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Gene Review

NOTCH4  -  notch 4

Homo sapiens

Synonyms: INT3, Neurogenic locus notch homolog protein 4, Notch 4, hNotch4
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Disease relevance of NOTCH4


Psychiatry related information on NOTCH4


High impact information on NOTCH4

  • Truncation of Notch1 has been shown to cause a subtype of acute leukemia, and activation of Notch4 has been associated with mammary and salivary gland carcinomas of mice [11].
  • Linkage disequilibrium mapping of the MHC region in 80 British parent-offspring trios showed that NOTCH4 was highly associated with schizophrenia [12].
  • The A-->G substitution in the promoter region and the (CTG)n repeat in exon 1 of NOTCH4 may be candidate sites conferring susceptibility to schizophrenia [12].
  • Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia [13].
  • In mice, the Notch4 receptor and the Delta-like 4 (Dll4) ligand are specifically expressed in arterial endothelial cells, suggesting a similar role [14].

Chemical compound and disease context of NOTCH4


Biological context of NOTCH4


Anatomical context of NOTCH4


Associations of NOTCH4 with chemical compounds

  • In addition, two intermediate endophenotypes suggested being of importance in schizophrenia, dopamine D(2) receptor density in striatum and monoamine metabolites in cerebrospinal fluid, respectively, were investigated with regard to the two NOTCH4 variants [7].
  • Notch-4 expression could only be detected after stimulation with Dexamethasone and Vitamin D(3) [2].
  • In this study, we determined that constitutively active Notch4 (Notch4 intracellular domain) inhibited endothelial apoptosis triggered by lipopolysaccharide [21].
  • Analysis of the sequence identities of the human and mouse genomic regions between NOTCH4 and complement C2 yields important information on the locations of the coding and regulatory sequences [22].
  • Mutations result in either a gain or loss of one (or rarely, 3) cysteine residue(s) in one of the 34 epidermal growth factor-like repeats in the extracellular amino-terminal region of Notch3 [23].

Physical interactions of NOTCH4


Regulatory relationships of NOTCH4


Other interactions of NOTCH4

  • RESULTS: Patients carrying both NOTCH4 C/C genotype and COMT low/low genotype, had more than ten times higher risk of being a non-responder than responder to treatment with typical neuroleptics [OR = 10.25 (95% CI 2.21-47.53), P < 0.001] [18].
  • Variants of NOTCH4 are associated with schizophrenia, thus DLL4 is both a functional as well as a positional candidate for schizophrenia [20].
  • For TNF, located 0.7 Mb telomeric of NOTCH4, SNPs at positions -308 and -238 were studied in the same dataset [1].
  • Because the TNXB gene is less than 100 kb away from the NOTCH4 locus that was also reported to be associated with schizophrenia, allelic and locus heterogeneity could be possible reasons for the failure to replicate the TNXB finding [28].
  • RESULTS: Notch2 and Notch4 were expressed in limited areas in a few samples or in small blood vessels, respectively [29].

Analytical, diagnostic and therapeutic context of NOTCH4

  • We conducted a prospective case-control study to explore the impact of NOTCH4 T-25C polymorphism on the factors associated with schizophrenia [30].
  • The NOTCH4 variants were also analysed in schizophrenic patients with regard to subdiagnosis, age at first hospitalization, abuse/dependence of alcohol, solvents, or drugs, previous suicide attempts, extrapyramidal symptoms, treatment with anticholinergic drugs, and response to anti-psychotic drug treatment [7].
  • The weak, punctate staining of Notch-4 in the neuroepithelium of the spinal cord could not be confirmed with Western blotting [31].
  • Notch1 and Notch3 expression overlapped with that of Jagged1, as determined by confocal microscopy [29].
  • Five NOTCH4 polymorphisms show weak evidence for association with schizophrenia: evidence from meta-analyses [32].


