NOTCH3

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.

Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).^[6] Mutations in NOTCH3 have also been identified in families with Alzheimer's disease.^[7] Adult Notch3 knock-out mice show incomplete neuronal maturation in the spinal cord dorsal horn, resulting in permanently increased nociceptive sensitivity.^[8] Mutations in NOTCH3 are associated to lateral meningocele syndrome.^[9]

Notch3 is being investigated as a target for anti-cancer drugs, as it is overexpressed in several types of cancers.^[10] Early clinical trials of Pfizer's PF-06650808, an anti-Notch3 antibody linked to a cytotoxic drug, showed efficacy against solid tumors.^[11]

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^[12] a rare splice isoform in humans shared with a small number of other species, and a regulatory-region deletion in Brandt's bat.^[13]