{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T03:52:10Z","timestamp":1790481130020,"version":"4.1.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T00:00:00Z","timestamp":1655424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002081","name":"The Irish Research Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002081","id-type":"DOI","asserted-by":"crossref"}]},{"name":"FutureNeuro"},{"name":"European Research Council"},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,10,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Claudin-5 is the most enriched tight junction protein at the blood\u2013brain barrier. Perturbations in its levels of expression have been observed across numerous neurological and neuropsychiatric conditions; however, pathogenic variants in the coding sequence of the gene have never been reported previously. Here, we report the identification of a novel de novo mutation (c.178G&amp;gt;A) in the CLDN5 gene in two unrelated cases of alternating hemiplegia with microcephaly. This mutation (G60R) lies within the first extracellular loop of claudin-5 and based on protein modelling and sequence alignment, we predicted it would modify claudin-5 to become an anion-selective junctional component as opposed to a purely barrier-forming protein.<\/jats:p>\n               <jats:p>Generation of stably transfected cell lines expressing wild-type or G60R claudin-5 showed that the tight junctions could still form in the presence of the G60R mutation but that the barrier against small molecules was clearly attenuated and displayed higher Cl\u2212 ion permeability and lower Na+ permeability.<\/jats:p>\n               <jats:p>While this study strongly suggests that CLDN5 associated alternating hemiplegia is a channelopathy, it is also the first study to identify the conversion of the blood\u2013brain barrier to an anion-selective channel mediated by a dominant acting variant in CLDN5.<\/jats:p>","DOI":"10.1093\/brain\/awac215","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T18:14:56Z","timestamp":1655489696000},"page":"3374-3382","source":"Crossref","is-referenced-by-count":31,"title":["Recurrent <i>de novo<\/i> mutations in <i>CLDN5<\/i> induce an anion-selective blood\u2013brain barrier and alternating hemiplegia"],"prefix":"10.1093","volume":"145","author":[{"given":"Yosuke","family":"Hashimoto","sequence":"first","affiliation":[{"name":"Smurfit Institute of Genetics, Trinity College Dublin , Dublin 2 , Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Poirier","sequence":"additional","affiliation":[{"name":"INSERM UMR1163, Institut Imagine, Universit\u00e9 Paris Cit\u00e9 , F-75015, Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Boddaert","sequence":"additional","affiliation":[{"name":"INSERM UMR1163, Institut Imagine, Universit\u00e9 Paris Cit\u00e9 , F-75015, Paris , France"},{"name":"Department of Pediatric Radiology, Hospital Necker Enfants Malades , Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Hubert","sequence":"additional","affiliation":[{"name":"INSERM UMR1163, Institut Imagine, Universit\u00e9 Paris Cit\u00e9 , F-75015, Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melodie","family":"Aubart","sequence":"additional","affiliation":[{"name":"Departments of Pediatric Neurology and Medical Genetics, Hospital Necker Enfants Malades, Universit\u00e9 Paris Cit\u00e9 , F-75015, Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Kaminska","sequence":"additional","affiliation":[{"name":"Departments of Pediatric Neurology and Medical Genetics, Hospital Necker Enfants Malades, Universit\u00e9 Paris Cit\u00e9 , F-75015, Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Alison","sequence":"additional","affiliation":[{"name":"Department of Pediatric Radiology, Hospital Robert Debr\u00e9, Universit\u00e9 Paris Cit\u00e9 , F-75015, Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Desguerre","sequence":"additional","affiliation":[{"name":"Departments of Pediatric Neurology and Medical Genetics, Hospital Necker Enfants Malades, Universit\u00e9 Paris Cit\u00e9 , F-75015, Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnold","family":"Munnich","sequence":"additional","affiliation":[{"name":"INSERM UMR1163, Institut Imagine, Universit\u00e9 Paris Cit\u00e9 , F-75015, Paris , France"},{"name":"Departments of Pediatric Neurology and Medical Genetics, Hospital Necker Enfants Malades, Universit\u00e9 Paris Cit\u00e9 , F-75015, Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3008-9563","authenticated-orcid":false,"given":"Matthew","family":"Campbell","sequence":"additional","affiliation":[{"name":"Smurfit Institute of Genetics, Trinity College Dublin , Dublin 2 , Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,6,17]]},"reference":[{"key":"2022102119191598100_awac215-B1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.nbd.2009.07.030","article-title":"Structure and function of the blood-brain barrier","volume":"37","author":"Abbott","year":"2010","journal-title":"Neurobiol Dis"},{"key":"2022102119191598100_awac215-B2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12987-019-0123-z","article-title":"Claudin-5: gatekeeper of neurological function","volume":"16","author":"Greene","year":"2019","journal-title":"Fluids Barriers 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