Systematic Review of Cysteine-Sparing NOTCH3 Missense Mutations in Patients with Clinical Suspicion of CADASIL.

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  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI, [2000-
    • Subject Terms:
      Mutation, Missense*; CADASIL/*genetics ; Cysteine/*genetics ; Receptor, Notch3/*genetics; Biopsy ; CADASIL/diagnostic imaging ; CADASIL/metabolism ; Cysteine/metabolism ; Databases, Factual ; Exons/genetics ; Humans ; Magnetic Resonance Imaging ; Polymorphism, Genetic ; Receptor, Notch3/metabolism
    • Abstract:
      CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by mutations in the NOTCH3 gene, affecting the number of cysteines in the extracellular domain of the receptor, causing protein misfolding and receptor aggregation. The pathogenic role of cysteine-sparing NOTCH3 missense mutations in patients with typical clinical CADASIL syndrome is unknown. The aim of this article is to describe these mutations to clarify if any could be potentially pathogenic. Articles on cysteine-sparing NOTCH3 missense mutations in patients with clinical suspicion of CADASIL were reviewed. Mutations were considered potentially pathogenic if patients had: (a) typical clinical CADASIL syndrome; (b) diffuse white matter hyperintensities; (c) the 33 NOTCH3 exons analyzed; (d) mutations that were not polymorphisms; and (e) Granular osmiophilic material (GOM) deposits in the skin biopsy. Twenty-five different mutations were listed. Four fulfill the above criteria: p.R61W; p.R75P; p.D80G; and p.R213K. Patients carrying these mutations had typical clinical CADASIL syndrome and diffuse white matter hyperintensities, mostly without anterior temporal pole involvement. Cysteine-sparing NOTCH3 missense mutations are associated with typical clinical CADASIL syndrome and typical magnetic resonance imaging (MRI) findings, although with less involvement of the anterior temporal lobe. Hence, these mutations should be further studied to confirm their pathological role in CADASIL.
      Competing Interests: The authors declare no conflict of interest.
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    • Contributed Indexing:
      Keywords: CADASIL; NOTCH3; cysteine; mutation; temporal pole
    • Accession Number:
      0 (NOTCH3 protein, human)
      0 (Receptor, Notch3)
      K848JZ4886 (Cysteine)
    • Publication Date:
      Date Created: 20170914 Date Completed: 20180529 Latest Revision: 20240327
    • Publication Date:
      20240327
    • Accession Number:
      PMC5618613
    • Accession Number:
      10.3390/ijms18091964
    • Accession Number:
      28902129