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Variants of WNT7A and GPR124 are associated with hemorrhagic transformation following intravenous thrombolysis in ischemic stroke

AIMS: The canonical Wnt signaling pathway plays an essential role in blood‐brain barrier integrity and intracerebral hemorrhage in preclinical stroke models. Here, we sought to explore the association between canonical Wnt signaling and hemorrhagic transformation (HT) following intravenous thromboly...

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Autores principales: Ta, Song, Rong, Xianfang, Guo, Zhen‐Ni, Jin, Hang, Zhang, Peng, Li, Fenge, Li, Zhihuan, Lin, Lilong, Zheng, Chenqing, Gu, Qingquan, Zhang, Yuan, Liu, Wenlan, Yang, Yi, Chang, Junlei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804912/
https://www.ncbi.nlm.nih.gov/pubmed/32991049
http://dx.doi.org/10.1111/cns.13457
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author Ta, Song
Rong, Xianfang
Guo, Zhen‐Ni
Jin, Hang
Zhang, Peng
Li, Fenge
Li, Zhihuan
Lin, Lilong
Zheng, Chenqing
Gu, Qingquan
Zhang, Yuan
Liu, Wenlan
Yang, Yi
Chang, Junlei
author_facet Ta, Song
Rong, Xianfang
Guo, Zhen‐Ni
Jin, Hang
Zhang, Peng
Li, Fenge
Li, Zhihuan
Lin, Lilong
Zheng, Chenqing
Gu, Qingquan
Zhang, Yuan
Liu, Wenlan
Yang, Yi
Chang, Junlei
author_sort Ta, Song
collection PubMed
description AIMS: The canonical Wnt signaling pathway plays an essential role in blood‐brain barrier integrity and intracerebral hemorrhage in preclinical stroke models. Here, we sought to explore the association between canonical Wnt signaling and hemorrhagic transformation (HT) following intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) patients as well as to determine the underlying cellular mechanisms. METHODS: 355 consecutive AIS patients receiving IVT were included. Blood samples were collected on admission, and HT was detected at 24 hours after IVT. 117 single‐nucleotide polymorphisms (SNPs) of 28 Wnt signaling genes and exon sequences of 4 core cerebrovascular Wnt signaling components (GPR124, RECK, FZD4, and CTNNB1) were determined using a customized sequencing chip. The impact of identified genetic variants was further studied in HEK 293T cells using cellular and biochemical assays. RESULTS: During the study period, 80 patients experienced HT with 27 parenchymal hematoma (PH). Compared to the non‐PH patients, WNT7A SNPs (rs2163910, P = .001, OR 2.727; rs1124480, P = .002, OR 2.404) and GPR124 SNPs (rs61738775, P = .012, OR 4.883; rs146016051, P < .001, OR 7.607; rs75336000, P = .044, OR 2.503) were selectively enriched in the PH patients. Interestingly, a missense variant of GPR124 (rs75336000, c.3587G>A) identified in the PH patients resulted in a single amino acid alteration (p.Cys1196Tyr) in the intracellular domain of GPR124. This variant substantially reduced the activity of WNT7B‐induced canonical Wnt signaling by decreasing the ability of GPR124 to recruit cytoplasmic DVL1 to the cellular membrane. CONCLUSION: Variants of WNT7A and GPR124 are associated with increased risk of PH in patients with AIS after intravenous thrombolysis, likely through regulating the activity of canonical Wnt signaling.
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spelling pubmed-78049122021-01-29 Variants of WNT7A and GPR124 are associated with hemorrhagic transformation following intravenous thrombolysis in ischemic stroke Ta, Song Rong, Xianfang Guo, Zhen‐Ni Jin, Hang Zhang, Peng Li, Fenge Li, Zhihuan Lin, Lilong Zheng, Chenqing Gu, Qingquan Zhang, Yuan Liu, Wenlan Yang, Yi Chang, Junlei CNS Neurosci Ther Original Articles AIMS: The canonical Wnt signaling pathway plays an essential role in blood‐brain barrier integrity and intracerebral hemorrhage in preclinical stroke models. Here, we sought to explore the association between canonical Wnt signaling and hemorrhagic transformation (HT) following intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) patients as well as to determine the underlying cellular mechanisms. METHODS: 355 consecutive AIS patients receiving IVT were included. Blood samples were collected on admission, and HT was detected at 24 hours after IVT. 117 single‐nucleotide polymorphisms (SNPs) of 28 Wnt signaling genes and exon sequences of 4 core cerebrovascular Wnt signaling components (GPR124, RECK, FZD4, and CTNNB1) were determined using a customized sequencing chip. The impact of identified genetic variants was further studied in HEK 293T cells using cellular and biochemical assays. RESULTS: During the study period, 80 patients experienced HT with 27 parenchymal hematoma (PH). Compared to the non‐PH patients, WNT7A SNPs (rs2163910, P = .001, OR 2.727; rs1124480, P = .002, OR 2.404) and GPR124 SNPs (rs61738775, P = .012, OR 4.883; rs146016051, P < .001, OR 7.607; rs75336000, P = .044, OR 2.503) were selectively enriched in the PH patients. Interestingly, a missense variant of GPR124 (rs75336000, c.3587G>A) identified in the PH patients resulted in a single amino acid alteration (p.Cys1196Tyr) in the intracellular domain of GPR124. This variant substantially reduced the activity of WNT7B‐induced canonical Wnt signaling by decreasing the ability of GPR124 to recruit cytoplasmic DVL1 to the cellular membrane. CONCLUSION: Variants of WNT7A and GPR124 are associated with increased risk of PH in patients with AIS after intravenous thrombolysis, likely through regulating the activity of canonical Wnt signaling. John Wiley and Sons Inc. 2020-09-29 /pmc/articles/PMC7804912/ /pubmed/32991049 http://dx.doi.org/10.1111/cns.13457 Text en © 2020 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Ta, Song
Rong, Xianfang
Guo, Zhen‐Ni
Jin, Hang
Zhang, Peng
Li, Fenge
Li, Zhihuan
Lin, Lilong
Zheng, Chenqing
Gu, Qingquan
Zhang, Yuan
Liu, Wenlan
Yang, Yi
Chang, Junlei
Variants of WNT7A and GPR124 are associated with hemorrhagic transformation following intravenous thrombolysis in ischemic stroke
title Variants of WNT7A and GPR124 are associated with hemorrhagic transformation following intravenous thrombolysis in ischemic stroke
title_full Variants of WNT7A and GPR124 are associated with hemorrhagic transformation following intravenous thrombolysis in ischemic stroke
title_fullStr Variants of WNT7A and GPR124 are associated with hemorrhagic transformation following intravenous thrombolysis in ischemic stroke
title_full_unstemmed Variants of WNT7A and GPR124 are associated with hemorrhagic transformation following intravenous thrombolysis in ischemic stroke
title_short Variants of WNT7A and GPR124 are associated with hemorrhagic transformation following intravenous thrombolysis in ischemic stroke
title_sort variants of wnt7a and gpr124 are associated with hemorrhagic transformation following intravenous thrombolysis in ischemic stroke
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804912/
https://www.ncbi.nlm.nih.gov/pubmed/32991049
http://dx.doi.org/10.1111/cns.13457
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