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

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.

Nat Genet. 2011 Mar 8; 43(4):303-5

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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