Bioinformatics, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.

    • Jacqueline A C Goos
    •  & Peter J van der Spek
  8. Department of Clinical Genetics, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.

    • A Jeannette M Hoogeboom
  9. Kennedy Galton Centre, North West London Hospitals NHS Trust, London, UK.

    • Angela F Brady
  10. Department of Neurosurgery, Great Ormond Street Hospital for Children NHS Trust, London, UK.

    • Nu Owase Jeelani
  11. National Centre for Medical Genetics, Our Lady's Children's Hospital, Dublin, Ireland.

    • Sally Ann Lynch
  12. Department of Plastic and Oral Surgery, Children's Hospital, Boston, Massachusetts, USA.

    • John B Mulliken
  13. National Paediatric Craniofacial Centre, Children's University Hospital, Dublin, Ireland.

    • Dylan J Murray
  14. Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.

    • Elizabeth Sweeney
  15. Clinical Genetics Department, Musgrove Park Hospital, Taunton, UK.

    • Susan E Tomkins
  16. North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK.

    • Louise C Wilson
  17. Medical Research Council (MRC) Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

    • Sophia Bennett
    •  & Richard J Cornall
  18. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • John Broxholme
    •  & Alexander Kanapin

Consortia

  1. 500 Whole-Genome Sequences (WGS500) Consortium

    A list of members and affiliations is provided in the Supplementary Note.

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Contributions

S.R.F.T., R.E.M. and A.O.M.W. conceived the project. V.P.S., A.L.F., M.S.B. and S.R.F.T. performed experimental analyses. S.B. and R.J.C. performed immune function tests. S.J.M., J.B., A.K. and WGS500 coordinated or performed bioinformatics analyses. V.P.S., J.A.C.G., A.J.M.H., A.F.B., N.O.J., S.A.L., J.B.M., D.J.M., J.M.P., E.S., S.E.T., L.C.W., D.J., S.A.W., P.J.v.d.S., I.M.J.M. and A.O.M.W. recruited samples from subjects and collected clinical information. V.P.S., A.L.F., R.E.M., S.R.F.T. and A.O.M.W. drafted the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Robert E Maxson or Andrew O M Wilkie.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Note, Supplementary Figures 1–6 and Supplementary Tables 1–6

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DOI

https://doi.org/10.1038/ng.2531

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