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

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.

Keywords: CADASIL; genomic; proteomic; transcriptomic.

Figure 1

PRISMA flow diagram.

Figure 2

Graphical representation of the frequency of pathogenic CADASIL mutations according to the populations included in the ExAC database (currently called gnomAD). Figure adapted from Rutten et al. (2016) [17].

Figure 3

Distribution of different EGFr cysteine altering NOTCH3 mutations in ExAC (currently called gnomAD) compared with those reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients. Figure adapted from Rutten et al. (2016) [17].

Figure 4

Schematic diagram of those molecules found in the -omics studies regarding its possible aetiopathogenic mechanism. Molecules found in at least two studies and with the same direction of effect have been considered. Graphic created through the smart.servier.com website.

Figure 5

Location of NOTCH3 mutations in European CADASIL patients versus gnomAD database individuals. Figure extracted from Rutten et al. (2018) [18].