Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Phenotype associated with TCF12 or Tcf12 haploinsufficiency in humans and mice.
Figure 2: Structure of TCF12 and the encoded protein showing the location of mutations identified in coronal synostosis.

Similar content being viewed by others

Accession codes

Primary accessions

NCBI Reference Sequence

Referenced accessions

Protein Data Bank

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.

References

  1. Lajeunie, E., Le Merrer, M., Bonaïti-Pellie, C., Marchac, D. & Renier, D. Genetic study of nonsyndromic coronal craniosynostosis. Am. J. Med. Genet. 55, 500–504 (1995).

    Article  CAS  Google Scholar 

  2. Boulet, S.L., Rasmussen, S.A. & Honein, M.A. A population-based study of craniosynostosis in metropolitan Atlanta, 1989–2003. Am. J. Med. Genet. 146A, 984–991 (2008).

    Article  Google Scholar 

  3. Wilkie, A.O.M. et al. Prevalence and complications of single-gene and chromosomal disorders in craniosynostosis. Pediatrics 126, e391–e400 (2010).

    Article  Google Scholar 

  4. Howard, T.D. et al. Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome. Nat. Genet. 15, 36–41 (1997).

    Article  Google Scholar 

  5. El Ghouzzi, V. et al. Mutations of the TWIST gene in the Saethre-Chotzen syndrome. Nat. Genet. 15, 42–46 (1997).

    Article  CAS  Google Scholar 

  6. Jabs, E.W. TWIST and the Saethre-Chotzen syndrome. in Inborn Errors of Development. The Molecular Basis of Clinical Disorders of Morphogenesis, 2nd edn (eds. Epstein, C.J., Erickson, R.P. & Wynshaw-Boris, A.) 474–481 (Oxford University Press, Oxford, 2008).

  7. Ng, S.B. et al. Exome sequencing identifies the cause of a mendelian disorder. Nat. Genet. 42, 30–35 (2010).

    Article  CAS  Google Scholar 

  8. Johnson, D. & Wilkie, A.O.M. Craniosynostosis. Eur. J. Hum. Genet. 19, 369–376 (2011).

    Article  CAS  Google Scholar 

  9. Hu, J.S., Olson, E.N. & Kingston, R.E. HEB, a helix-loop-helix protein related to E2A and ITF2, that can modulate the DNA-binding ability of myogenic regulatory factors. Mol. Cell Biol. 12, 1031–1042 (1992).

    Article  CAS  Google Scholar 

  10. Nielsen, A.L., Pallisgaard, N., Pedersen, F.S. & Jørgensen, P. Murine helix-loop-helix transcriptional activator proteins binding to the E-box motif of the Akv murine leukemia-virus enhancer identified by cDNA cloning. Mol. Cell Biol. 12, 3449–3459 (1992).

    Article  CAS  Google Scholar 

  11. Gan, T.-I. Genomic organization of human TCF12 gene and spliced mRNA variants producing isoforms of transcription factor HTF4. Cytogenet. Genome Res. 98, 245–248 (2002).

    Article  CAS  Google Scholar 

  12. Hiraki, Y. et al. Craniosynostosis in a patient with a de novo 15q15-q22 deletion. Am. J. Med. Genet. 146A, 1462–1465 (2008).

    Article  Google Scholar 

  13. Wang, D. et al. The basic helix-loop-helix transcription factor HEBAlt is expressed in pro-T cells and enhances the generation of T cell precursors. J. Immunol. 177, 109–119 (2006).

    Article  CAS  Google Scholar 

  14. Whalen, S. et al. Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum. Hum. Mutat. 33, 64–72 (2012).

    Article  CAS  Google Scholar 

  15. Laursen, K.B., Mielke, E., Iannaccone, P. & Fuchtbauer, E.M. Mechanism of transcriptional activation by the proto-oncogene Twist1. J. Biol. Chem. 282, 34623–34633 (2007).

    Article  CAS  Google Scholar 

  16. Wojciechowski, J., Lai, A., Kondo, M. & Zhuang, Y. E2A and HEB are required to block thymocyte proliferation prior to pre-TCR expression. J. Immunol. 178, 5717–5726 (2007).

    Article  CAS  Google Scholar 

  17. Connerney, J. et al. Twist1 dimer selection regulates cranial suture patterning and fusion. Dev. Dyn. 235, 1345–1357 (2006).

    Article  CAS  Google Scholar 

  18. Lakso, M. et al. Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. Proc. Natl. Acad. Sci. USA 93, 5860–5865 (1996).

    Article  CAS  Google Scholar 

  19. Chen, Z.F. & Behringer, R.R. twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev. 9, 686–699 (1995).

    Article  CAS  Google Scholar 

  20. Merrill, A.E. et al. Cell mixing at a neural crest–mesoderm boundary and deficient ephrin-Eph signaling in the pathogenesis of craniosynostosis. Hum. Mol. Genet. 15, 1319–1328 (2006).

    Article  CAS  Google Scholar 

  21. Chai, Y. & Maxson, R.E. Jr. Recent advances in craniofacial morphogenesis. Dev. Dyn. 235, 2353–2375 (2006).

    Article  Google Scholar 

  22. Bialek, P. et al. A Twist code determines the onset of osteoblast differentiation. Dev. Cell 6, 423–435 (2004).

    Article  CAS  Google Scholar 

  23. Hayashi, M. et al. Comparative roles of Twist-1 and Id1 in transcriptional regulation by BMP signaling. J. Cell Sci. 120, 1350–1357 (2007).

    Article  CAS  Google Scholar 

  24. Aronheim, A., Shiran, R., Rosen, A. & Walker, M.D. The E2A gene-product contains two separable and functionally distinct transcription activation domains. Proc. Natl. Acad. Sci. USA 90, 8063–8067 (1993).

    Article  CAS  Google Scholar 

  25. Markus, M., Du, Z.M. & Benezra, R. Enhancer-specific modulation of E protein activity. J. Biol. Chem. 277, 6469–6477 (2002).

    Article  CAS  Google Scholar 

  26. Longo, A., Guanga, G.P. & Rose, R.B. Crystal structure of E47-NeuroD1/β2 bHLH domain-DNA complex: heterodimer selectivity and DNA recognition. Biochemistry 47, 218–229 (2008).

    Article  CAS  Google Scholar 

Download references

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

Authors and Affiliations

Authors

Consortia

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.

Corresponding authors

Correspondence to Robert E Maxson or Andrew O M Wilkie.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

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

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–6 and Supplementary Tables 1–6 (PDF 2360 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sharma, V., Fenwick, A., Brockop, M. et al. Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis. Nat Genet 45, 304–307 (2013). https://doi.org/10.1038/ng.2531

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing