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Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis

Nature Genetics volume 43, pages 306–308 (2011)Cite this article

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Abstract

Hajdu-Cheney syndrome is a rare autosomal dominant skeletal disorder with facial anomalies, osteoporosis and acro-osteolysis. We sequenced the exomes of six unrelated individuals with this syndrome and identified heterozygous nonsense and frameshift mutations in NOTCH2 in five of them. All mutations cluster to the last coding exon of the gene, suggesting that the mutant mRNA products escape nonsense-mediated decay and that the resulting truncated NOTCH2 proteins act in a gain-of-function manner.

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Figure 1: Identification of NOTCH2 mutations in individuals with Hajdu-Cheney syndrome.

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NCBI Reference Sequence

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Acknowledgements

We are grateful to the affected subjects and their families who participated in this study. We thank F. Gros, H. Eldjouzi, A. Briand, C. Beneteau and S. Lecointe for technical assistance, and R. Houlgatte and C. Chevalier from Biogenouest de Nantes. This research was funded by grants from Inserm, Fondation pour la Recherche Médicale, Fédération Française de Cardiologie and Région Pays-de-la-Loire. P.L. is supported by the Direction Hospitalière de l'Organisation des Soins (DHOS). S.J. is funded by the “bourse de relève acadèmique de la Facultè de Biologie et Mèdecine de l'Université de Lausanne.”

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Author notes

  1. Bertrand Isidor and Pierre Lindenbaum: These authors contributed equally to this work.

Authors and Affiliations

  1. CHU Nantes, Service de Génétique Médicale, Nantes, France

    Bertrand Isidor, Pierre Lindenbaum, Olivier Pichon, Stéphane Bézieau, Albert David, Richard Redon & Cédric Le Caignec

  2. INSERM, UMR915, L'Institut du Thorax, Nantes, France

    Pierre Lindenbaum, Christian Dina, Richard Redon & Cédric Le Caignec

  3. Université de Nantes, Nantes, France

    Pierre Lindenbaum, Stéphane Bézieau, Christian Dina, Richard Redon & Cédric Le Caignec

  4. CNRS, ERL3147, Nantes, France

    Christian Dina & Cédric Le Caignec

  5. Centre Hospitalier Universitaire Vaudois (CHUV), Service de Génétique Médicale, Lausanne, Switzerland

    Sébastien Jacquemont

  6. Unité de Génétique Clinique, Centre Hospitalier du Mans, Le Mans, France

    Dominique Martin-Coignard

  7. Centre de Génétique, Centre de Référence Maladies Rares 'Anomalies du développement et syndromes malformatifs de l'interrégion Est' Hôpital d'Enfants, CHU, Dijon, France

    Christel Thauvin-Robinet & Laurence Faivre

  8. Université de Bourgogne, Dijon, France

    Christel Thauvin-Robinet & Laurence Faivre

  9. INSERM U781, Paris, France

    Martine Le Merrer & Valérie Cormier-Daire

  10. Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France

    Martine Le Merrer & Valérie Cormier-Daire

  11. Université Paris Descartes, Paris, France

    Martine Le Merrer & Valérie Cormier-Daire

  12. Translational Medicine and Neurogenetics Program, Institut de Génétique et de Biologie, Moléculaire et Cellulaire (IGBMC), Collège de France, Illkirch, France

    Jean-Louis Mandel

  13. INSERM U964, Illkirch, France

    Jean-Louis Mandel

  14. CNRS UMR 7104, Illkirch, France

    Jean-Louis Mandel

  15. Université de Strasbourg, Illkirch, France

    Jean-Louis Mandel

  16. CHU de Strasbourg, Strasbourg, France

    Jean-Louis Mandel

Authors
  1. Bertrand Isidor
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  2. Pierre Lindenbaum
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  3. Olivier Pichon
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  4. Stéphane Bézieau
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  5. Christian Dina
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  6. Sébastien Jacquemont
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  7. Dominique Martin-Coignard
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  8. Christel Thauvin-Robinet
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  9. Martine Le Merrer
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  10. Jean-Louis Mandel
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  11. Albert David
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  12. Laurence Faivre
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  13. Valérie Cormier-Daire
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  14. Richard Redon
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  15. Cédric Le Caignec
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Contributions

C.L.C., B.I., S.B., V.C.-D., L.F. and A.D. conceived the project and planned the experiments. B.I., V.C.-D., L.F., M.L.M., S.J., D.M.-C., C.T.-R. and A.D. clinically characterized the HCS cases and collected blood samples. O.P. performed validation experiments. P.L., C.D., R.R., B.I., J.-L.M. and C.L.C. analyzed and interpreted the exome data. C.L.C., B.I., R.R., J.-L.M. and S.J. wrote the manuscript. All authors contributed to the final manuscript.

Corresponding author

Correspondence to Cédric Le Caignec.

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The authors declare no competing financial interests.

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Supplementary Text and Figures

Supplementary Tables 1–5, Supplementary Figures 1–3 and Supplementary Methods. (PDF 465 kb)

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Isidor, B., Lindenbaum, P., Pichon, O. et al. Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet 43, 306–308 (2011). https://doi.org/10.1038/ng.778

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