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CADASIL RESEARCH:
Notch3

Background Information: Notch3 and CADASIL
Article Summaries
Graphics
Links to Abstracts and Articles: Notch3

Background Information: Notch3 and CADASIL
CADASIL is caused by a mutation in the Notch3 gene. Notch3 is one of four mammalian genes in the Notch family of transmembrane receptors.
CADASIL-associated mutations are found within the 34 epidermal growth factor (EGF)-like repeats that comprise the extracellular domain of the Notch3 receptor, causing a loss or gain of a cysteine residue. The majority of documented CADASIL mutations occur in exons 3 and 4.

The Notch family of receptors and ligands plays an important role in cell fate determination, vasculogenesis, and organogenesis. In human adults, Notch3 is expressed only in vascular smooth muscle cells. However, the exact function of Notch3 in human adult tissues is not entirely clear, and the molecular mechanism by which Notch3 mutations cause the vascular smooth-muscle degeneration characteristic of CADASIL is not well understood. As summarized by Bianchi et al., the main hypotheses for the mechanism of the CADASIL phenotype are:

  1. a primary Notch3 signalling defect due to incorrect presentation of receptors on the cell membrane, that blocks the normal cascade of event
  2. an irreversible accumulation of Notch3ECD in the membrane that dominantly inhibits the normal
    signalling system by competitive inhibition or by sequestering the ligand
  3. a toxic effect caused by accumulation of the mutant receptor form, as observed in other neurodegenerative diseases. (Bianchi S et al. J. Cell. Physiol. 2006;207:300–308)

(Other references: Donahue CP et al. Genomics. 2004;83:59–65. Joutel A et al. Am. J. Hum. Genet. 2004;74:338–347. Campos A. Circ Res. 2002;91:999-1006.)

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Article Summaries

Joutel A et al.
Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.
Lancet. 1997;350:1511-1515.   Abstract
In order to create a diagnostic test for CADASIL the authors screened CADASIL patients and healthy controls for mutations in the Notch3 gene sequence. Notch3 proteins function as transmembrane receptors that help determine the fate of a cell during development. Extracellular regions of these receptors bind to ligands; intracellular regions are responsible for signal transduction. CADASIL patients have mis-sense mutations within the extracellular epidermal-growth-factor-like repeats of the Notch3 gene. These mis-sense mutations resulted in the addition or loss of a cysteine residue. As a result of this finding, a diagnostic test for CADASIL was possible. Furthermore, as a cysteine residue appears to be involved, aberrant disulphide bond formation may play a role in the vessel pathology seen in CADASIL.

Joutel A et al.
Notch3 mutations in CADASIL, a hereditary adult onset condition causing stroke and dementia.
Nature. 1996;383:707-710.   Abstract
The authors expand on previous work which had localized the mutatin in CADASIL to the Notch3 gene on chromosome 19 and suggested that the Notch3 protein product could be implicated in CADASIL. They identified point mutations resulting in amino acid substitutions, usually cysteine, which altered the Notch3 protein. Identification of the Notch3 gene advanced the understanding of CADASIL in two significant ways. First, identifying the responsible gene provides a potential means to test patients and families for CADASIL. Second, the Notch3 signaling pathway was implicated in the pathogenesis of CADASIL.

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Graphics
Above: Notch3 predicted protein structure. EGF-like repeat domains: extracellular domain containing 34 tandemly arranged EGF-like repeats; LNR: 3 cysteine-rich Notch/Lin-12 repeats; TM: transmembrane region; Ankyrin: intracellular domain containing 6 ankyrin repeats. (Federico A, Bianchi S, Dotti MT. The spectrum of mutations for CADASIL diagnosis. Neurol Sci. 2005;26:117-24)

