NOTCH3 — Notch Receptor 3

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NOTCH3 — Notch Receptor 3

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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">Agin

...

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 sequence

Signal 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 flow

Cerebral 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)

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)

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Related Entities

NOTCH3

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slug	genes-notch3
kg_node_id	NOTCH3
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-86cebfa44528
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-notch3'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

35%

Debates

0

Incoming

7

Outgoing

19

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

NOTCH3 — Notch Receptor 3

NOTCH3 — Notch Receptor 3

NOTCH3 — Notch Receptor 3

NOTCH3 — Notch Receptor 3

Introduction

Overview

Function

Notch Signaling Pathway

Structure

Signal Transduction

Brain Expression

Disease Associations

CADASIL

Clinical Features

Pathophysiology

Cerebral Small Vessel Disease (cSVD)

Other Associations

Key Mutations

Diagnosis

Genetic Testing

Neuroimaging

Skin Biopsy

Treatment and Management

Current Approaches

Emerging Therapies

Clinical Trials

Key Publications

External Links

See Also

Background

Brain Atlas Resources

References

Pathway Diagram

💬 Discussion