  1. A NOTCH4 association with multiple sclerosis is secondary to HLA-DR*1501. Duvefelt, K., Anderson, M., Fogdell-Hahn, A., Hillert, J. Tissue Antigens (2004) [Pubmed]
  2. Differential expression of Notch genes in human osteoblastic cells. Schnabel, M., Fichtel, I., Gotzen, L., Schlegel, J. Int. J. Mol. Med. (2002) [Pubmed]
  3. Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Williams, C.K., Li, J.L., Murga, M., Harris, A.L., Tosato, G. Blood (2006) [Pubmed]
  4. Notch receptor expression in adult human liver: a possible role in bile duct formation and hepatic neovascularization. Nijjar, S.S., Crosby, H.A., Wallace, L., Hubscher, S.G., Strain, A.J. Hepatology (2001) [Pubmed]
  5. Imbalanced expression of TAN-1 and human Notch4 in endometrial cancers. Suzuki, T., Aoki, D., Susumu, N., Udagawa, Y., Nozawa, S. Int. J. Oncol. (2000) [Pubmed]
  6. Genetic analysis of the (CTG)n NOTCH4 polymorphism in 65 multiplex bipolar pedigrees. Swift-Scanlan, T., Lan, T.H., Fallin, M.D., Coughlin, J.M., Potash, J.B., DePaulo, J.R., McInnis, M.G. Psychiatr. Genet. (2002) [Pubmed]
  7. Two NOTCH4 polymorphisms and their relation to schizophrenia susceptibility and different personality traits. Carmine, A., Chheda, M.G., Jönsson, E.G., Sedvall, G.C., Farde, L., Gustavsson, J.P., Bergman, H., Anvret, M., Buervenich, S., Olson, L. Psychiatr. Genet. (2003) [Pubmed]
  8. Association study of Notch 4 polymorphisms with Alzheimer's disease. Lambert, J.C., Mann, D., Harris, J., Araria-Goumidi, L., Chartier-Harlin, M.C., Cottel, D., Iwatsubo, T., Amouyel, P., Lendon, C. J. Neurol. Neurosurg. Psychiatr. (2004) [Pubmed]
  9. NOTCH4 gene polymorphism and susceptibility to schizophrenia and schizoaffective disorder. Ujike, H., Takehisa, Y., Takaki, M., Tanaka, Y., Nakata, K., Takeda, T., Kodama, M., Fujiwara, Y., Yamamoto, A., Kuroda, S. Neurosci. Lett. (2001) [Pubmed]
  10. Triplet repeat polymorphism within the NOTCH4 gene located near the junction of the HLA class II and class III regions in narcolepsy. Ando, A., Shigenari, A., Naruse, T.K., Sugaya, K., Juji, T., Honda, Y., Ikemura, T., Inoko, H. Tissue Antigens (1997) [Pubmed]
  11. t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Tonon, G., Modi, S., Wu, L., Kubo, A., Coxon, A.B., Komiya, T., O'Neil, K., Stover, K., El-Naggar, A., Griffin, J.D., Kirsch, I.R., Kaye, F.J. Nat. Genet. (2003) [Pubmed]
  12. The NOTCH4 locus is associated with susceptibility to schizophrenia. Wei, J., Hemmings, G.P. Nat. Genet. (2000) [Pubmed]
  13. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenga, V., Cécillion, M., Marechal, E., Maciazek, J., Vayssiere, C., Cruaud, C., Cabanis, E.A., Ruchoux, M.M., Weissenbach, J., Bach, J.F., Bousser, M.G., Tournier-Lasserve, E. Nature (1996) [Pubmed]
  14. Dosage-sensitive requirement for mouse Dll4 in artery development. Duarte, A., Hirashima, M., Benedito, R., Trindade, A., Diniz, P., Bekman, E., Costa, L., Henrique, D., Rossant, J. Genes Dev. (2004) [Pubmed]
  15. Characteristics of CADASIL in Korea: a novel cysteine-sparing Notch3 mutation. Kim, Y., Choi, E.J., Choi, C.G., Kim, G., Choi, J.H., Yoo, H.W., Kim, J.S. Neurology (2006) [Pubmed]
  16. Molecular determinants of NOTCH4 transcription in vascular endothelium. Wu, J., Iwata, F., Grass, J.A., Osborne, C.S., Elnitski, L., Fraser, P., Ohneda, O., Yamamoto, M., Bresnick, E.H. Mol. Cell. Biol. (2005) [Pubmed]
