title: Mice carrying a R142C Notch 3 knock-in mutation do not develop a CADASIL-like phenotype.
abstract: CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, MIM 125310) is a genetic vascular dementia disease that is linked to missense mutations, small in-frame deletions, and splice site mutations in the human Notch 3 gene. Here we describe the generation of a mouse knockin model for one of the most prevalent CADASIL mutations, an arginine to cysteine transition at position 141, R141C, which corresponds to mutation R142C in mouse NOTCH 3. CADASIL(R142C) mice show no apparent CADASIL-like phenotype after histological and MRI analysis. The NOTCH 3 (R142C) receptor is processed normally and does not appear to accumulate the ectodomain, which has been observed in CADASIL patients. We discuss possible reasons for the different outcomes of the same germline CADASIL mutation in mice and humans.
authors.affiliation: Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Lundkvist
authors.forename: Shunwei
authors.initials: S
authors.lastname: Zhu
authors.forename: Emil M
authors.initials: EM
authors.lastname: Hansson
authors.forename: Petra
authors.initials: P
authors.lastname: Schweinhardt
authors.forename: Qing
authors.initials: Q
authors.lastname: Miao
authors.forename: Paul
authors.initials: P
authors.lastname: Beatus
authors.forename: Karin
authors.initials: K
authors.lastname: Dannaeus
authors.forename: Helena
authors.initials: H
authors.lastname: Karlström
authors.forename: Clas B
authors.initials: CB
authors.lastname: Johansson
authors.forename: Matti
authors.initials: M
authors.lastname: Viitanen
authors.forename: Björn
authors.initials: B
authors.lastname: Rozell
authors.forename: Christian
authors.initials: C
authors.lastname: Spenger
authors.forename: Abdul
authors.initials: A
authors.lastname: Mohammed
authors.forename: Hannu
authors.initials: H
authors.lastname: Kalimo
authors.forename: Urban
authors.initials: U
authors.lastname: Lendahl
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology / Q000648:ultrastructure; D001522:Behavior, Animal; D015153:Blotting, Western; D046589:CADASIL / Q000235:genetics*; D017536:Carotid Artery, Common / Q000473:pathology / Q000648:ultrastructure; D003545:Cysteine / Q000378:metabolism; D018095:Germ-Line Mutation; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface / Q000235:genetics*; D051880:Receptors, Notch; D017422:Sequence Analysis, DNA; D013904:Thoracic Vertebrae / Q000000981:diagnostic imaging; D014463:Ultrasonography
chemical_list: D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; C073572:Notch4 protein, mouse; D003545:Cysteine