{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T20:07:13Z","timestamp":1789589233833,"version":"build-2803163510"},"reference-count":38,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T00:00:00Z","timestamp":1681776000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Hong Kong RGC Fund","award":["16102522, C6021-19EF"],"award-info":[{"award-number":["16102522, C6021-19EF"]}]},{"DOI":"10.13039\/501100007162","name":"Department of Science and Technology of Guangdong Province","doi-asserted-by":"crossref","award":["2020A0505090007"],"award-info":[{"award-number":["2020A0505090007"]}],"id":[{"id":"10.13039\/501100007162","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Hong Kong ITC Fund","award":["ITCPD\/17-9"],"award-info":[{"award-number":["ITCPD\/17-9"]}]},{"name":"Beijing Advanced Innovation Center for Big Data-based Precision Medicine","award":["PXM2020_014226_000066"],"award-info":[{"award-number":["PXM2020_014226_000066"]}]},{"name":"Genomics Platform Construction for Chinese Major Brain Disease-AVM","award":["PXM2019_026280_000002-AVM"],"award-info":[{"award-number":["PXM2019_026280_000002-AVM"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Stroke Vasc Neurol"],"accepted":{"date-parts":[[2023,3,2]]},"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Extra-axial cavernous hemangiomas (ECHs) are sporadic and rare intracranial occupational lesions that usually occur within the cavernous sinus. The aetiology of ECHs remains unknown.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Whole-exome sequencing was performed on ECH lesions from 12 patients (discovery cohort) and droplet digital polymerase-chain-reaction (ddPCR) was used to confirm the identified mutation in 46 additional cases (validation cohort). Laser capture microdissection (LCM) was carried out to capture and characterise subgroups of tissue cells. Mechanistic and functional investigations were carried out in human umbilical vein endothelial cells and a newly established mouse model.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We detected somatic <jats:italic>GJA4<\/jats:italic> mutation (c.121G&gt;T, p.G41C) in 5\/12 patients with ECH in the discovery cohort and confirmed the finding in the validation cohort (16\/46). LCM followed by ddPCR revealed that the mutation was enriched in lesional endothelium. In vitro experiments in endothelial cells demonstrated that the <jats:italic>GJA4<\/jats:italic> mutation activated SGK-1 signalling that in turn upregulated key genes involved in cell hyperproliferation and the loss of arterial specification. Compared with wild-type littermates, mice overexpressing the <jats:italic>GJA4<\/jats:italic> mutation developed ECH-like pathological morphological characteristics (dilated venous lumen and elevated vascular density) in the retinal superficial vascular plexus at the postnatal 3 weeks, which were reversed by an SGK1 inhibitor, EMD638683.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>We identified a somatic <jats:italic>GJA4<\/jats:italic> mutation that presents in over one-third of ECH lesions and proposed that ECHs are vascular malformations due to <jats:italic>GJA4<\/jats:italic>-induced activation of the SGK1 signalling pathway in brain endothelial cells.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/svn-2022-002227","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T22:45:12Z","timestamp":1681857912000},"page":"453-462","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["Somatic <i>GJA4<\/i> mutation in intracranial extra-axial cavernous hemangiomas"],"prefix":"10.1136","volume":"8","author":[{"given":"Ran","family":"Huo","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingxi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaozhi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Song","sequence":"additional","affiliation":[{"name":"Division of Life Science, Center for Systems Biology and Human Health and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiancong","family":"Weng","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruochen","family":"Ma","sequence":"additional","affiliation":[{"name":"Division of Life Science, Center for Systems Biology and Human Health and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingfan","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8351-4602","authenticated-orcid":false,"given":"Yuming","family":"Jiao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junze","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6715-298X","authenticated-orcid":false,"given":"Qiheng","family":"He","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruolei","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Medical