PHACTR1 genetic variability is not critical in small vessel ischemic disease patients and PcomA recruitment in C57BL/6J mice

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Messerschmidt , C , Foddis , M , Blumenau , S , Mueller , S , Bentele , K , Holtgrewe , M , Kun-Rodrigues , C , Alonso , I , Macario , M D C , Morgadinho , A S , Velon , A G , Santo , G , Santana , I , Mönkäre , S , Kuuluvainen , L , Schleutker , J , Pöyhönen , M , Myllykangas , L , Senatore , A , Berchtold , D , Winek , K , Meisel , A , Pavlovic , A , Kostic , V , Dobricic , V , Lohmann , E , Hanagasi , H , Guven , G , Bilgic , B , Bras , J , Guerreiro , R , Beule , D , Dirnagl , U & Sassi , C 2021 , ' PHACTR1 genetic variability is not critical in small vessel ischemic disease patients and PcomA recruitment in C57BL/6J mice ' , Scientific Reports , vol. 11 , no. 1 , 6072 .

Title: PHACTR1 genetic variability is not critical in small vessel ischemic disease patients and PcomA recruitment in C57BL/6J mice
Author: Messerschmidt, Clemens; Foddis, Marco; Blumenau, Sonja; Mueller, Susanne; Bentele, Kajetan; Holtgrewe, Manuel; Kun-Rodrigues, Celia; Alonso, Isabel; Macario, Maria do Carmo; Morgadinho, Ana Sofia; Velon, Ana Graca; Santo, Gustavo; Santana, Isabel; Mönkäre, Saana; Kuuluvainen, Liina; Schleutker, Johanna; Pöyhönen, Minna; Myllykangas, Liisa; Senatore, Assunta; Berchtold, Daniel; Winek, Katarzyna; Meisel, Andreas; Pavlovic, Aleksandra; Kostic, Vladimir; Dobricic, Valerija; Lohmann, Ebba; Hanagasi, Hasmet; Guven, Gamze; Bilgic, Basar; Bras, Jose; Guerreiro, Rita; Beule, Dieter; Dirnagl, Ulrich; Sassi, Celeste
Contributor organization: HUSLAB
Department of Medical and Clinical Genetics
University of Helsinki
Helsinki University Hospital Area
Minna Pöyhönen / Principal Investigator
Department of Pathology
Date: 2021-03-16
Language: eng
Number of pages: 11
Belongs to series: Scientific Reports
ISSN: 2045-2322
Abstract: 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.
Subject: 3111 Biomedicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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