  17. NOTCH4 gene haplotype is associated with schizophrenia in African Americans. Luo, X., Klempan, T.A., Lappalainen, J., Rosenheck, R.A., Charney, D.S., Erdos, J., van Kammen, D.P., Kranzler, H.R., Kennedy, J.L., Gelernter, J. Biol. Psychiatry (2004) [Pubmed]
  18. Interaction between NOTCH4 and catechol-O-methyltransferase genotypes in schizophrenia patients with poor response to typical neuroleptics. Anttila, S., Illi, A., Kampman, O., Mattila, K.M., Lehtimäki, T., Leinonen, E. Pharmacogenetics (2004) [Pubmed]
  19. Gene organization of human NOTCH4 and (CTG)n polymorphism in this human counterpart gene of mouse proto-oncogene Int3. Sugaya, K., Sasanuma, S., Nohata, J., Kimura, T., Fukagawa, T., Nakamura, Y., Ando, A., Inoko, H., Ikemura, T., Mita, K. Gene (1997) [Pubmed]
  20. No causative DLL4 mutations in periodic catatonia patients from 15q15 linked families. McKeane, D.P., Meyer, J., Dobrin, S.E., Melmed, K.M., Ekawardhani, S., Tracy, N.A., Lesch, K.P., Stephan, D.A. Schizophr. Res. (2005) [Pubmed]
  21. Notch4 inhibits endothelial apoptosis via RBP-Jkappa-dependent and -independent pathways. MacKenzie, F., Duriez, P., Wong, F., Noseda, M., Karsan, A. J. Biol. Chem. (2004) [Pubmed]
  22. The human and mouse MHC class III region: a parade of 21 genes at the centromeric segment. Yung Yu, C., Yang, Z., Blanchong, C.A., Miller, W. Immunol. Today (2000) [Pubmed]
  23. CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. Kalimo, H., Ruchoux, M.M., Viitanen, M., Kalaria, R.N. Brain Pathol. (2002) [Pubmed]
  24. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation. Wu, G., Lyapina, S., Das, I., Li, J., Gurney, M., Pauley, A., Chui, I., Deshaies, R.J., Kitajewski, J. Mol. Cell. Biol. (2001) [Pubmed]
  25. Activated Notch4 inhibits angiogenesis: role of beta 1-integrin activation. Leong, K.G., Hu, X., Li, L., Noseda, M., Larrivée, B., Hull, C., Hood, L., Wong, F., Karsan, A. Mol. Cell. Biol. (2002) [Pubmed]
  26. Notch4-induced inhibition of endothelial sprouting requires the ankyrin repeats and involves signaling through RBP-Jkappa. MacKenzie, F., Duriez, P., Larrivée, B., Chang, L., Pollet, I., Wong, F., Yip, C., Karsan, A. Blood (2004) [Pubmed]
  27. Activation of the Notch-regulated transcription factor CBF1/RBP-Jkappa through the 13SE1A oncoprotein. Ansieau, S., Strobl, L.J., Leutz, A. Genes Dev. (2001) [Pubmed]
  28. Lack of a genetic association between the TNXB locus and schizophrenia in a Chinese population. Liu, L.L., Wei, J., Zhang, X., Li, X.Y., Shen, Y., Liu, S.Z., Ju, G.Z., Shi, J.P., Yu, Y.Q., Xu, Q., Hemmings, G.P. Neurosci. Lett. (2004) [Pubmed]
  29. Immunohistological localization of Notch receptors and their ligands Delta and Jagged in synovial tissues of rheumatoid arthritis. Yabe, Y., Matsumoto, T., Tsurumoto, T., Shindo, H. Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association. (2005) [Pubmed]
  30. NOTCH4 gene promoter polymorphism is associated with the age of onset in schizophrenia. Anttila, S., Kampman, O., Illi, A., Roivas, M., Mattila, K.M., Lassila, V., Lehtimäki, T., Leinonen, E. Psychiatr. Genet. (2003) [Pubmed]
  31. Distribution of presenilin 1 and 2 and their relation to Notch receptors and ligands in human embryonic/foetal central nervous system. Kostyszyn, B., Cowburn, R.F., Seiger, A., Kjaeldgaard, A., Sundström, E. Brain Res. Dev. Brain Res. (2004) [Pubmed]
  32. Five NOTCH4 polymorphisms show weak evidence for association with schizophrenia: evidence from meta-analyses. Glatt, S.J., Wang, R.S., Yeh, Y.C., Tsuang, M.T., Faraone, S.V. Schizophr. Res. (2005) [Pubmed]
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