Technology, Beijing Institute of Technology, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Zong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiguang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, China"},{"name":"Division of Life Science, Center for Systems Biology and Human Health and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China"},{"name":"Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8289-1120","authenticated-orcid":false,"given":"Yong","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"name":"China National Clinical Research Center for Neurological Diseases, Beijing, China"},{"name":"Beijing Neurosurgical Institute, Capital Medical University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,4,18]]},"reference":[{"key":"2025082410271611000_8.6.453.1","first-page":"91","article-title":"Intracranial extra-axial cavernous (hem) angiomas: tumors or vascular malformations?","volume":"29","author":"Biondi","year":"2002","journal-title":"J Neuroradiol"},{"key":"2025082410271611000_8.6.453.2","doi-asserted-by":"publisher","DOI":"10.1227\/00006123-199201000-00018"},{"key":"2025082410271611000_8.6.453.3","doi-asserted-by":"publisher","DOI":"10.3171\/jns.1990.73.2.0187"},{"key":"2025082410271611000_8.6.453.4","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.wneu.2010.07.015","article-title":"Intracranial extra-axial cavernous angioma of the cerebellar falx","volume":"74","author":"Melone","year":"2010","journal-title":"World Neurosurgery"},{"key":"2025082410271611000_8.6.453.5","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1007\/s10143-002-0219-8","article-title":"Extra-Axial cavernomas of the cerebellopontine angle involving the seventh-eighth nerve complex","volume":"25","author":"Beskonakli","year":"2002","journal-title":"Neurosurg Rev"},{"key":"2025082410271611000_8.6.453.6","doi-asserted-by":"crossref","first-page":"311","DOI":"10.4103\/0976-3147.203832","article-title":"Dynamic contrast-enhanced magnetic resonance imaging in diagnosis of cavernous hemangioma of cavernous sinus","volume":"08","author":"Naik","year":"2017","journal-title":"Journal of Neurosciences in Rural Practice"},{"key":"2025082410271611000_8.6.453.7","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.118.022314"},{"key":"2025082410271611000_8.6.453.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.04.005"},{"issue":"Suppl 2","key":"2025082410271611000_8.6.453.9","doi-asserted-by":"crossref","DOI":"10.1186\/1752-0509-7-S2-S2","article-title":"SAVI: a statistical algorithm for variant frequency identification","volume":"7 Suppl 2","author":"Trifonov","year":"2013","journal-title":"BMC Syst Biol"},{"key":"2025082410271611000_8.6.453.10","doi-asserted-by":"publisher","DOI":"10.1016\/S0090-3019(03)00190-3"},{"key":"2025082410271611000_8.6.453.11","doi-asserted-by":"publisher","DOI":"10.1097\/00006123-199912000-00006"},{"key":"2025082410271611000_8.6.453.12","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1161\/CIRCRESAHA.121.319004","article-title":"De novo germline and somatic variants convergently promote endothelial-to-mesenchymal transition in simplex brain arteriovenous malformation","volume":"129","author":"Li","year":"2021","journal-title":"Circ Res"},{"key":"2025082410271611000_8.6.453.13","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.jconrel.2017.08.005","article-title":"Application of polyploid adeno-associated virus vectors for transduction enhancement and neutralizing antibody evasion","volume":"262","author":"Chai","year":"2017","journal-title":"Journal of Controlled Release"},{"key":"2025082410271611000_8.6.453.14","doi-asserted-by":"crossref","first-page":"100028","DOI":"10.1016\/j.xhgg.2021.100028","article-title":"Cutaneous and hepatic vascular lesions due to a recurrent somatic gja4 mutation reveal a pathway for vascular malformation","volume":"2","author":"Ugwu","year":"2021","journal-title":"Human Genetics and Genomics Advances"},{"key":"2025082410271611000_8.6.453.15","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s40478-022-01384-x","article-title":"The dural angioleiomyoma harbors frequent gja4 mutation and a distinct DNA methylation profile","volume":"10","author":"Tauzi\u00e8de-Espariat","year":"2022","journal-title":"Acta Neuropathol Commun"},{"key":"2025082410271611000_8.6.453.16","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s10456-022-09846-5","article-title":"Somatic gja4 gain-of-function mutation in orbital cavernous venous