title: Activating NOTCH3 mutation in a patient with small-vessel-disease of the brain.
abstract: The most common causative diagnosis of hereditary small-vessel-disease of the brain, CADASIL, is due to highly stereotyped mutations in the NOTCH3 receptor. NOTCH3 has 33 exons but all CADASIL mutations occur within the Epidermal Growth Factor-like Repeats encoded by exons 2-24, lead to an odd number of cysteine residues and are associated with GOM deposits and abnormal NOTCH3 protein accumulation. The majority of CADASIL mutations appear to retain normal level of signaling activity, while very few mutations show reduced activity. Herein we identified a novel heterozygous missense mutation (c.4544T>C) in exon 25 of NOTCH3 in a patient with cerebral small-vessel-disease but lacking GOM deposits and NOTCH3 accumulation. The mutation should result in a p.L1515P substitution in the evolutionarily highly conserved juxtamembranous region of NOTCH3, which constitutes the heterodimerization domain. The p.L1515P mutant exhibits increased canonical NOTCH3 signaling, although in a ligand-independent fashion. Biochemical analysis suggests that the mutation renders NOTCH3 hyperactive through destabilization of the heterodimer. Therefore, our study suggests that the p.L1515P mutation falls in a novel mechanistic class of NOTCH3 mutations and that NOTCH3 activating mutations should be further considered for molecular analysis of patients with cerebral small-vessel-disease.
authors.affiliation: INSERM, U740, Paris, F-75010, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Fouillade
authors.forename: Hugues
authors.initials: H
authors.lastname: Chabriat
authors.forename: Florence
authors.initials: F
authors.lastname: Riant
authors.forename: Manuèle
authors.initials: M
authors.lastname: Mine
authors.forename: Minh
authors.initials: M
authors.lastname: Arnoud
authors.forename: Laurent
authors.initials: L
authors.lastname: Magy
authors.forename: Marie Germaine
authors.initials: MG
authors.lastname: Bousser
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Tournier-Lasserve
authors.forename: Anne
authors.initials: A
authors.lastname: Joutel
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D046589:CADASIL / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019281:Dimerization; D005260:Female; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008875:Middle Aged; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D020836:Protein Structure, Quaternary; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D011994:Recombinant Proteins