<i>Ide</i> Copy Number Variant Does Not Influence Stroke Severity in 2 C57BL/6J Mouse Models nor in Humans: An Exploratory Study.

Abstract

Contrary to the common belief, the most commonly used laboratory C57BL/6J mouse inbred strain presents a distinctive genetic and phenotypic variability, and for several traits, the genotype-phenotype link remains still unknown. Recently, we characterized the most important stroke survival factor such as brain collateral plasticity in 2 brain ischemia C57BL/6J mouse models (bilateral common carotid artery stenosis and middle cerebral artery occlusion) and observed a Mendelian-like fashion of inheritance of the posterior communicating artery (PcomA) patency. Interestingly, a copy number variant (CNV) spanning <i>Ide</i> locus was reported to segregate in an analogous Mendelian-like pattern in the C57BL/6J colonies of the Jackson Laboratory. Given <i>IDE</i> critical role in vascular plasticity, we hypothesized <i>Ide</i> CNV may have explained PcomA variability in C57BL/6J inbred mice. We applied a combination of techniques (T2-weighted magnetic resonance imaging, time-of-flight angiography, cerebral blood flow imaging, and histology) to characterize the collaterome in 77 C57BL/6J bilateral common carotid artery stenosis, middle cerebral artery occlusion, naive, and sham mice and performed on these Taqman genotyping, exome sequencing, and RNA sequencing. We then investigated the hypothesis that <i>IDE</i> structural variants (CNVs, gain/loss of function mutations) may have influenced the cerebrovascular phenotype in a large cohort of 454 040 cases and controls (UK Biobank, Genomics England). We detected an <i>Ide</i> CNV in a bilateral common carotid artery stenosis mouse with 2 patent PcomAs (minor allele frequency, 1.3%), not segregating with the PcomA patency phenotype. In addition, 2 heterozygous <i>IDE</i> CNVs, resulting in loss of function were found in 1 patient with hereditary ataxia, a patient with hereditary congenital heart disease, and 2 healthy individuals (minor allele frequency 9×10^-6). Moreover, we report 4 <i>IDE</i> loss of function point mutations (p.Leu5X, p.Met394ValfsX29, p.Pro14SerfsX26, p.Leu889X, minor allele frequency 0.02%) present also in controls or inherited from healthy parents. <i>Ide</i> CNV and loss of function variants are rare, do not crucially influence PcomA variability in C57BL/6J inbred mice, and do not cause a vascular phenotype in humans.