                         
Above: Simplified overview of Notch signaling in mammals. Ligands of the Jagged (JAG1 and JAG2) and Delta-like (DLL1, DLL3, DLL4) families (upper cell, shown in green) interact with Notch family transmembrane receptors (NOTCH1–NOTCH4) on an adjacent cell (lower cell, shown in yellow). The Notch receptor exists at the cell surface as a proteolytically cleaved product consisting of a large ectodomain and a membrane-tethered intracellular domain. The receptor-ligand interaction induces two additional proteolytic cleavages that free the intracellular domain of the Notch receptor from the cell membrane. The cleaved fragment translocates to the nucleus (shown in blue) owing to the presence of nuclear localization signals located in the Notch intracellular domain. Once in the nucleus, the Notch intracellular domain forms a complex with the RBPSUH protein, displacing a histone deacetylase (HDAc)/corepressor (CoR) complex from the RBPSUH protein, leading to the transcriptional activation of Notch target genes. (Gridley T. Human Molecular Genetics. 2003;12, Review Issue 1:R9-R13.)

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Links to Abstracts and Articles:
Notch3

Bianchi S, Dotti MT, Federico A. Physiology and Pathology of Notch Signalling System. J. Cell. Physiol. 2006;207:300–308.
Abstract

Louvi A, Arboleda-Velasquez JF, Artavanis-Tsakonas S. CADASIL: a critical look at a Notch disease. Dev Neurosci. 2006;28:5-12.
Abstract

Arboleda-Velasquez JF, Rampal R, Fung E, Darland DC, Liu M, Martinez MC, Donahue CP, Navarro-Gonzalez MF, Libby P, D'Amore PA, Aikawa M, Haltiwanger RS, Kosik KS. CADASIL mutations impair Notch3 glycosylation by Fringe. Hum Mol Genet. 2005;14:1631-9.
Abstract


Dotti MT, Federico A, Mazzei R, Bianchi S, Scali O, Conforti FL, Sprovieri T, Guidetti D, Aguglia U, Consoli D, Pantoni L, Sarti C, Inzitari D, Quattrone A. The spectrum of Notch3 mutations in 28 Italian CADASIL families. J Neurol Neurosurg Psychiatry. 2005;76:736–738.
Abstract


Federico A, Bianchi S, Dotti MT. The spectrum of mutations for CADASIL diagnosis. Neurol Sci. 2005;26:117-24.
Abstract


Haritunians T, Chow T, De Lange RP, Nichols JT, Ghavimi D, Dorrani N, St Clair DM, Weinmaster G, Schanen C. Functional analysis of a recurrent missense mutation in Notch3 in CADASIL. J Neurol Neurosurg Psychiatry. 2005 Sep;76(9):1242-8.
Abstract

Lasky JL, Wu H. Notch signaling, brain development, and human disease. Pediatr Res. 2005;57:104R–109R.
Abstract
   Free Full Text Article


Lundkvist J, Zhu S, Hansson EM, Schweinhardt P, Miao Q, Beatus P, Dannaeus K, Karlstrom H, Johansson CB, Viitanen M, Rozell B, Spenger C, Mohammed A, Kalimo H, Lendahl U. Mice carrying a R142C Notch 3 knock-in mutation do not develop a CADASIL-like phenotype. Genesis. 2005 Jan;41(1):13-22.
Abstract


Peters N, Opherk C, Bergmann T, Castro M, Herzog J, Dichgans M. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol. 2005 Jul;62(7):1091-4.
Abstract

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Singhal S, Bevan S, Barrick T, Rich P, Markus HS. The influence of genetic and cardiovascular risk factors on the CADASIL phenotype. Brain. 2004;127:2031–2038.
Abstract

Donahue CP, Kosik KS. Distribution pattern of Notch3 mutations suggests a gain-of-function mechanism for CADASIL. Genomics. 2004;83:59–65.
Abstract


Joutel A, Monet M, Domenga V, Riant F, Tournier-Lasserve E. Pathogenic mutations associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy differently affect Jagged1 binding and Notch3 activity via the RBP/JK signaling pathway. Am. J. Hum. Genet. 2004;74:338–347.
Abstract
  Free Full Text Article

Peters N, Opherk C, Zacherle S, Capell A, Gempel P, Dichgans M. CADASIL-associated Notch3 mutations have differential effects both on ligand binding and ligand-induced Notch3 receptor signaling through RBP-Jk. Exp Cell Res. 2004;299:454-64.
Abstract

