{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:17:01Z","timestamp":1790619421445,"version":"4.1.0"},"reference-count":51,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2017,6,6]],"date-time":"2017-06-06T00:00:00Z","timestamp":1496707200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008358","name":"Hersenstichting","doi-asserted-by":"publisher","award":["2011[1]\u201015"],"award-info":[{"award-number":["2011[1]\u201015"]}],"id":[{"id":"10.13039\/501100008358","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2017,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Megalencephalic leukoencephalopathy with cysts (<jats:styled-content style=\"fixed-case\">MLC<\/jats:styled-content>) is a genetic infantile\u2010onset disease characterized by macrocephaly and white matter edema due to loss of<jats:styled-content style=\"fixed-case\">MLC<\/jats:styled-content>1 function. Recessive mutations in either<jats:italic><jats:styled-content style=\"fixed-case\">MLC<\/jats:styled-content>1<\/jats:italic>or<jats:italic><jats:styled-content style=\"fixed-case\">GLIALCAM<\/jats:styled-content><\/jats:italic>cause the disease.<jats:styled-content style=\"fixed-case\">MLC<\/jats:styled-content>1 is involved in astrocytic volume regulation; Glial<jats:styled-content style=\"fixed-case\">CAM<\/jats:styled-content>ensures the correct membrane localization of<jats:styled-content style=\"fixed-case\">MLC<\/jats:styled-content>1. Their exact role in brain ion\u2010water homeostasis is only partly defined. We characterized<jats:italic>Glialcam<\/jats:italic>\u2010null mice for further studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated the consequences of loss of Glial<jats:styled-content style=\"fixed-case\">CAM<\/jats:styled-content>in<jats:italic>Glialcam<\/jats:italic>\u2010null mice and compared Glial<jats:styled-content style=\"fixed-case\">CAM<\/jats:styled-content>developmental expression in mice and men.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Glialcam<\/jats:italic>\u2010null mice had early\u2010onset megalencephaly and increased brain water content. From 3 weeks, astrocytes were abnormal with swollen processes abutting blood vessels. Concomitantly, progressive white matter vacuolization developed due to intramyelinic edema.<jats:italic>Glialcam<\/jats:italic>\u2010null astrocytes showed abolished expression of<jats:styled-content style=\"fixed-case\">MLC<\/jats:styled-content>1, reduced expression of the chloride channel ClC\u20102 and increased expression and redistribution of the water channel aquaporin4. Expression of other<jats:styled-content style=\"fixed-case\">MLC<\/jats:styled-content>1\u2010interacting proteins and the volume regulated anion channel<jats:styled-content style=\"fixed-case\">LRRC<\/jats:styled-content>8A was unchanged. In mice, Glial<jats:styled-content style=\"fixed-case\">CAM<\/jats:styled-content>expression increased until 3 weeks and then stabilized. In humans, Glial<jats:styled-content style=\"fixed-case\">CAM<\/jats:styled-content>expression was highest in the first 3 years to then decrease and stabilize from approximately 5 years.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p><jats:italic>Glialcam<\/jats:italic>\u2010null mice replicate the early stages of the human disease with early\u2010onset intramyelinic edema. The earliest change is astrocytic swelling, further substantiating that a defect in astrocytic volume regulation is the primary cellular defect in<jats:styled-content style=\"fixed-case\">MLC<\/jats:styled-content>. Glial<jats:styled-content style=\"fixed-case\">CAM<\/jats:styled-content>expression affects expression of<jats:styled-content style=\"fixed-case\">MLC<\/jats:styled-content>1, ClC\u20102 and aquaporin4, indicating that abnormal interplay between these proteins is a disease mechanism in megalencephalic leukoencephalopathy with cysts.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.405","type":"journal-article","created":{"date-parts":[[2017,6,7]],"date-time":"2017-06-07T04:18:37Z","timestamp":1496809117000},"page":"450-465","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Megalencephalic leukoencephalopathy with cysts: the<i>Glialcam<\/i>\u2010null mouse model"],"prefix":"10.1002","volume":"4","author":[{"given":"Marianna","family":"Bugiani","sequence":"first","affiliation":[{"name":"Department of Pediatrics\/Child Neurology Amsterdam Neuroscience VU University Medical Center Amsterdam The Netherlands"},{"name":"Department of Pathology Amsterdam Neuroscience VU University Medical Center Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohit","family":"Dubey","sequence":"additional","affiliation":[{"name":"Department of Pediatrics\/Child Neurology Amsterdam Neuroscience VU University Medical Center Amsterdam The Netherlands"},{"name":"Department of Integrative Neurophysiology Center for Neurogenomics and Cognitive Research Amsterdam Neuroscience VU University Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjolein","family":"Breur","sequence":"additional","affiliation":[{"name":"Department of Pediatrics\/Child Neurology Amsterdam Neuroscience VU University Medical Center Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nienke L.","family":"Postma","sequence":"additional","affiliation":[{"name":"Department of Pediatrics\/Child Neurology Amsterdam Neuroscience VU University Medical Center Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marien P.","family":"Dekker","sequence":"additional","affiliation":[{"name":"Department of Functional Genomics Center for Neurogenomics and Cognitive Research Amsterdam Neuroscience VU University Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"ter Braak","sequence":"additional","affiliation":[{"name":"Department of Pediatrics\/Child Neurology Amsterdam Neuroscience VU University Medical Center Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Boschert","sequence":"additional","affiliation":[{"name":"Translational Innovation Platform Immunology\/Neurology EMD Serono Research &amp; Development Institute Billerica 01821 Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Truus E. 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