Cysteine-sparing CADASIL mutations in NOTCH3 show proaggregatory properties in vitro.

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  • Additional Information
    • Source:
      Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0235266 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4628 (Electronic) Linking ISSN: 00392499 NLM ISO Abbreviation: Stroke Subsets: MEDLINE
    • Publication Information:
      Publication: 1998- : Baltimore, Md. : Lippincott Williams & Wilkins
      Original Publication: Dallas : American Heart Association
    • Subject Terms:
      Mutation*; CADASIL/*genetics ; Cysteine/*genetics ; Receptors, Notch/*genetics; Aged ; Biopsy ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Protein Binding ; Protein Folding ; Receptor, Notch3 ; Sequence Analysis, DNA ; Skin/ultrastructure
    • Abstract:
      Background and Purpose: Mutations in NOTCH3 cause cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common monogenic cause of stroke and vascular dementia. Misfolding and aggregation of NOTCH3 proteins triggered by cysteine-affecting mutations are considered to be the key disease mechanisms. However, the significance of cysteine-sparing mutations is still debated.
      Methods: We studied a family with inherited small vessel disease by standardized medical history, clinical examination, MRI, ultrastructural analysis of skin biopsies, and Sanger sequencing of all NOTCH3 exons. In addition, we performed in vitro characterization of NOTCH3 variants using recombinant protein fragments and a single-particle aggregation assay.
      Results: We identified a novel cysteine-sparing NOTCH3 mutation (D80G) in 4 family members, which was absent in a healthy sibling. All mutation carriers exhibited a CADASIL typical brain imaging and clinical phenotype, whereas skin biopsy showed inconsistent results. In vitro aggregation behavior of the D80G mutant was similar compared with cysteine-affecting mutations. This was reproduced with cysteine-sparing mutations from previously reported families having a phenotype consistent with CADASIL.
      Conclusions: Our findings support the view that cysteine-sparing mutations, such as D80G, might cause CADASIL with a phenotype largely indistinguishable from cysteine mutations. The in vitro aggregation analysis of atypical NOTCH3 mutations offers novel insights into pathomechanisms and might represent a tool for estimating their clinical significance.
      (© 2015 American Heart Association, Inc.)
    • Comments:
      Comment in: Stroke. 2015 Jun;46(6):e153. (PMID: 25922511)
      Comment in: Stroke. 2015 Jun;46(6):e154. (PMID: 25922512)
    • Grant Information:
      ETM/244 United Kingdom CSO_ Chief Scientist Office; MR/N003403/1 United Kingdom MRC_ Medical Research Council
    • Contributed Indexing:
      Keywords: CADASIL; NOTCH3 protein, human; cerebral small vessel disease; genetic testing; recombinant proteins
    • Accession Number:
      0 (NOTCH3 protein, human)
      0 (Receptor, Notch3)
      0 (Receptors, Notch)
      K848JZ4886 (Cysteine)
    • Publication Date:
      Date Created: 20150122 Date Completed: 20150513 Latest Revision: 20220410
    • Publication Date:
      20240829
    • Accession Number:
      10.1161/STROKEAHA.114.007472
    • Accession Number:
      25604251