malformations","volume":"26","author":"Hongo","year":"2023","journal-title":"Angiogenesis"},{"key":"2025082410271611000_8.6.453.17","doi-asserted-by":"publisher","DOI":"10.1038\/S41586-021-03819-2"},{"key":"2025082410271611000_8.6.453.18","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1056\/NEJMoa1709449","article-title":"Somatic activating KRAS mutations in arteriovenous malformations of the brain","volume":"378","author":"Nikolaev","year":"2018","journal-title":"N Engl J Med"},{"key":"2025082410271611000_8.6.453.19","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.608722"},{"key":"2025082410271611000_8.6.453.20","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00683.2011"},{"key":"2025082410271611000_8.6.453.21","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202000257R"},{"key":"2025082410271611000_8.6.453.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01742-7"},{"key":"2025082410271611000_8.6.453.23","doi-asserted-by":"publisher","DOI":"10.1159\/000354486"},{"key":"2025082410271611000_8.6.453.24","doi-asserted-by":"crossref","DOI":"10.3171\/foc.2006.21.1.7","article-title":"Are cavernous sinus hemangiomas and cavernous malformations different entities?","volume":"21","author":"Gonzalez","year":"2006","journal-title":"Neurosurg Focus"},{"key":"2025082410271611000_8.6.453.25","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.03-0062"},{"key":"2025082410271611000_8.6.453.26","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.639645"},{"key":"2025082410271611000_8.6.453.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.01.007"},{"key":"2025082410271611000_8.6.453.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.01.018"},{"key":"2025082410271611000_8.6.453.29","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.humpath.2022.10.002","article-title":"A clinicopathological reappraisal of orbital vascular malformations and distinctive gja4 mutation in cavernous venous malformations","volume":"130","author":"Chen","year":"2022","journal-title":"Hum Pathol"},{"key":"2025082410271611000_8.6.453.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03562-8"},{"key":"2025082410271611000_8.6.453.31","doi-asserted-by":"crossref","first-page":"2648","DOI":"10.1093\/brain\/awab117","article-title":"Somatic map3k3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations","volume":"144","author":"Hong","year":"2021","journal-title":"Brain"},{"key":"2025082410271611000_8.6.453.32","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.10-5176"},{"key":"2025082410271611000_8.6.453.33","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.2002.0826"},{"key":"2025082410271611000_8.6.453.34","first-page":"778","article-title":"Radiosurgery for hemangiomas of the cavernous sinus and orbit: technical case report","volume":"47","author":"Thompson","year":"2000","journal-title":"Neurosurgery"},{"key":"2025082410271611000_8.6.453.35","doi-asserted-by":"publisher","DOI":"10.1055\/s-2008-1065346"},{"key":"2025082410271611000_8.6.453.36","doi-asserted-by":"crossref","first-page":"109954","DOI":"10.1016\/j.biopha.2020.109954","article-title":"Targeting sgk1 enhances the efficacy of radiotherapy in locally advanced rectal cancer","volume":"125","author":"Zhou","year":"2020","journal-title":"Biomed Pharmacother"},{"key":"2025082410271611000_8.6.453.37","doi-asserted-by":"crossref","first-page":"245","DOI":"10.2165\/00003495-197611040-00002","article-title":"Carbenoxolone: A review of its pharmacological properties and therapeutic efficacy in peptic ulcer disease","volume":"11","author":"Pinder","year":"1976","journal-title":"Drugs"},{"key":"2025082410271611000_8.6.453.38","doi-asserted-by":"crossref","unstructured":"Batterink J , Stabler S , Tejani A , et al . Spironolactone for hypertension. the cochrane database of systematic reviews. 2010. doi:10.1002\/14651858.CD008169.pub2","DOI":"10.1002\/14651858.CD008169.pub2"}],"container-title":["Stroke and Vascular Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/svn-2022-002227","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,24]],"date-time":"2025-08-24T17:27:34Z","timestamp":1756056454000},"score":1,"resource":{"primary":{"URL":"https:\/\/svn.bmj.com\/lookup\/doi\/10.1136\/svn-2022-002227"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,18]]},"references-count":38,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,12,29]]},"published-print":{"date-parts":[[2023,12]]}},"alternative-id":["10.1136\/svn-2022-002227"],"URL":"https:\/\/doi.org\/10.1136\/svn-2022-002227","relation":{},"ISSN":["2059-8688","2059-8696"],"issn-type":[{"value":"2059-8688","type":"print"},{"value":"2059-8696","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,18]]}}}