Distribution pattern of Notch3 mutations suggests a gain-of-function mechanism for CADASIL.
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.
Donahue
Christine P
CP
Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Kosik
Kenneth S
KS
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
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