Systematic review of cysteine-sparing NOTCH3 missense mutations in patients with clinical suspicion of CADASIL

Elena Muiño, Cristina Gallego-Fabrega, Natalia Cullell, Caty Carrera, Nuria Torres, Jurek Krupinski, Jaume Roquer, Joan Montaner, Israel Fernández-Cadenas*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

36 Citations (Scopus)

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.

Original languageEnglish
Article number1964
JournalInternational Journal of Molecular Sciences
Volume18
Issue number9
DOIs
Publication statusPublished - 13 Sept 2017

Keywords

  • CADASIL
  • Cysteine
  • Mutation
  • NOTCH3
  • Temporal pole

Fingerprint

Dive into the research topics of 'Systematic review of cysteine-sparing NOTCH3 missense mutations in patients with clinical suspicion of CADASIL'. Together they form a unique fingerprint.

Cite this