New mutations in the Notch3 gene in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)

作者：Abramycheva Natalya; Stepanova Maria; Kalashnikova Lyudmila; Zakharova Maria; Maximova Marina; Tanashyan Marine; Lagoda Olga; Fedotova Ekaterina; Klyushnikov Sergey; Konovalov Rodion; Sakharova Alla; Illarioshkin Sergey^*

来源：Journal of the Neurological Sciences, 2015, 349(1-2): 196-201.

DOI：10.1016/j.jns.2015.01.018

• CADASIL
• White matter lesions
• NOTCH3 gene
• Mutations
• Phenotypic heterogeneity
• Russian population

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.

• 出版日期2015-2-15