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

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

doi:10.3390/ijms18091964

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.

Highlights

CADASIL is an inherited systemic arterial vessel disease caused by mutations in the NOTCH3 gene, located on the 19p13 chromosome [1,2], which encodes a transmembrane receptor that is mainly expressed in the smooth muscle cells of blood vessels and pericytes [3].This receptor has three domains: (1) a large extracellular domain (ECD) with 34 epidermal growth factor (EGF)-like repeats encoded by exons 2–24, where NOTCH3 mutations are typically located; (2) a transmembrane domain; and (3) an intracellular domain (ICD)
We considered that p.R61W [23], p.R75P [25], p.D80G [27], andp.R213K [33] could be potentially pathogenic mutations, because they were associated with typical clinical CADASIL syndrome and extensive white matter hyperintensities (WMH) in magnetic resonance imaging (MRI), the 33 NOTCH3 exons were analyzed and no other potential pathogenic mutations were found; they had an minor allele frequency (MAF) < 0.1% (ExAC, 1000 Genomes Project) and Granular osmiophilic material (GOM) deposits were observed in the skin biopsy. (The criteria for considering mutations as potentially pathogenic are explained in the Material and Methods section)
We conducted a thorough search for cysteine-sparing NOTCH3 missense mutations in patients with typical clinical CADASIL syndrome in order to determine whether these mutations could be considered pathogenic and to describe the patients that carry this type of mutation

Summary

Introduction

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an inherited systemic arterial vessel disease caused by mutations in the NOTCH3 gene, located on the 19p13 chromosome [1,2], which encodes a transmembrane receptor that is mainly expressed in the smooth muscle cells of blood vessels and pericytes [3]. This receptor has three domains: (1) a large extracellular domain (ECD) with 34 epidermal growth factor (EGF)-like repeats encoded by exons 2–24, where NOTCH3 mutations are typically located; (2) a transmembrane domain; and (3) an intracellular domain (ICD). Its role in the pathogenic mechanism is controversial, and several authors have shown that altered NOTCH3 function is not the primary determinant of the disease [7,8,9]

Objectives

Methods

Conclusion