2oo4

Structural highlights

Disease

[NOTC2_HUMAN] Defects in NOTCH2 are the cause of Alagille syndrome type 2 (ALGS2) [MIM:610205]. Alagille syndrome is an autosomal dominant multisystem disorder defined clinically by hepatic bile duct paucity and cholestasis in association with cardiac, skeletal, and ophthalmologic manifestations. There are characteristic facial features and less frequent clinical involvement of the renal and vascular systems.^[1] Defects in NOTCH2 are the cause of Hajdu-Cheney syndrome (HJCYS) [MIM:102500]. A rare skeletal disorder characterized by the association of facial anomalies, acro-osteolysis, general osteoporosis, insufficient ossification of the skull, and periodontal disease (premature loss of permanent teeth). Other features include cleft palate, congenital heart defects, polycystic kidneys, orthopedic problems and anomalies of the genitalia, intestines and eyes. Note=NOTCH2 mutations associated with Hajdu-Cheney syndrome cluster to the last coding exon of the gene. This suggests that the mutant mRNA products may escape nonsense-mediated decay and the resulting truncated NOTCH2 proteins act in a gain-of-function manner.^{[2] [3]}

Function

[NOTC2_HUMAN] Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity). Involved in bone remodeling and homeostasis. In collaboration with RELA/p65 enhances NFATc1 promoter activity and positively regulates RANKL-induced osteoclast differentiation.^{[4] [5]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, Spinner NB. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. 2006 Jul;79(1):169-73. Epub 2006 May 10. PMID:16773578 doi:S0002-9297(07)60019-6
2. ↑ Isidor B, Lindenbaum P, Pichon O, Bezieau S, Dina C, Jacquemont S, Martin-Coignard D, Thauvin-Robinet C, Le Merrer M, Mandel JL, David A, Faivre L, Cormier-Daire V, Redon R, Le Caignec C. Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet. 2011 Mar 6;43(4):306-8. doi: 10.1038/ng.778. PMID:21378989 doi:10.1038/ng.778
3. ↑ 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. Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat Genet. 2011 Mar 6;43(4):303-5. doi: 10.1038/ng.779. PMID:21378985 doi:10.1038/ng.779
4. ↑ Isidor B, Lindenbaum P, Pichon O, Bezieau S, Dina C, Jacquemont S, Martin-Coignard D, Thauvin-Robinet C, Le Merrer M, Mandel JL, David A, Faivre L, Cormier-Daire V, Redon R, Le Caignec C. Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet. 2011 Mar 6;43(4):306-8. doi: 10.1038/ng.778. PMID:21378989 doi:10.1038/ng.778
5. ↑ 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. Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat Genet. 2011 Mar 6;43(4):303-5. doi: 10.1038/ng.779. PMID:21378985 doi:10.1038/ng.779
6. ↑ Gordon WR, Vardar-Ulu D, Histen G, Sanchez-Irizarry C, Aster JC, Blacklow SC. Structural basis for autoinhibition of Notch. Nat Struct Mol Biol. 2007 Apr;14(4):295-300. Epub 2007 Apr 1. PMID:17401372 doi:10.1038/nsmb1227