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

Clemens Messerschmidt, Marco Foddis, Sonja Blumenau, Susanne Müller, Kajetan Bentele, Manuel Holtgrewe, Celia Kun-Rodrigues, Isabel Alonso, Maria do Carmo Macario, Ana Sofia Morgadinho, Ana Graça Velon, Gustavo Santo, Isabel Santana, Saana Mönkäre, Liina Kuuluvainen, Johanna Schleutker, Minna Pöyhönen, Liisa Myllykangas, Assunta Senatore, Daniel BerchtoldKatarzyna Winek, Andreas Meisel, Aleksandra Pavlovic, Vladimir Kostic, Valerija Dobricic, Ebba Lohmann, Hasmet Hanagasi, Gamze Guven, Basar Bilgic, Jose Bras, Rita Guerreiro, Dieter Beule, Ulrich Dirnagl, Celeste Sassi*

*Corresponding author for this work


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.

Original languageEnglish
Article number6072
JournalScientific Reports
Issue number1
Pages (from-to)6072
Publication statusPublished - 12.2021


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