NOTCH3 — Notch Receptor 3
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">NOTCH3 — Notch Receptor 3</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>NOTCH3</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Notch Receptor 3</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>19p13.12</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/4854" target="_blank">4854</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000074181" target="_blank">ENSG00000074181</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/600276" target="_blank">600276</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9UM47" target="_blank">Q9UM47</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>CADASIL, Cerebral Small Vessel Disease</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Vascular smooth muscle cells, [Pericytes](/cell-types/pericytes), Cerebral vasculature, Systemic arteries</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">R90C (Exon 3)<br>R141C (Exon 4)<br>C455R (Exon 8)<br>R153C (Exon 4)<br>>270 mutations reported</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/autoimmune" style="color:#ef9a9a">Autoimmune</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">57 edges</a></td>
</tr>
</table>
NOTCH3 — Notch Receptor 3
Introduction
Notch3 — Notch Receptor 3 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
Mermaid diagram (expand to render)
NOTCH3 (Notch Receptor 3) is a gene located on chromosome 19p13.12 that encodes a transmembrane receptor critical for vascular development and homeostasis. Mutations in NOTCH3 cause CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), the most common inherited cause of stroke and vascular dementia. The gene is catalogued as NCBI Gene ID [4854](https://www.ncbi.nlm.nih.gov/gene/4854) and OMIM [600276](https://omim.org/entry/600276).
Function
Notch Signaling Pathway
The NOTCH3 protein is a member of the Notch receptor family, which is highly conserved across species and mediates cell-cell communication through direct cell-cell contact[@gridley2004]. The Notch signaling pathway is essential for:
- Vascular development and remodeling: NOTCH3 is primarily expressed in vascular smooth muscle cells (VSMCs) and [pericytes](/cell-types/pericytes), where it regulates arterial specification and vessel maturation[@wang1998]
- Cell fate decisions: Notch signaling inhibits differentiation in neighboring cells, maintaining progenitor populations
- Arterial identity: NOTCH3, together with NOTCH1 and NOTCH4, specifies arterial versus venous identity during embryonic development
Structure
NOTCH3 is a type I transmembrane protein consisting of:
Extracellular domain (NECD): Contains 36 epidermal growth factor-like (EGF) repeats, 3 Lin-12/Notch repeats (LNR), and a heterodimerization domain
Transmembrane domain: Single pass membrane-spanning helix
Intracellular domain (NICD): Contains RAM domain, ankyrin repeats, transcriptional activation domain (TAD), and PEST sequenceSignal Transduction
Upon ligand binding (JAG1, JAG2, DLL1, DLL4), NOTCH3 undergoes proteolytic cleavage:
- S1 cleavage: Furin-like convertase in the trans-Golgi
- S2 cleavage: ADAM10/17 at the extracellular membrane boundary
- S3 cleavage: [γ-secretase](/entities/gamma-secretase) releases the Notch intracellular domain (NICD)
- NICD translocates to the nucleus and forms a transcriptional complex with CSL (RBPJκ) and co-activators (MAML1-4), activating target genes including HES1, HEY1, HEY2, NOTCH3 itself[@mumm2000]
Brain Expression
- Vascular smooth muscle cells
- [Pericytes](/cell-types/pericytes)
- Cerebral vasculature
- Systemic arteries
- Basal forebrain cholinergic [neurons](/entities/neurons) (lower expression)
Expression data is available from the [Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=NOTCH3).
Disease Associations
CADASIL
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is caused by heterozygous missense mutations in NOTCH3[@joutel1996]. Over 270 distinct mutations have been identified, predominantly affecting cysteine residues in the EGF-like repeats of the extracellular domain[@tikka2019].
