NOTCH3

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Protein-coding gene in humans

title: "NOTCH3" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public description: "Protein-coding gene in humans" topic_path: "uncategorized" source: "https://en.wikipedia.org/wiki/NOTCH3" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Protein-coding gene in humans ::

Neurogenic locus notch homolog protein 3 (Notch 3) is a protein that in humans is encoded by the NOTCH3 gene.

Function

This gene encodes the third discovered human homologue of the Drosophila melanogaster type I membrane protein notch. In Drosophila, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined.

Pathology

::figure[src="https://upload.wikimedia.org/wikipedia/commons/e/eb/CADASIL_-_very_high_mag.jpg" caption="[[Micrograph]] showing [[CADASIL]] with a Notch 3 [[immunostain"] ::

Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Mutations in NOTCH3 have also been identified in families with Alzheimer's disease. Adult Notch3 knock-out mice show incomplete neuronal maturation in the spinal cord dorsal horn, resulting in permanently increased nociceptive sensitivity. Mutations in NOTCH3 are associated to lateral meningocele syndrome.

Pharmaceutical target

Notch3 is being investigated as a target for anti-cancer drugs, as it is overexpressed in several types of cancers. Early clinical trials of Pfizer's PF-06650808, an anti-Notch3 antibody linked to a cytotoxic drug, showed efficacy against solid tumors.

Mammalian evolution

An extensive cross-species investigation of the NOTCH3 gene has revealed unexpected natural diversity in a protein that is otherwise highly conserved among mammals. The analysis uncovered multiple cysteine-altering variants in jaguar a rare splice isoform in humans shared with a small number of other species, and a regulatory-region deletion in Brandt’s bat.

References

References

  1. (September 1994). "Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3". Genomics.
  2. "Entrez Gene: NOTCH3 Notch homolog 3 (Drosophila)".
  3. (May 2012). "Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease". Neurobiology of Aging.
  4. (October 2014). "Notch3 is necessary for neuronal differentiation and maturation in the adult spinal cord". Journal of Cellular and Molecular Medicine.
  5. (February 2015). "Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome". American Journal of Medical Genetics. Part A.
  6. (2012). "Notch Signaling in Embryology and Cancer".
  7. "Pfizer Oncology: ADC Development Overview (2016) » ADC Review".
  8. (July 2017). "Genome-wide signatures of complex introgression and adaptive evolution in the big cats". Science Advances.
  9. (2013). "Genome analysis reveals insights into physiology and longevity of the Brandt's bat Myotis brandtii". Nature Communications.

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