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Review
. 2018 Mar:80:48-56.
doi: 10.1016/j.metabol.2017.08.002. Epub 2017 Aug 24.

Clinical and experimental aspects of notch receptor signaling: Hajdu-Cheney syndrome and related disorders

Ernesto Canalis  1
Affiliations
Review

Clinical and experimental aspects of notch receptor signaling: Hajdu-Cheney syndrome and related disorders

Ernesto Canalis. Metabolism. 2018 Mar.

Abstract

Background: There are four Notch transmembrane receptors that determine the fate and function of cells. Notch is activated following its interactions with ligands of the Jagged and Delta-like families that lead to the cleavage and release of the Notch intracellular domain (NICD); this translocates to the nucleus to induce the transcription of Notch target genes. Genetic disorders of loss- and gain-of-NOTCH function present with severe clinical manifestations.

Basic procedures: In this article, current knowledge of Hajdu Cheney Syndrome (HCS) and related disorders is reviewed.

Main findings: HCS is a rare genetic disorder characterized by acroosteolysis, fractures, short stature, neurological manifestations, craniofacial developmental abnormalities, cardiovascular defects and polycystic kidneys. HCS is associated with NOTCH2 gain-of-function mutations. An experimental mouse model of the disease revealed that the bone loss is secondary to increased osteoclastogenesis and bone resorption due to enhanced expression of receptor activator of nuclear factor kappa B ligand (Rankl). This would suggest that inhibitors of bone resorption might prove to be beneficial in the treatment of the bone loss associated with HCS. Notch2 is a determinant of B-cell allocation in the marginal zone of the spleen and "somatic" mutations analogous to those found in HCS are associated with B-cell lymphomas of the marginal zone, but there are no reports of lymphomas associated with HCS.

Conclusion: In conclusion, HCS is a serious genetic disorder associated with NOTCH2 mutations. New experimental models have offered insight on mechanisms responsible for the manifestations of HCS.

Keywords: Acroosteolysis; Genetic disorders; Hajdu Cheney Syndrome; Notch; Osteoporosis.

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Figures

Figure 1
Figure 1. Domains of the four Notch receptors
The upper panel shows the domain and motif organization of a generic human/murine Notch receptor before cleavage at the S1 site by furin-like convertases in the Golgi compartment. The extracellular domain contains a leader peptide (LP) and multiple epidermal growth factor (EGF)-like tandem repeats followed by Lin12-Notch repeats (LNR) and the heterodimerization domain (HD). The transmembrane domain (TMD) is located between the extracellular and intracellular domains. The Notch intracellular domain (NICD) contains an Rbpjκ-association module (RAM), a nuclear localization sequence (NLS), ankyrin (ANK) repeats and tandem NLS, which are followed by a proline (P)-, glutamic acid (E)-, serine (S)- and threonine (T)-rich (PEST) domain. The lower panel shows the domains and motifs of heterodimeric individual receptors, the negative regulatory region (NRR) is formed by the LNR and HD following cleavage at the S1 site. Notch1 and Notch2 have 36 EGF-like repeats; in green are those required for binding of Notch1 and Notch2 to cognate Delta/Serrate/Lag2 ligands. Notch1 and Notch2 have a similar NICD, and Notch3 has 34 EGF-like repeats and a shorter NICD than Notch1 and Notch2. Notch4 has 29 EGF-like repeats and an NICD that is shorter than that of other receptors and lacks the tandem NLS located between the ANK repeats and the PEST domain. Reproduced with permission from Zanotti and Canalis, Endocrine Reviews 37:223, 2016.
Figure 2
Figure 2. Canonical Notch Signaling
Under resting conditions, Notch receptors are intact and Rbpjκ binds histone deacetylases (HDAC) and co-repressors. Following Delta-like or Jagged interactions with the extracellular domain of Notch, the Notch intracellular domain (NICD) is released and translocates to the nucleus to form a complex with mastermind-like (Maml) and Rbpjκ. As a consequence, co-repressors and HDAC is displaced, CBP/p300 is recruited and histone acetylation ensues leading to the induction of Hes and Hey.
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