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Figure 1 | Orphanet Journal of Rare Diseases

Figure 1

From: Hajdu-Cheney syndrome: a review

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.

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