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Gene Review

NOTCH3  -  notch 3

Homo sapiens

Synonyms: CADASIL, CASIL, IMF2, Neurogenic locus notch homolog protein 3, Notch 3
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Disease relevance of NOTCH3


Psychiatry related information on NOTCH3


High impact information on NOTCH3

  • While investigating CADASIL, mapped previously to chromosome 19, we observed that some patients had recurrent attacks of migraine with aura [10].
  • Although the clinical and neuroimaging features of familial hemiplegic migraine differ markedly from CADASIL, we hypothesized that the same gene could be involved in the pathogenesis of both conditions [10].
  • A maximum lod score > 8 was found with two markers that are also strongly linked to CADASIL [10].
  • CADASIL (for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent subcortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuroimaging [6].
  • CADASIL arteriopathy is characterized by major alterations of vascular smooth muscle cells and the presence of specific granular osmiophilic deposits [11].

Chemical compound and disease context of NOTCH3


Biological context of NOTCH3

  • The disease is caused by at least 91 missense mutations, four deletions and one splice site mutation in the NOTCH3 gene, which maps to 19p13 [13].
  • Our findings emphasize the importance of genetic analysis of NOTCH3 for Asians with a phenotype typical of CADASIL [14].
  • We compared the sensitivity and specificity of this method in two groups of patients suspected of having CADASIL with complete scanning of mutation-causing exons of NOTCH3 (in a retrospective series of 39 patients) and with limited scanning of four exons that are mutation hotspots (prospective series of 42 patients) [15].
  • Mitochondrial dysfunction in patients with CADASIL may be an epiphenomenon, but results of this study suggest that the pathophysiology of the disease could include a defect in oxidative phosphorylation [16].
  • METHODS: Mutation analysis of the Notch3 gene was performed in 2 patients belonging to a large kindred manifesting CADASIL, as well as in 7 clinically unaffected members of the family and 200 control chromosomes [17].

Anatomical context of NOTCH3

  • Cells cultured under conditions of defined equibiaxial cyclic strain (10% strain, 60 cycles/min, 24 h) exhibited a significant reduction in Notch 1 IC and Notch 3 IC expression concomitant with a significant increase in VSMC differentiation marker expression [18].
  • Notch3 intracellular domain accumulates in HepG2 cell line [19].
  • METHODS: Biochemical, histochemical, molecular, and genetic analyses were performed on muscle biopsy specimens and fibroblasts obtained from patients of a Spanish family with CADASIL [16].
  • We show that throughout development, Notch 1 and 3 are expressed in cells retained within the lamina propria, where Notch 3 is expressed in olfactory ensheathing cells (OECs) [20].
  • Genetic, clinical and pathological studies of CADASIL in Japan: a partial contribution of Notch3 mutations and implications of smooth muscle cell degeneration for the pathogenesis [21].

Associations of NOTCH3 with chemical compounds

  • All mutations of NOTCH3 described so far are strictly stereotyped, leading to the gain or loss of a cysteine residue in a given epidermal growth factor (EGF)-like repeat of NOTCH3 [22].
  • RESULTS: Sequence analysis of the Notch3 gene showed a new missense mutation CGC-->TGC in codon 332 of exon 6, resulting in the replacement of an arginine residue with a cysteine [17].
  • The authors used phase-contrast MRI in 40 NOTCH3 mutation carriers (mean age 45 +/- 10 years) and 22 nonmutated family members (mean age 39 +/- 12 years), to assess baseline total cerebral blood flow (TCBF) and cerebrovascular reactivity after acetazolamide [23].
  • The purpose of this study was to assess whether cerebral blood flow (CBF) and regional cerebral metabolic rates of glucose (rCMR(gluc)) in CADASIL patients are affected in early adulthood [24].
  • In order to explain the molecular mechanisms behind the alterations to the blood vessels in CADASIL subjects, we scrutinized the expression of glycan and glycan-binding sites in the wall of vessels taken from five such subjects (vs. five control subjects matched for age and sex) [25].

Regulatory relationships of NOTCH3


Other interactions of NOTCH3


Analytical, diagnostic and therapeutic context of NOTCH3

  • METHODS: 50 unrelated patients with CADASIL and 100 healthy controls were screened for mutations along the entire Notch3 sequence, by means of single-strand conformation polymorphism, heteroduplex, and sequence analysis [30].
  • INTERPRETATION: Because of the strong clustering and highly stereotyped nature of the pathogenetic mutations detected in CADASIL patients, and easy and reliable diagnostic test for CADASIL is feasible [30].
  • It is also of interest to know that Notch3 mutant CADASIL exists in other Asian countries.We next examined the localization of Notch3 protein in the tissue by immunohistochemistry [21].
  • These precise similarities, together with the fact that the structure and function of Notch has been highly conserved throughout the animal kingdom, provide an animal model for the molecular and genetic aspects of human CADASIL [27].
  • Retinal abnormalities in CADASIL: a retrospective study of 18 patients [31].


