NOTCH3 Gene: Structure, Function, and Clinical Significance
A comprehensive guide to the NOTCH3 gene, its protein product, associated diseases, and mutation spectrum.
Gene Information Card
| Symbol | NOTCH3 |
|---|---|
| Full Name | Notch receptor 3 |
| Gene Type | Protein coding |
| Chromosomal Location | 19p13.12 |
| NCBI Gene ID | 4854 ncbi.nlm.nih.gov/gene/4854 |
| Ensembl ID | ENSG00000074181 |
| UniProt ID | Q9UM47 |
| OMIM ID | 600276 |
| HGNC ID | 7883 |
| Aliases | CADASIL, CASIL, IMF2 |
Description
The NOTCH3 gene encodes a member of the Notch family of transmembrane receptors. It plays a critical role in cell fate determination, vascular smooth muscle cell maturation, and arterial development. Mutations in NOTCH3 are primarily associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary small vessel disease leading to stroke and dementia.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) | Missense mutations leading to gain or loss of cysteine residues in EGF-like domains, causing aberrant Notch3 signaling and accumulation of the protein in vascular smooth muscle cells. | ClinVar, OMIM |
| Lacunar Stroke | NOTCH3 mutations predispose to small vessel occlusion and lacunar infarcts, often as part of CADASIL. | ClinVar, PubMed |
| Vascular Dementia | Progressive degeneration of cerebral small vessels due to NOTCH3 dysfunction contributes to cognitive decline. | OMIM, PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Artery | 12.5 | High |
| Smooth Muscle | 10.2 | High |
| Brain | 5.1 | Medium |
| Heart | 4.3 | Medium |
| Liver | 1.2 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Primary Vascular Smooth Muscle Cells | 15.0 | High expression; key site of CADASIL pathology |
| Endothelial Cells | 8.5 | Moderate expression |
| HEK293 | 2.0 | Low endogenous expression; used for transfection studies |
| SH-SY5Y (Neuroblastoma) | 3.5 | Moderate expression; neuronal model |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1630T>C (p.Cys544Arg) | Missense | Common in CADASIL cohorts | Disrupts disulfide bond in EGF-like domain, leading to protein aggregation |
| c.268C>T (p.Arg90Cys) | Missense | Reported in CADASIL | Cysteine alteration; aberrant Notch3 signaling |
| c.397C>T (p.Arg133Cys) | Missense | Pathogenic | Loss of cysteine; protein misfolding |
| c.458C>T (p.Pro153Leu) | Missense | Rare | Potential gain-of-function; altered receptor activity |
Mutation functional classification
Loss of Function (LOF)
Complete loss of NOTCH3 function is not typically observed in CADASIL; however, some missense mutations may impair signaling.
Gain of Function (GOF)
Most CADASIL mutations are considered gain-of-function, leading to abnormal protein accumulation and toxicity in vascular smooth muscle cells.
Dominant Negative (DN)
Some mutations may exert dominant-negative effects by interfering with wild-type NOTCH3 signaling, though evidence is limited.
View complete mutation data：
Gene Ontology (GO)
| • Notch binding | • Calcium ion binding |
| • Receptor activity | • Signal transduction |
| • Cell differentiation | • Vascular smooth muscle cell differentiation |
Pathways
• Notch signaling pathway
• Cardiovascular development
• Regulation of cell fate
Protein Summary
The NOTCH3 protein is a single-pass transmembrane receptor with 34 EGF-like repeats in its extracellular domain. It undergoes proteolytic cleavage upon ligand binding, releasing the intracellular domain to regulate gene transcription. In the vasculature, NOTCH3 is essential for arterial specification and smooth muscle cell survival. Mutations, particularly those affecting cysteine residues, lead to protein misfolding and aggregation, causing CADASIL.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| NOTCH3 Knockout HEK293 Cell Line | EDJ-KQ437 | Human | 4854 | Details Get a Quote |
| NOTCH3 Knockout HeLa Cell Line | EDJ-KQ18002 | Human | 4854 | Details Get a Quote |
| NOTCH3 Knockout A-549 Cell Line | EDJ-KQ18737 | Human | 4854 | Details Get a Quote |
| NOTCH3 Knockout HCT 116 Cell Line | EDJ-KQ18738 | Human | 4854 | Details Get a Quote |
| NOTCH3 Knockout Huh-7 Cell Line | EDJ-KZ369 | Human | 4854 | Details Get a Quote |
| NOTCH3 (p.R182H) Point Mutation in HAP1 Cell Line | EDC03565 | Human | 4854 | Details Get a Quote |
| NOTCH3 (c.1192+15A>G )Point Mutation in HAP1 Cell Line | EDC03564 | Human | 4854 | Details Get a Quote |
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