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Int. J. Mol. Sci. 2017, 18(9), 1964; doi:10.3390/ijms18091964

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

1
Stroke Pharmacogenomics and Genetics, Fundació Docència i Recerca Mútua Terrassa, Hospital Mútua de Terrassa, 08221 Terrassa, Spain
2
Neurovascular Research Laboratory, Vall d’Hebron Institute of Research, Hospital Vall d’Hebron, 08035 Barcelona, Spain;catycarrerav@gmail.com (C.C.)
3
Neurology Service, Hospital Mútua de Terrassa, 08221 Terrassa, Spain
4
Neurology Service, Institut Hospital del Mar d’investigacions Mèdiques, IMIM-Hospital del Mar, 08003 Barcelona, Spain
*
Author to whom correspondence should be addressed.
Received: 27 July 2017 / Revised: 7 September 2017 / Accepted: 10 September 2017 / Published: 13 September 2017
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies)
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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. View Full-Text
Keywords: CADASIL; cysteine; NOTCH3; mutation; temporal pole CADASIL; cysteine; NOTCH3; mutation; temporal pole
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Muiño, E.; Gallego-Fabrega, C.; Cullell, N.; Carrera, C.; Torres, N.; Krupinski, J.; Roquer, J.; Montaner, J.; Fernández-Cadenas, I. Systematic Review of Cysteine-Sparing NOTCH3 Missense Mutations in Patients with Clinical Suspicion of CADASIL. Int. J. Mol. Sci. 2017, 18, 1964.

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