NOTCH3 gene

The NOTCH3 gene (NOTCH3 stands for: Notch receptor 3) is a protein-coding gene located on chromosome 19p13.12. The NOTCH3 gene encodes the third discovered human homolog of the type I membrane protein Notch from Drosophilia melanogaster. In Drosophilia, the interaction of Notch with its cell-bound ligands establishes an intercellular signaling pathway that plays a key role in neuronal development. The signaling pathways associated with this receptor protein include pre-NOTCH expression and processing as well as gene expression (transcription). Gene Ontology (GO) annotations for this gene include calcium ion binding and enzyme binding. An important paralog of this gene is NOTCH1.

NOTCH3 functions as a receptor for the membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell fate determination (Peters N et al.2004). After ligand activation by the released Notch intracellular domain (NICD), it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer-of-split locus. NOTCH3 influences the implementation of differentiation, proliferation and apoptosis programs.

NOTCH3 mutations have also been shown to be associated with a reduction in Notch3 expression in vitro. Induced cerebrovascular disease(CADASIL) mainly involves smooth muscle cells but also fibroblasts (study on skin fibroblasts) (Muiño E et al. 2021). This is understandable, as they are directly involved in the formation of the vascular basal lamina and the maintenance of vascular integrity (Qualtieri A et al. 2018).

Homologs of the Notch ligands have also been identified in humans, but the exact interactions between these ligands and the human Notch homologs remain to be determined. Mutations in the NOTCH3 gene have been identified as the cause of autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (Yuan L et al. 2024; Lee YC et al. 2026). Furthermore, lateral meningocele syndrome is associated with a defect in this gene.

CADASIL is a disease of the small vessels of the brain (small vessel angiopathy/microangiopathy) caused by mutations in the NOTCH3 gene. The mutations in this gene lead to an odd number of cysteines in the EGF-like repeat domain, which results in misfolding and aggregation of the protein. The main symptoms are migraine, psychiatric disorders, recurrent apoplexy and dementia, with executive functions characteristically impaired. The molecular signaling pathways altered by this receptor aggregation are still unclear. Livedo syndromes do not belong to the clinical picture of cerebral hereditary microangiopathy, which shows a clear organ preference for the brain. Other systemic vascular manifestations are also atypical for CADASIL.

1. Lee YC et al. (2026) Comparison of clinical and imaging features of cerebral small vessel disease associated with heterozygous HTRA1 and NOTCH3 mutations. Int J Stroke 21:79-88.
2. Muiño E et al. (2021) Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment. Sci Rep 11:6846.
3. Qualtieri A et al. (2018) Notch3 protein expression in skin fibroblasts from CADASIL patients. J Neurol Sci 390:121-128.
4. Peters N et al.(2004) CADASIL-associated Notch3 mutations have differential effects both on ligand binding and ligand-induced Notch3 receptor signaling through RBP-Jk. Exp Cell Res 299:454-464.
5. Yuan L et al. (2024) CADASIL: A NOTCH3-associated cerebral small vessel disease. J Adv Res 66:223-235.