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

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

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

Schleutker Johanna
Pöyhönen Minna
Meisel Andreas
Müller Susanne
Dirnagl Ulrich
Guven Gamze
Winek Katarzyna
Kun-Rodrigues Celia
Macario Maria do Carmo
Beule Dieter
Morgadinho Ana Sofia
Kuuluvainen Liina
Velon Ana Graça
Kostic Vladimir
Sassi Celeste
Senatore Assunta
Mönkäre Saana
Myllykangas Liisa
Holtgrewe Manuel
Foddis Marco
Dobricic Valerija
Blumenau Sonja
Bras Jose
Berchtold Daniel
Alonso Isabel
Pavlovic Aleksandra
Lohmann Ebba
Guerreiro Rita
Santana Isabel
Santo Gustavo
Hanagasi Hasmet
Messerschmidt Clemens
Bilgic Basar
Bentele Kajetan
Katso/Avaa
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NATURE RESEARCH
doi:10.1038/s41598-021-84919-x
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042824938
Tiivistelmä

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.

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