title: Distribution pattern of Notch3 mutations suggests a gain-of-function mechanism for CADASIL.
abstract: Mutations in Notch3 cause the syndrome CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). The mechanism by which these mutations result in a CADASIL phenotype has been widely speculated upon. A first step toward understanding a disease mechanism is to learn whether the mutations result in the loss of Notch3 function, in particular, its role in signaling or in the gain of a novel function. Notch3 genomic sequences were analyzed for sites of conservation across species. We present here a bioinformatic analysis of the Notch paralogs and orthologs that suggest that CADASIL mutations result in a gain of function. This finding diminishes the likelihood that a Notch3 signaling deficit is responsible for the phenotype and increases the likelihood that CADASIL joins the growing list of neurological diseases with protein deposits due to misfolding and aggregation.
authors.affiliation: Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Christine P
authors.initials: CP
authors.lastname: Donahue
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kosik
mesh_terms: D000818:Animals; D018899:CpG Islands / Q000235:genetics; D015161:Dementia, Multi-Infarct / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005091:Exons / Q000235:genetics; D005787:Gene Frequency; D006801:Humans; D051379:Mice; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D051381:Rats; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology; D051880:Receptors, Notch; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; C499374:NOTCH3 protein, human; C497762:Notch1 protein, mouse; C497763:Notch1 protein, rat; C497765:Notch2 protein, mouse; C497766:Notch2 protein, rat; C499373:Notch3 protein, mouse; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D014157:Transcription Factors; C073572:Notch4 protein, mouse