title: New mutations in the Notch3 gene in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL).
abstract: BACKGROUND
  Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a cerebrovascular small-vessel disease caused by stereotyped mutations in the Notch3 gene altering the number of cysteine residues.
  
  
  METHODS
  We directly sequenced exons 2-23 of the Notch3 gene in 30 unrelated Russian patients with clinical/neuroimaging picture suggestive of CADASIL. To confirm the pathogenicity of new nucleotide variants, we used the standard bioinformatics tools and screened 200 ethnically matched individuals as controls.
  
  
  RESULTS
  We identified 16 different point mutations in the Notch3 gene in 18 unrelated patients, including 4 new missense mutations (C194G, V252M, C338F, and C484G). All but two mutations affected the cysteine residue. The non-cysteine change V322M was shown to be associated with CADASIL-specific deposits of granular osmiophilic material in the vascular smooth-muscle cells, which confirmed the pathogenicity of this Notch3 variant. Two patients were shown to be compound-heterozygotes carrying two pathogenic Notch3 mutations. The disease was characterized by marked clinical variability, without evident phenotype-genotype correlations.
  
  
  CONCLUSIONS
  In our sample, 60% of Russian patients with 'clinically suspected' CADASIL received the definitive molecularly proven diagnosis. Careful assessment of genealogical, clinical, and neuroimaging data in patients with lacunar stroke can help selecting patients with a high probability of finding mutations on genetic screening.
authors.affiliation: Department of Neurogenetics, Research Center of Neurology, Russian Academy of Medical Sciences, Volokolamskoye Shosse 80, Moscow 125367, Russia.
authors.forename: Natalya
authors.initials: N
authors.lastname: Abramycheva
authors.affiliation: Department of Neurogenetics, Research Center of Neurology, Russian Academy of Medical Sciences, Volokolamskoye Shosse 80, Moscow 125367, Russia.
authors.forename: Maria
authors.initials: M
authors.lastname: Stepanova
authors.affiliation: Department of Neurorehabilitation, Research Center of Neurology, Russian Academy of Medical Sciences, Volokolamskoye Shosse 80, Moscow 125367, Russia.
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Kalashnikova
authors.affiliation: Department of Demyelinating Diseases, Research Center of Neurology, Russian Academy of Medical Sciences, Volokolamskoye Shosse 80, Moscow 125367, Russia.
authors.forename: Maria
authors.initials: M
authors.lastname: Zakharova
authors.affiliation: Department of Acute Stroke with Intensive Care Unit, Research Center of Neurology, Russian Academy of Medical Sciences, Volokolamskoye Shosse 80, Moscow 125367, Russia.
authors.forename: Marina
authors.initials: M
authors.lastname: Maximova
authors.affiliation: Department of Chronic Cerebrovascular Diseases, Research Center of Neurology, Russian Academy of Medical Sciences, Volokolamskoye Shosse 80, Moscow 125367, Russia.
authors.forename: Marine
authors.initials: M
authors.lastname: Tanashyan
authors.affiliation: Department of Chronic Cerebrovascular Diseases, Research Center of Neurology, Russian Academy of Medical Sciences, Volokolamskoye Shosse 80, Moscow 125367, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Lagoda
authors.affiliation: Department of Neurogenetics, Research Center of Neurology, Russian Academy of Medical Sciences, Volokolamskoye Shosse 80, Moscow 125367, Russia.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Fedotova
authors.affiliation: Department of Neurogenetics, Research Center of Neurology, Russian Academy of Medical Sciences, Volokolamskoye Shosse 80, Moscow 125367, Russia.
authors.forename: Sergey
authors.initials: S
authors.lastname: Klyushnikov
authors.affiliation: Department of Neuroradiology, Research Center of Neurology, Russian Academy of Medical Sciences, Volokolamskoye Shosse 80, Moscow 125367, Russia.
authors.forename: Rodion
authors.initials: R
authors.lastname: Konovalov
authors.affiliation: Department of Pathology, Research Center of Neurology, Russian Academy of Medical Sciences, Volokolamskoye Shosse 80, Moscow 125367, Russia.
authors.forename: Alla
authors.initials: A
authors.lastname: Sakharova
authors.affiliation: Department of Neurogenetics, Research Center of Neurology, Russian Academy of Medical Sciences, Volokolamskoye Shosse 80, Moscow 125367, Russia. Electronic address: snillario@gmail.com.
authors.forename: Sergey
authors.initials: S
authors.lastname: Illarioshkin
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain; D046589:CADASIL / Q000235:genetics* / Q000473:pathology; D005091:Exons; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*; D055815:Young Adult
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch
keywords: CADASIL; Mutations; NOTCH3 gene; Phenotypic heterogeneity; Russian population; White matter lesions