Contribution of "Omic" Studies to the Understanding of Cadasil. A Systematic Review.

Elena Muiño,Israel Fernández-Cadenas,Adrià Arboix

doi:10.3390/ijms22147357

Abstract

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the epidermal growth factor (EGF)-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraines, psychiatric disorders, recurrent strokes, and dementia. Omic technologies allow the massive study of different molecules for understanding diseases in a non-biased manner or even for discovering targets and their possible treatments. We analyzed the progress in understanding CADASIL that has been made possible by omics sciences. For this purpose, we included studies that focused on CADASIL and used omics techniques, searching bibliographic resources, such as PubMed. We excluded studies with other phenotypes, such as migraine or leukodystrophies. A total of 18 articles were reviewed. Due to the high prevalence of NOTCH3 mutations considered pathogenic to date in genomic repositories, one can ask whether all of them produce CADASIL, different degrees of the disease, or whether they are just a risk factor for small vessel disease. Besides, proteomics and transcriptomics studies found that the molecules that are significantly altered in CADASIL are mainly related to cell adhesion, the cytoskeleton or extracellular matrix components, misfolding control, autophagia, angiogenesis, or the transforming growth factor β (TGFβ) signaling pathway. The omics studies performed on CADASIL have been useful for understanding the biological mechanisms and could be key factors for finding potential drug targets.

Highlights

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy; OMIM#125310) is a systemic arteriopathy of non-atherosclerotic and non-amyloid cause
It is thought to be triggered by mutations in NOTCH3 that cause an odd number of cysteines in the domain hosting the epidermal growth factor-like repetitions (EGFr) of the receptor encoded by this gene, leading to disruption of disulfide bonds and protein aggregation [2,3]
[19,20] and the Geisinger DiscovEHR [21], the authors found that subjects with pathogenic variants were correlated with spatial distribution and extent of white matter hyperintensities (WMH), a higher frequency and number of lacunes and microbleeds, family history of stroke, and vascular dementia

Summary

Introduction

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy; OMIM#125310) is a systemic arteriopathy of non-atherosclerotic and non-amyloid cause. It is a rare disease affecting fewer than 2/1000 individuals, caused by mutations in the NOTCH3 gene. CADASIL is characterized by the following symptoms: migraine with aura; psychiatric disorders; recurrent small subcortical infarcts; and dementia at an early age [4]. It is the most common cause of stroke and dementia of genetic origin. On MRI scans, white matter hyperintensities (WMH) in the temporal lobe and external capsule are characteristic of the disease [5,6]

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