title: Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.
abstract: BACKGROUND
  CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is commonly overlooked or misdiagnosed owing to its recent identification and its variable mode of presentation. The defective gene in CADASIL is Notch3, which encodes a large transmembrane receptor. To set up a diagnostic test and to delineate the Notch3 domains involved in CADASIL., we undertook mutations analysis in this gene in a group of CADASIL patients.
  
  
  METHODS
  50 unrelated patients with CADASIL and 100 healthy controls were screened for mutations along the entire Notch3 sequence, by means of single-strand conformation polymorphism, heteroduplex, and sequence analysis.
  
  
  RESULTS
  Strongly stereotyped mis-sense mutations, located within the epidermal-growth-factor-like (EGF-like) repeats, in the extracellular domain of Notch3, were detected in 45 patients. Clustering of mutations within the two exons encoding the first five EGF-like repeats was observed (32 patients). All these mutations lead to loss or gain of a cysteine residue and therefore to an unpaired number of cysteine residues within a given EGF domain. None of these mutations was found in the 100 controls.
  
  
  CONCLUSIONS
  Because of the strong clustering and highly stereotyped nature of the pathogenetic mutations detected in CADASIL patients, and easy and reliable diagnostic test for CADASIL is feasible. The findings suggest that aberrant dimerisation of Notch3, due to abnormal disulphide bridging with another Notch3 molecule or with another protein, may be involved in the pathogenesis of this disorder.
authors.affiliation: INSERM U25, Faculté Médecine Necker-Enfants Malades, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Joutel
authors.forename: K
authors.initials: K
authors.lastname: Vahedi
authors.forename: C
authors.initials: C
authors.lastname: Corpechot
authors.forename: A
authors.initials: A
authors.lastname: Troesch
authors.forename: H
authors.initials: H
authors.lastname: Chabriat
authors.forename: C
authors.initials: C
authors.lastname: Vayssière
authors.forename: C
authors.initials: C
authors.lastname: Cruaud
authors.forename: J
authors.initials: J
authors.lastname: Maciazek
authors.forename: J
authors.initials: J
authors.lastname: Weissenbach
authors.forename: M G
authors.initials: MG
authors.lastname: Bousser
authors.forename: J F
authors.initials: JF
authors.lastname: Bach
authors.forename: E
authors.initials: E
authors.lastname: Tournier-Lasserve
mesh_terms: D016022:Case-Control Studies; D002539:Cerebral Arterial Diseases / Q000175:diagnosis / Q000235:genetics*; D002544:Cerebral Infarction / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D004815:Epidermal Growth Factor / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007968:Leukoencephalopathy, Progressive Multifocal / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface; D051880:Receptors, Notch
chemical_list: C499374:NOTCH3 protein, human; D011518:Proto-Oncogene Proteins; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D004815:Epidermal Growth Factor