PHACTR1 genetic variability is not critical in small vessel ischemic disease patients and PcomA recruitment in C57BL/6J mice
Creators: name: Messerschmidt, Clemens
name: Foddis, Marco
name: Blumenau, Sonja
name: Müller, Susanne
name: Bentele, Kajetan
name: Holtgrewe, Manuel
name: Kun-Rodrigues, Celia
name: Alonso, Isabel
name: Do Carmo Macario, Maria
name: Morgadinho, Ana Sofia
name: Velon, Ana Graça
name: Santo, Gustavo
name: Santana, Isabel
name: Mönkäre, Saana
name: Kuuluvainen, Liina
name: Schleutker, Johanna
name: Pöyhönen, Minna
name: Myllykangas, Liisa
name: Senatore, Assunta
name: Berchtold, Daniel
name: Winek, Katarzyna
name: Meisel, Andreas
name: Pavlovic, Aleksandra
name: Kostic, Vladimir
name: Dobricic, Valerija
name: Lohmann, Ebba
name: Hanagasi, Hasmet
name: Guven, Gamze
name: Bilgic, Basar
name: Bras, Jose
name: Guerreiro, Rita
name: Beule, Dieter
name: Dirnagl, Ulrich
name: Sassi, Celeste
Publisher: name: Charité - Universitätsmedizin Berlin
Year: 2021
Subjects: subject: PHACTR1
subject: C57BL/6J mice
subject: PcomA
subject: 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit

description: Recently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical artery dissection and hypertension. Although these represent significant risk factors or comorbidities for ischemic stroke, PHACTR1 role in brain small vessel ischemic disease and ischemic stroke most important survival mechanism, such as the recruitment of brain collateral arteries like posterior communicating arteries (PcomAs), remains unknown. Therefore, we applied exome and genome sequencing in a multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic brain small vessel ischemic disease and CADASIL-like Caucasian patients from US, Portugal, Finland, Serbia and Turkey and in 2 C57BL/6J stroke mouse models (bilateral common carotid artery stenosis [BCCAS] and middle cerebral artery occlusion [MCAO]), characterized by different degrees of PcomAs patency. We report 3 very rare coding variants in the small vessel ischemic disease-CADASIL-like cohort (p.Glu198Gln, p.Arg204Gly, p.Val251Leu) and a stop-gain mutation (p.Gln273*) in one MCAO mouse. These coding variants do not cluster in PHACTR1 known pathogenic domains and are not likely to play a critical role in small vessel ischemic disease or brain collateral circulation. We also exclude the possibility that copy number variants (CNVs) or a variant enrichment in Phactr1 may be associated with PcomA recruitment in BCCAS mice or linked to diverse vascular traits (cerebral blood flow pre-surgery, PcomA size, leptomeningeal microcollateral length and junction density during brain hypoperfusion) in C57BL/6J mice, respectively. Genetic variability in PHACTR1 is not likely to be a common susceptibility factor influencing small vessel ischemic disease in patients and PcomA recruitment in C57BL/6J mice. Nonetheless, rare variants in PHACTR1 RPEL domains may influence the stroke outcome and are worth investigating in a larger cohort of small vessel ischemic disease patients, different ischemic stroke subtypes and with functional studies.