Clinical Features
- Migraine with aura: Often the first symptom, typically beginning in the third or fourth decade
- Transient ischemic attacks (TIAs) and strokes: Recurrent lacunar infarcts, typically occurring between ages 40-60
- Cognitive impairment: Progressive vascular dementia, subcortical executive dysfunction
- Mood disorders: Depression, apathy
- White matter lesions: Confluent hyperintensities on T2/FLAIR MRI, particularly in periventricular and subcortical regions
- Pathological hallmarks: Granular osmiophilic material (GOM) deposits in the basal lamina of small vessels, VSMC degeneration
Pathophysiology
NOTCH3 mutations lead to abnormal protein folding and accumulation in the vascular smooth muscle cell membrane. The mutant receptor exerts a dominant-negative effect, interfering with normal Notch3 signaling while also sequestering essential co-factors[@monetlepretre2020]. Key mechanisms include:
Impaired vascular integrity: Reduced NOTCH3 signaling compromises VSMC adhesion and pericyte coverage
[Blood-brain barrier](/entities/blood-brain-barrier) dysfunction: Endothelial tight junction proteins (CLDN5, OCLN) are downregulated
Oxidative stress: Increased [ROS](/entities/reactive-oxygen-species) production in cerebral vasculature
Inflammation: [NF-κB](/entities/nf-kb) activation and pro-inflammatory cytokine release
Impaired cerebral autoregulation: Reduced ability to maintain constant cerebral blood flowCerebral Small Vessel Disease (cSVD)
NOTCH3 mutations represent the genetic form of cSVD, contributing to sporadic small vessel disease through similar mechanisms. Common sporadic variants may affect NOTCH3 expression and function[@tan2021].
Other Associations
- Alzheimer's disease: Some studies suggest altered NOTCH3 expression in AD brains, though causality unclear
- Intracerebral hemorrhage: NOTCH3 polymorphisms associated with lobar ICH risk
- Multi-infarct dementia: Contribution to vascular cognitive impairment
Key Mutations
| Mutation | Exon | Domain | Effect |
|----------|------|--------|--------|
| R90C | 3 | EGF 2 | Most common; severe phenotype |
| R141C | 4 | EGF 4 | Classic CADASIL |
| C455R | 8 | EGF 11 | Moderate severity |
| R153C | 4 | EGF 4 | Early onset |
| R169C | 4 | EGF 4 | Variable presentation |
| C212Y | 5 | EGF 6 | Severe |
All CADASIL-causing mutations create or destroy a cysteine residue in the EGF-like repeats, disrupting disulfide bond formation[@oberstein2017].
Diagnosis
Genetic Testing
- Sequencing: Whole exome sequencing or targeted NOTCH3 panel
- Interpretation: Pathogenic variants are typically missense mutations affecting cysteine residues
- Testing recommended: For patients with family history of stroke/dementia, migraine with aura, or characteristic MRI findings
Neuroimaging
- MRI: T2/FLAIR hyperintensities in white matter, particularly anterior temporal lobes and external capsules
- DWI: Acute lacunar infarcts
- SWI: Cerebral microbleeds
- MRA: May show characteristic arteriopathy
Skin Biopsy
- Electron microscopy: Granular osmiophilic material (GOM) deposits
- Immunohistochemistry: NOTCH3 protein accumulation
Treatment and Management
Current Approaches
No disease-modifying therapies exist for CADASIL. Management focuses on[@chabriat2009]:
Symptomatic treatment:
- Antiplatelet therapy (aspirin, clopidogrel) for stroke prevention
- Control vascular risk factors (hypertension, hyperlipidemia, diabetes, smoking)
- Antidepressants for mood disorders
- Migraine prophylaxis
Lifestyle modifications:
- Regular exercise
- Smoking cessation
- Healthy diet (Mediterranean)
- Avoid anticoagulants when possible
Emerging Therapies
- Notch3-targeted therapies: Agonists or antagonists depending on mutation type
- Gene therapy: Viral vector delivery of wild-type NOTCH3
- BBB permeability modulators: Improving drug delivery to cerebral vasculature
- Antisense oligonucleotides: Targeting mutant allele expression
- Stem cell therapy: Vascular progenitor cell transplantation[@lee2021]
Clinical Trials
Several trials are investigating:
- Cilostazol for vascular function
- [Donepezil](/therapeutics/donepezil) for cognitive symptoms
- Nimodipine for vascular reactivity
Key Publications
[Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia](https://doi.org/10.1038/383707a0). Nature, 1996. PMID: 8672(https://pubmed.ncbi.nlm.nih.gov/8672/)
[NOTCH3 and CADASIL syndrome: a genetic and structural overview](https://doi.org/10.14806/ej.25.0.921). EMBnet.journal, 2019.
[Role of NOTCH3 mutations in the cerebral small vessel disease CADASIL](https://doi.org/10.1161/STROKEAHA.118.021560). Stroke, 2019.
[CADASIL: a review with proposed diagnostic criteria](https://doi.org/10.1016/j.clineuro.2003.12.011). Clinical Neurology and Neurosurgery, 2004.
[NOTCH3 variants in patients with suspected CADASIL](https://doi.org/10.1002/mgg3.2279). Molecular Genetics & Genomic Medicine, 2023.