  1. NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL. Dichgans, M., Herzog, J., Gasser, T. Neurology (2001) [Pubmed]
  2. Myocardial infarction in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Lesnik Oberstein, S.A., Jukema, J.W., Van Duinen, S.G., Macfarlane, P.W., van Houwelingen, H.C., Breuning, M.H., Ferrari, M.D., Haan, J. Medicine (Baltimore) (2003) [Pubmed]
  3. Genetic variants of the NOTCH3 gene in migraine--a mutation analysis and association study. Schwaag, S., Evers, S., Schirmacher, A., Stögbauer, F., Ringelstein, E.B., Kuhlenbäumer, G. Cephalalgia : an international journal of headache. (2006) [Pubmed]
  4. Mitochondrial DNA sequence variation and mutation rate in patients with CADASIL. Annunen-Rasila, J., Finnilä, S., Mykkänen, K., Moilanen, J.S., Veijola, J., Pöyhönen, M., Viitanen, M., Kalimo, H., Majamaa, K. Neurogenetics (2006) [Pubmed]
  5. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Opherk, C., Peters, N., Herzog, J., Luedtke, R., Dichgans, M. Brain (2004) [Pubmed]
  6. 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]
  7. Investigation of Notch3 as a candidate gene for bipolar disorder using brain hyperintensities as an endophenotype. Ahearn, E.P., Speer, M.C., Chen, Y.T., Steffens, D.C., Cassidy, F., Van Meter, S., Provenzale, J.M., Weisler, R.H., Krishnan, K.R. Am. J. Med. Genet. (2002) [Pubmed]
  8. CADASIL with NOTCH3 S180C presenting anticipation of onset age and hallucinations. Nakamura, T., Watanabe, H., Hirayama, M., Inukai, A., Kabasawa, H., Matsubara, M., Mitake, S., Nakamura, M., Ando, Y., Uchino, M., Sobue, G. J. Neurol. Sci. (2005) [Pubmed]
  9. Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL. Low, W.C., Junna, M., Börjesson-Hanson, A., Morris, C.M., Moss, T.H., Stevens, D.L., St Clair, D., Mizuno, T., Zhang, W.W., Mykkänen, K., Wahlstrom, J., Andersen, O., Kalimo, H., Viitanen, M., Kalaria, R.N. Brain (2007) [Pubmed]
  10. A gene for familial hemiplegic migraine maps to chromosome 19. Joutel, A., Bousser, M.G., Biousse, V., Labauge, P., Chabriat, H., Nibbio, A., Maciazek, J., Meyer, B., Bach, M.A., Weissenbach, J. Nat. Genet. (1993) [Pubmed]
  11. The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. Joutel, A., Andreux, F., Gaulis, S., Domenga, V., Cecillon, M., Battail, N., Piga, N., Chapon, F., Godfrain, C., Tournier-Lasserve, E. J. Clin. Invest. (2000) [Pubmed]
  12. Acetazolamide-responsive migraine in CADASIL. Weller, M., Dichgans, J., Klockgether, T. Neurology (1998) [Pubmed]
  13. Detection of the founder effect in Finnish CADASIL families. Mykkänen, K., Savontaus, M.L., Juvonen, V., Sistonen, P., Tuisku, S., Tuominen, S., Penttinen, M., Lundkvist, J., Viitanen, M., Kalimo, H., Pöyhönen, M. Eur. J. Hum. Genet. (2004) [Pubmed]
  14. Arg332Cys mutation of NOTCH3 gene in the first known Taiwanese family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Tang, S.C., Lee, M.J., Jeng, J.S., Yip, P.K. J. Neurol. Sci. (2005) [Pubmed]
  15. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Joutel, A., Favrole, P., Labauge, P., Chabriat, H., Lescoat, C., Andreux, F., Domenga, V., Cécillon, M., Vahedi, K., Ducros, A., Cave-Riant, F., Bousser, M.G., Tournier-Lasserve, E. Lancet (2001) [Pubmed]
  16. Mitochondrial dysfunction associated with a mutation in the Notch3 gene in a CADASIL family. de la Peña, P., Bornstein, B., del Hoyo, P., Fernández-Moreno, M.A., Martín, M.A., Campos, Y., Gómez-Escalonilla, C., Molina, J.A., Cabello, A., Arenas, J., Garesse, R. Neurology (2001) [Pubmed]
