{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T05:18:38Z","timestamp":1792819118365,"version":"4.5.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T00:00:00Z","timestamp":1680134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"CIBR funds"},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009592","name":"Beijing Municipal Science and Technology Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009592","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cerebral cavernous malformations (CCMs) and spinal cord cavernous malformations (SCCMs) are common vascular abnormalities of the CNS that can lead to seizure, haemorrhage and other neurological deficits. Approximately 85% of patients present with sporadic (versus congenital) CCMs. Somatic mutations in MAP3K3 and PIK3CA were recently reported in patients with sporadic CCM, yet it remains unknown whether MAP3K3 mutation is sufficient to induce CCMs. Here we analysed whole-exome sequencing data for patients with CCM and found that \u223c40% of them have a single, specific MAP3K3 mutation [c.1323C&amp;gt;G (p.Ile441Met)] but not any other known mutations in CCM-related genes.<\/jats:p>\n                  <jats:p>We developed a mouse model of CCM with MAP3K3I441M uniquely expressed in the endothelium of the CNS. We detected pathological phenotypes similar to those found in patients with MAP3K3I441M. The combination of in vivo imaging and genetic labelling revealed that CCMs were initiated with endothelial expansion followed by disruption of the blood\u2013brain barrier. Experiments with our MAP3K3I441M mouse model demonstrated that CCM can be alleviated by treatment with rapamycin, the mTOR inhibitor. CCM pathogenesis has usually been attributed to acquisition of two or three distinct genetic mutations involving the genes CCM1\/2\/3 and\/or PIK3CA. However, our results demonstrate that a single genetic hit is sufficient to cause CCMs.<\/jats:p>","DOI":"10.1093\/brain\/awad104","type":"journal-article","created":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T21:02:12Z","timestamp":1680210132000},"page":"3634-3647","source":"Crossref","is-referenced-by-count":42,"title":["Somatic variants of\n                    <i>MAP3K3<\/i>\n                    are sufficient to cause cerebral and spinal cord cavernous malformations"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2478-6653","authenticated-orcid":false,"given":"Jian","family":"Ren","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University , Beijing 100053 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazi","family":"Huang","sequence":"additional","affiliation":[{"name":"Chinese Institute for Brain Research , Beijing 102206 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeqing","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University , Beijing 100053 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianqi","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University , Beijing 100053 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoshan","family":"Qiu","sequence":"additional","affiliation":[{"name":"Chinese Institute for Brain Research , Beijing 102206 , China"},{"name":"Department of Neurology, Beijing Tiantan Hospital, Capital Medical University , Beijing 100070 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daosheng","family":"Ai","sequence":"additional","affiliation":[{"name":"Chinese Institute for Brain Research , Beijing 102206 , China"},{"name":"Academy for Advanced Interdisciplinary Studies (AAIS), Peking University , Beijing 100871 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanying","family":"Bi","sequence":"additional","affiliation":[{"name":"Chinese Institute for Brain Research , Beijing 102206 , China"},{"name":"College of Life Sciences, Nankai University , Tianjin 300071 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Bai","sequence":"additional","affiliation":[{"name":"Chinese Institute for Brain Research , Beijing 102206 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengzhi","family":"Li","sequence":"additional","affiliation":[{"name":"Chinese Institute for Brain Research , Beijing 102206 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Liszt","family":"Li","sequence":"additional","affiliation":[{"name":"Chinese Institute for Brain Research , Beijing 102206 , China"},{"name":"Academy for Advanced Interdisciplinary Studies (AAIS), Peking University , Beijing 100871 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing-jun","family":"Chen","sequence":"additional","affiliation":[{"name":"Chinese Institute for Brain Research , Beijing 102206 , China"},{"name":"Academy for Advanced Interdisciplinary Studies (AAIS), Peking University , Beijing 100871 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyan","family":"Feng","sequence":"additional","affiliation":[{"name":"Chinese Institute for Brain Research , Beijing 102206 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongpei","family":"Guo","sequence":"additional","affiliation":[{"name":"Chinese Institute for Brain Research , Beijing 102206 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfeng","family":"Lei","sequence":"additional","affiliation":[{"name":"Medical Imaging laboratory of Core Facility Center, Capital Medical University , Beijing 100054 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University , Beijing 100053 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziwei","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Xuanwu Hospital, China International Neuroscience Institute, Capital Medical University , Beijing 100053 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volkhard","family":"Lindner","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, MaineHealth Institute for Research , Scarborough, ME 04074 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3031-7677","authenticated-orcid":false,"given":"Ralf H","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Tissue Morphogenesis, Max-Planck-Institute for Molecular Biomedicine, and Faculty of Medicine, University of M\u00fcnster , D-48149 M\u00fcnster , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9984-581X","authenticated-orcid":false,"given":"Yibo","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100037 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Chinese 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