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Review
. 2014 Dec 10:9:200.
doi: 10.1186/s13023-014-0200-y.

Hajdu-Cheney syndrome: a review

Ernesto Canalis  1 , Stefano Zanotti  2
Affiliations
Review

Hajdu-Cheney syndrome: a review

Ernesto Canalis et al. Orphanet J Rare Dis. .

Abstract

Hajdu Cheney Syndrome (HCS), Orpha 955, is a rare disease characterized by acroosteolysis, severe osteoporosis, short stature, specific craniofacial features, wormian bones, neurological symptoms, cardiovascular defects and polycystic kidneys. HCS is rare and is inherited as autosomal dominant although many sporadic cases have been reported. HCS is associated with mutations in exon 34 of NOTCH2 upstream the PEST domain that lead to the creation of a truncated and stable NOTCH2 protein with enhanced NOTCH2 signaling activity. Although the number of cases with NOTCH2 mutations reported are limited, it would seem that the diagnosis of HCS can be established by sequence analysis of exon 34 of NOTCH2. Notch receptors are single-pass transmembrane proteins that determine cell fate, and play a critical role in skeletal development and homeostasis. Dysregulation of Notch signaling is associated with skeletal developmental disorders. There is limited information about the mechanisms of the bone loss and acroosteolysis in HCS making decisions regarding therapeutic intervention difficult. Bone antiresorptive and anabolic agents have been tried to treat the osteoporosis, but their benefit has not been established. In conclusion, Notch regulates skeletal development and bone remodeling, and gain-of-function mutations of NOTCH2 are associated with HCS.

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Figures

Figure 1
Figure 1
Structure of NOTCH2 and mutations associated with Hajdu- Cheney syndrome. The extracellular domain (ECD) of Notch consists of multiple epidermal growth factor (EGF) repeats, upstream the transmembrane domain (TMD). The intracellular domain of NOTCH2 (NICD) consists of a transcriptional domain formed by the Rbpjκ association module (RAM) linked to ankyrin (ANK) repeats, and nuclear localization sequences. The C-terminus contains the proline (P)-, glutamic acid (E)-, serine (S)-, and threonine (T)-rich motifs (PEST) domain which is required for the ubiquitinylation and degradation of the NICD. Nonsense and deletion mutations in exon 34 associated with Hajdu-Cheney syndrome (HCS) and pointed by the arrow lead to the formation of a truncated protein consisting of all NOTCH2 sequences necessary for the formation of the transcriptional complex, but lacking the PEST domain needed for the ubiquitinylation and degradation of NOTCH2. As such, a stable and active NOTCH2 protein is synthesized.
Figure 2
Figure 2
Activation of Notch signaling. Notch receptors and Jagged/Delta ligands are expressed as single-pass transmembrane proteins. Receptor-ligand interactions lead to the cleavage of the Notch receptor and release of the Notch intracellular domain (NICD) to the cytoplasm. NICD translocates to the nucleus and forms a ternary complex with Rbpjκ and Mastermind-like, displacing transcriptional repressors and associating with transcriptional activators, and inducing expression of Notch target genes.
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