  17. A novel mutation in the Notch3 gene in an Italian family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: genetic and magnetic resonance spectroscopic findings. Oliveri, R.L., Muglia, M., De Stefano, N., Mazzei, R., Labate, A., Conforti, F.L., Patitucci, A., Gabriele, A.L., Tagarelli, G., Magariello, A., Zappia, M., Gambardella, A., Federico, A., Quattrone, A. Arch. Neurol. (2001) [Pubmed]
  18. Notch-mediated CBF-1/RBP-J{kappa}-dependent regulation of human vascular smooth muscle cell phenotype in vitro. Morrow, D., Scheller, A., Birney, Y.A., Sweeney, C., Guha, S., Cummins, P.M., Murphy, R., Walls, D., Redmond, E.M., Cahill, P.A. Am. J. Physiol., Cell Physiol. (2005) [Pubmed]
  19. Notch3 intracellular domain accumulates in HepG2 cell line. Giovannini, C., Lacchini, M., Gramantieri, L., Chieco, P., Bolondi, L. Anticancer Res. (2006) [Pubmed]
  20. Notch 2 and Notch 1/3 segregate to neuronal and glial lineages of the developing olfactory epithelium. Carson, C., Murdoch, B., Roskams, A.J. Dev. Dyn. (2006) [Pubmed]
  21. Genetic, clinical and pathological studies of CADASIL in Japan: a partial contribution of Notch3 mutations and implications of smooth muscle cell degeneration for the pathogenesis. Santa, Y., Uyama, E., Chui, d.e. .H., Arima, M., Kotorii, S., Takahashi, K., Tabira, T. J. Neurol. Sci. (2003) [Pubmed]
  22. Two novel mutations of the NOTCH3 gene in Korean patients with CADASIL. Kim, Y., Kim, J.S., Kim, G., No, Y.J., Yoo, H.W. Mutat. Res. (2006) [Pubmed]
  23. Cerebral hemodynamics and white matter hyperintensities in CADASIL. van den Boom, R., Lesnik Oberstein, S.A., Spilt, A., Behloul, F., Ferrari, M.D., Haan, J., Westendorp, R.G., van Buchem, M.A. J. Cereb. Blood Flow Metab. (2003) [Pubmed]
  24. Positron emission tomography examination of cerebral blood flow and glucose metabolism in young CADASIL patients. Tuominen, S., Miao, Q., Kurki, T., Tuisku, S., Pöyhönen, M., Kalimo, H., Viitanen, M., Sipilä, H.T., Bergman, J., Rinne, J.O. Stroke (2004) [Pubmed]
  25. Glycohistochemical characterization of vascular muscle cell destruction in CADASIL subjects by lectins, neoglycoconjugates and galectin-specific antibodies. Brulin-Fardoux, P., Godfrain, C., Maurage, C.A., De Reuck, J., Hauw, J.J., Kaltner, H., Bovin, N.V., Gabius, H.J., Ruchoux, M.M., Kiss, R., Camby, I. Neuropathol. Appl. Neurobiol. (2003) [Pubmed]
  26. Notch2 negatively regulates myofibroblastic differentiation of myoblasts. Ono, Y., Sensui, H., Okutsu, S., Nagatomi, R. J. Cell. Physiol. (2007) [Pubmed]
  27. An animal model for the molecular genetics of CADASIL. (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). Fryxell, K.J., Soderlund, M., Jordan, T.V. Stroke (2001) [Pubmed]
  28. Brain stem MRI signal abnormalities in CADASIL. Chabriat, H., Mrissa, R., Levy, C., Vahedi, K., Taillia, H., Iba-Zizen, M.T., Joutel, A., Tournier-Lasserve, E., Bousser, M.G. Stroke (1999) [Pubmed]
  29. EGF-like domain calcium affinity modulated by N-terminal domain linkage in human fibrillin-1. Smallridge, R.S., Whiteman, P., Doering, K., Handford, P.A., Downing, A.K. J. Mol. Biol. (1999) [Pubmed]
  30. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Joutel, A., Vahedi, K., Corpechot, C., Troesch, A., Chabriat, H., Vayssière, C., Cruaud, C., Maciazek, J., Weissenbach, J., Bousser, M.G., Bach, J.F., Tournier-Lasserve, E. Lancet (1997) [Pubmed]
  31. Retinal abnormalities in CADASIL: a retrospective study of 18 patients. Cumurciuc, R., Massin, P., Pâques, M., Krisovic, V., Gaudric, A., Bousser, M.G., Chabriat, H. J. Neurol. Neurosurg. Psychiatr. (2004) [Pubmed]
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