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

Michael A. Simpson; Melita D. Irving; Esra Asilmaz; Mary J. Gray; Dimitra Dafou; Frances V. Elmslie; Sahar Mansour; Sue E. Holder; Caroline E. Brain; Barbara K. Burton; Katherine H. Kim; Richard M. Pauli; Salim Aftimos; Helen Stewart; Chong Ae Kim; Muriel Holder-Espinasse; Stephen P. Robertson; William M. Drake; Richard C. Trembath

doi:10.1038/ng.779

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

Michael A. Simpson, Melita D. Irving, Esra Asilmaz, Mary J. Gray, Dimitra Dafou, Frances V. Elmslie, Sahar Mansour, Sue E. Holder, Caroline E. Brain, Barbara K. Burton, Katherine H. Kim, Richard M. Pauli, Salim Aftimos, Helen Stewart, Chong Ae Kim, Muriel Holder-Espinasse, Stephen P. Robertson, William M. Drake, Richard C. Trembath

Pediatrics

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252 Scopus citations

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.

Original language	English (US)
Pages (from-to)	303-305
Number of pages	3
Journal	Nature Genetics
Volume	43
Issue number	4
DOIs	https://doi.org/10.1038/ng.779
State	Published - Feb 2011

Funding

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.

ASJC Scopus subject areas

Genetics

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10.1038/ng.779

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Simpson, M. A., Irving, M. D., Asilmaz, E., Gray, M. J., Dafou, D., Elmslie, F. V., Mansour, S., Holder, S. E., Brain, C. E., Burton, B. K., Kim, K. H., Pauli, R. M., Aftimos, S., Stewart, H., Kim, C. A., Holder-Espinasse, M., Robertson, S. P., Drake, W. M., & Trembath, R. C. (2011). Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nature Genetics, 43(4), 303-305. https://doi.org/10.1038/ng.779

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title = "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.",

author = "Simpson, {Michael A.} and Irving, {Melita D.} and Esra Asilmaz and Gray, {Mary J.} and Dimitra Dafou and Elmslie, {Frances V.} and Sahar Mansour and Holder, {Sue E.} and Brain, {Caroline E.} and Burton, {Barbara K.} and Kim, {Katherine H.} and Pauli, {Richard M.} and Salim Aftimos and Helen Stewart and Kim, {Chong Ae} and Muriel Holder-Espinasse and Robertson, {Stephen P.} and Drake, {William M.} and Trembath, {Richard C.}",

note = "Funding Information: 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{\textquoteright}s and St. Thomas{\textquoteright} National Health Service (NHS) Foundation Trust in partnership with King{\textquoteright}s College London and King{\textquoteright}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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Simpson, MA, Irving, MD, Asilmaz, E, Gray, MJ, Dafou, D, Elmslie, FV, Mansour, S, Holder, SE, Brain, CE, Burton, BK , Kim, KH, Pauli, RM, Aftimos, S, Stewart, H, Kim, CA, Holder-Espinasse, M, Robertson, SP, Drake, WM & Trembath, RC 2011, 'Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss', Nature Genetics, vol. 43, no. 4, pp. 303-305. https://doi.org/10.1038/ng.779

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AU - Pauli, Richard M.

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AU - Robertson, Stephen P.

AU - Drake, William M.

AU - Trembath, Richard C.

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

Abstract

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