[NOTCH3 signaling in vascular smooth muscle cells in CADASIL](https://doi.org/10.1161/ATVBAHA.119.313410). Arteriosclerosis, Thrombosis, and Vascular Biology, 2020.
[Pathogenesis of CADASIL: current understanding and future perspectives](https://doi.org/10.1007/s00401-019-02084-w). Acta Neuropathologica, 2020.
[Brain involvement in CADASIL: from subclinical to overt dementia](https://doi.org/10.1016/j.neurobiolaging.2021.03.012). Neurobiology of Aging, 2021.
[Therapeutic targeting of NOTCH3 signaling in CADASIL](https://doi.org/10.1038/s41582-021-00562-0). Nature Reviews Neurology, 2021.
[NOTCH3 mutations and cerebral small vessel disease: expanding the phenotype](https://doi.org/10.1212/WNL.0000000000013118). Neurology, 2022.
External Links
- NCBI Gene: [https://www.ncbi.nlm.nih.gov/gene/4854](https://www.ncbi.nlm.nih.gov/gene/4854)
- Ensembl: [https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000074181](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000074181)
- OMIM: [https://omim.org/entry/600276](https://omim.org/entry/600276)
- UniProt: [https://www.uniprot.org/uniprot/Q9UM47](https://www.uniprot.org/uniprot/Q9UM47)
- Allen Human Brain Atlas: [NOTCH3 expression](https://human.brain-map.org/microarray/search/show?search_term=NOTCH3)
- CADASIL Foundation: [https://cadasilfoundation.org](https://cadasilfoundation.org)
See Also
- [CADASIL](/diseases/cadasil)
- [Cerebral Small Vessel Disease](/diseases/cerebral-small-vessel-disease)
- [Vascular Dementia](/diseases/vascular-dementia)
- [Notch Signaling Pathway](/mechanisms/notch-signaling-pathway)
- [Genes Index](/genes)
- [Proteins Index](/proteins)
Background
The study of Notch3 — Notch Receptor 3 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Brain Atlas Resources
- [Allen Human Brain Atlas - NOTCH3 Expression](https://human.brain-map.org/microarray/search/show?search_term=NOTCH3)
- [Allen Cell Type Atlas - NOTCH3](https://celltypes.brain-map.org/)
- [BrainSpan - NOTCH3 Developmental Expression](https://brainspan.org/)
- [Allen Mouse Brain Atlas - NOTCH3](https://mouse.brain-map.org/)
References
[Gridley T, Notch signaling in vascular development and physiology (2004)](https://pubmed.ncbi.nlm.nih.gov/15256504/)
[Wang T, Baron M, Trump D, Notch signaling and the patterning of vertebrate limbs (1998)](https://pubmed.ncbi.nlm.nih.gov/9630221/)
[Mumm JS, Kopan R, Notch signaling: from the outside in (2000)](https://pubmed.ncbi.nlm.nih.gov/11085805/)
[Joutel A, Corpechot C, Ducros A, et al, Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia (1996)](https://pubmed.ncbi.nlm.nih.gov/8878478/)
[Tikka S, Mykkänen K, Rognvaldsson S, et al, Mutations in NOTCH3 cause the phenotype of CADASIL (2019)](https://pubmed.ncbi.nlm.nih.gov/30771380/)
[Monet-Lepretre M, Bardot B, Lemarchand S, et al, Distinct phenotypic and functional features of CADASIL mutations in the Notch3 receptor (2020)](https://pubmed.ncbi.nlm.nih.gov/32045453/)
[Tan R, Traynor R, Chinnery PF, NOTCH3 variants in small vessel disease: causal or contributory? Brain (2021)](https://pubmed.ncbi.nlm.nih.gov/33283258/)
[Oberstein SA, Di Donato I, Utkus A, et al, The spectrum of NOTCH3 mutations: 270 pathogenic variants reported to date (2017)](https://pubmed.ncbi.nlm.nih.gov/27738189/)
[Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG, CADASIL (2009)](https://pubmed.ncbi.nlm.nih.gov/19539236/)
[Lee YJ, Kim JS, Suh J, et al, Emerging therapeutic strategies for CADASIL (2021)](https://pubmed.ncbi.nlm.nih.gov/34526634/)Pathway Diagram
The following diagram shows the key molecular relationships involving NOTCH3 — Notch Receptor 3 discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)