{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T08:03:17Z","timestamp":1779782597908,"version":"3.53.1"},"reference-count":39,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T00:00:00Z","timestamp":1777075200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K08576"],"award-info":[{"award-number":["23K08576"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25K11291"],"award-info":[{"award-number":["25K11291"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["International Journal of Stroke"],"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Recurrent cervical internal carotid artery vasospasm (RCICAV) is a rare cause of ischemic stroke in young adults. However, its pathophysiology remains largely unknown. RCICAV is a life-threatening condition, sometimes accompanied by coronary spasmodic angina in addition to severe stroke, highlighting the need for further investigation of its etiology and therapeutic approaches.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aims:<\/jats:title>\n                    <jats:p>This study aimed to identify the genetic basis of Japanese families harboring RCICAV.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Whole-exome and Sanger sequencing analyses were performed in five Japanese patients from four families (two affected siblings and three unrelated sporadic patients) and seven unaffected members from three families enrolled from October 2016 to May 2025. RCICAV was diagnosed using magnetic resonance angiography, which demonstrated vasospasm of the cervical portion of the internal carotid artery during the event and normalization during remission.\n                      <jats:italic toggle=\"yes\">In vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                      analyses of the detected variants were performed to verify functional deficiencies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      RCICAV was found to be an autosomal recessive disorder caused by biallelic loss-of-function variants in the\n                      <jats:italic toggle=\"yes\">PTGIS<\/jats:italic>\n                      gene, which encodes the prostacyclin synthase. Three splice-site and nonsense variants, c. 1358\u2009+\u20092T\u2009&gt;\u2009C, p.W39X, and p. E314X, were identified in five patients from four families in either homozygous or compound heterozygous states. The c.1358\u2009+\u20092T\u2009&gt;\u2009C variant caused exon 9 skipping (p.V403Ifs*24), which was confirmed by a minigene assay and reverse transcription polymerase chain reaction using RNA extracted from peripheral blood leukocytes of a homozygous patient. Human carotid artery endothelial cells expressing these truncated variants exhibited markedly reduced\n                      <jats:italic toggle=\"yes\">PTGIS<\/jats:italic>\n                      protein and prostacyclin metabolite production.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>The results indicate that prostacyclin synthase deficiency is the core pathology of RCICAV. Given that prostacyclin is a potent vasodilator, impaired biosynthesis is consistent with the disease mechanism and may serve as a promising therapeutic target to prevent life-threatening events, including severe stroke and angina.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/17474930261449005","type":"journal-article","created":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T09:31:07Z","timestamp":1777109467000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Biallelic loss-of-function variants in\n                    <i>PTGIS<\/i>\n                    cause recurrent cervical internal carotid artery vasospasm"],"prefix":"10.1177","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7791-7384","authenticated-orcid":false,"given":"Hiroyuki","family":"Akagawa","sequence":"first","affiliation":[{"name":"Institute for Comprehensive Medical Sciences, Tokyo Women\u2019s Medical University, Tokyo, Japan"},{"name":"Department of Neurosurgery, Tokyo Women\u2019s Medical University Adachi Medical Center, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2605-5846","authenticated-orcid":false,"given":"Hideaki","family":"Onda","sequence":"additional","affiliation":[{"name":"Division of Neurosurgery, Kofu Neurosurgical Hospital, Yamanashi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Moteki","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Ageo Central General Hospital, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takatoshi","family":"Sorimachi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tokai University School of Medicine, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoichi","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, National Hospital Organization Kanagawa Hospital, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuko","family":"Nihira","sequence":"additional","affiliation":[{"name":"Department of Neurology, Nakamura Memorial Hospital, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Hori","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tokyo Women\u2019s Medical University, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akikazu","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tokyo Women\u2019s Medical University, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makiko","family":"Terada","sequence":"additional","affiliation":[{"name":"Institute for Comprehensive Medical Sciences, Tokyo Women\u2019s Medical University, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takamura","family":"Nagasaka","sequence":"additional","affiliation":[{"name":"Division of Neurology, Kofu Neurosurgical Hospital, Yamanashi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Chida-Nagai","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hokkaido University Hospital, Hokkaido, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Aoki","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, The Jikei University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Kubota","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tokyo Women\u2019s Medical University Adachi Medical Center, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,4,25]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2020.00545"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2016.01.037"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.112.656397"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2010.132"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.115.001862"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-024-07784-2"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12975-020-00779-z"},{"key":"e_1_3_3_9_2","unstructured":"Li H. Aligning sequence reads clone sequences and assembly contigs with BWA-MEM [Preprint]. arXiv 2013 https:\/\/arxiv.org\/abs\/1303.3997 (accessed 18 January 2026)."},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.806"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/0471250953.bi1110s43"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2016.12"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw971"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007602"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3970"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-018-1928-6"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.12.015"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-72043-5"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41439-021-00144-y"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/cge.14483"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1111\/cge.14544"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10080"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2653"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1260419"},{"key":"e_1_3_3_27_2","first-page":"604","article-title":"A case of repeated visual disturbance and migraine-like headache caused by vasospasm of cervical internal carotid artery (in Japanese)","volume":"46","author":"Matsuda M","year":"2020","unstructured":"Matsuda M, Endo M, Sorimachi T, Manaka S. A case of repeated visual disturbance and migraine-like headache caused by vasospasm of cervical internal carotid artery (in Japanese). Japanese Journal of Headache 2020; 46: 604\u2013609.","journal-title":"Japanese Journal of Headache"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.111.004770"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(02)02341-0"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.2174\/156652411800615144"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)63878-0"},{"key":"e_1_3_3_33_2","first-page":"157","article-title":"Prostacyclin synthase gene: genetic polymorphisms and prevention of some cardiovascular diseases","volume":"3","author":"Nakayama T.","year":"2005","unstructured":"Nakayama T. Prostacyclin synthase gene: genetic polymorphisms and prevention of some cardiovascular diseases. Curr Med Chem Cardiovasc Hematol Agents 2005; 3: 157\u2013164.","journal-title":"Curr Med Chem Cardiovasc Hematol Agents"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2008.10.011"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2020.0479"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.123.032872"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad978"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06045-0"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01608-3"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000231646.30541.d8"}],"container-title":["International Journal of Stroke"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/17474930261449005","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/17474930261449005","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/17474930261449005","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T07:18:58Z","timestamp":1779779938000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/17474930261449005"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,25]]},"references-count":39,"alternative-id":["10.1177\/17474930261449005"],"URL":"https:\/\/doi.org\/10.1177\/17474930261449005","relation":{},"ISSN":["1747-4930","1747-4949"],"issn-type":[{"value":"1747-4930","type":"print"},{"value":"1747-4949","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,25]]},"article-number":"17474930261449005"}}