Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss

Abstract

We used an exome-sequencing strategy and identified an allelic series of NOTCH2 mutations in Hajdu-Cheney syndrome, an autosomal dominant multisystem disorder characterized by severe and progressive bone loss. The Hajdu-Cheney syndrome mutations are predicted to lead to the premature truncation of NOTCH2 with either disruption or loss of the C-terminal proline-glutamate-serine-threonine-rich proteolytic recognition sequence, the absence of which has previously been shown to increase Notch signaling.

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Figure 1: Clinical features of Hajdu-Cheney syndrome and a summary of NOTCH2 mutations.

References

  1. 1

    Brennan, A.M. & Pauli, R.M. Am. J. Med. Genet. 100, 292–310 (2001).

    CAS  Article  Google Scholar 

  2. 2

    Ralston, S.H. & Uitterlinden, A.G. Endocr. Rev. 31, 1–24 (2010).

    Article  Google Scholar 

  3. 3

    Albano, L.M. et al. Clin. Dysmorphol. 16, 27–33 (2007).

    Article  Google Scholar 

  4. 4

    Ostergaard, P. et al. J. Med. Genet. published online, doi:10.1136/jmg.2010.085563 (25 January 2011).

  5. 5

    Zanotti, S. & Canalis, E. Mol. Cell. Biol. 30, 886–896 (2010).

    CAS  Article  Google Scholar 

  6. 6

    Kopan, R. et al. Cell 137, 216–233 (2009).

    CAS  Article  Google Scholar 

  7. 7

    Rechsteiner, M. & Rogers, S.W. Trends Biochem. Sci. 21, 267–271 (1996).

    CAS  Article  Google Scholar 

  8. 8

    Nagy, E. & Maquat, L.E. Trends Biochem. Sci. 23, 198–199 (1998).

    CAS  Article  Google Scholar 

  9. 9

    Lee, S. et al. Cancer Sci. 100, 920–926 (2009).

    CAS  Article  Google Scholar 

  10. 10

    Weng, A.P. et al. Science 306, 269–271 (2004).

    CAS  Article  Google Scholar 

  11. 11

    McDaniell, R. et al. Am. J. Hum. Genet. 79, 169–173 (2006).

    CAS  Article  Google Scholar 

  12. 12

    Morrissette, J.D., Colliton, R.P. & Spinner, N.B. Hum. Mol. Genet. 10, 405–413 (2001).

    CAS  Article  Google Scholar 

  13. 13

    Hamada, Y. et al. Development 126, 3415–3424 (1999).

    CAS  PubMed  Google Scholar 

  14. 14

    Fukushima, H. et al. Mol. Cell. Biol. 28, 6402–6412 (2008).

    CAS  Article  Google Scholar 

  15. 15

    Kung, A.W.C. et al. Am. J. Hum. Genet. 86, 1–11 (2010).

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank the families for participating in this study. This work was supported by grants from the British Heart Foundation (BHF) to R.C.T. and from Cure Kids New Zealand to S.P.R. and M.J.G. The authors also acknowledge support from the UK Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. Grateful acknowledgment is also made to I. Marik, Chief of the Centre for Patients with Locomotor Defects, Prague, Czech Republic for assistance in recruitment to this study.

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Correspondence to Richard C Trembath.

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Supplementary Methods, Supplementary Tables 1–3 and Supplementary Figures 1–3. (PDF 595 kb)

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Simpson, M., Irving, M., Asilmaz, E. et al. Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat Genet 43, 303–305 (2011). https://doi.org/10.1038/ng.779

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