Gridley T. Notch signaling and inherited disease syndromes. Hum Mol Genet. 2003 Apr 1;12 Spec No 1:R9-13.
Abstract
   Free Full Text Article

Campos A, Wang W, Pollman MJ, Gibbons GH. Determinants of Notch-3 receptor expression and signaling in vascular smooth muscle cells: implications in cell-cycle regulation. Circ Res. 2002;91:999-1006.
Abstract
   Free Full Text Article

Dichgans M. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: phenotypic and mutational spectrum. J Neurol Sci. 2002;203-204:77-80.
Abstract

Haritunians T, Boulter J, Hicks C, Buhrman J, DiSibio G, Shawber C, Weinmaster G, Nofziger D, Schanen C. CADASIL Notch3 mutant proteins localize to the cell surface and bind ligand. Circ Res. 2002;90:506-8.
Abstract   Free Full Text Article

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Karlstrom H, Beatus P, Dannaeus K, Chapman G, Lendahl U, Lundkvist J. A CADASIL-mutated Notch 3 receptor exhibits impaired intracellular trafficking and maturation but normal ligand-induced signaling. PNAS. 2002;99:17119-24
Abstract
   Free Full Text Article

Wang W, Campos AH, Prince CZ, Mou Y, Pollman MJ. Coordinate Notch3-hairy-related transcription factor pathway regulation in response to arterial injury. Mediator role of platelet-derived growth factor and ERK. J Biol Chem. 2002 Jun 28;277(26):23165-71.
Abstract  Free Full Text Article

Broadley SA, Sawcer SJ, Chataway SJ, Coraddu F, Coles A, Gray J, Roxburgh R, Clayton D, Compston DA. No association between multiple sclerosis and the Notch3 gene responsible for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). J Neurol Neurosurg Psychiatry. 2001 Jul;71(1):97-9.
Abstract  Free Full Text Article

Kotorii S, Takahashi K, Kamimura K, Nishio T, Arima K, Yamada H, Uyama E, Uchino M, Suenaga A, Matsumoto M, Kuchel G, Rouleau GA, Tabira T. Mutations of the notch3 gene in non-caucasian patients with suspected CADASIL syndrome. Dement Geriatr Cogn Disord. 2001 May-Jun;12(3):185-93.
Abstract

Dichgans M, Ludwig H, Muller-Hocker J, Messerschmidt A, Gasser T. Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains. Eur J Hum Genet. 2000;8:280-5.
Abstract

Joutel A, Andreux F, Gaulis S, Domenga V, Cecillon M, Battail N, Piga N, Chapon F, Godfrain C, Tournier-Lasserve E. The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. J Clin Invest. 2000;105:597-605.
Abstract   Free Full Text Article

Wang T, Sharma SD, Fox N, Rossor M, Brown MJ, Sharma P. Description of a simple test for CADASIL disease and determination of mutation frequencies in sporadic ischaemic stroke and dementia patients. J Neurol Neurosurg Psychiatry. 2000 Nov;69(5):652-4.
Abstract   Free Full Text Article

Escary JL, Cecillon M, Maciazek J, Lathrop M, Tournier-Lasserve E, Joutel A. Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene with a high G-C content. Hum Mutat. 2000 Dec;16(6):518-26.
Abstract

Gray GE, Mann RS, Mitsiadis E, Henrique D, Carcangiu ML, Banks A, Leiman J, Ward D, Ish-Horowitz D, Artavanis-Tsakonas S. Human ligands of the Notch receptor. Am J Pathol. 1999 Mar;154(3):785-94.
Abstract    Free Full Text Article

Joutel A, Tournier-Lasserve E. Notch signalling pathway and human diseases. Semin Cell Dev Biol. 1998;9:619-25.
Abstract

Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssiere C, Cruaud C, Maciazek J, Weissenbach J, Bousser MG, Bach JF, Tournier-Lasserve E. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997;350:1511-5.
Abstract

Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cecillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E. Notch3 mutations in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a mendelian condition causing stroke and vascular dementia. Ann N Y Acad Sci. 1997 Sep 26;826:213-7.
Abstract

Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cecillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. 1996;24:383:707-10.
Abstract

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