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MLC is caused by mutations in <jats:italic>MLC1<\/jats:italic> or <jats:italic>GLIALCAM<\/jats:italic>, coding for two membrane proteins with an unknown function that form a complex specifically expressed in astrocytes at cell-cell junctions. Recent studies in <jats:italic>Mlc1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> or <jats:italic>Glialcam<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice and <jats:italic>mlc1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> zebrafish have shown that MLC1 regulates glial surface levels of GlialCAM in vivo and that GlialCAM is also required for MLC1 expression and localization at cell-cell junctions.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>We have generated and analysed <jats:italic>glialcama<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> zebrafish. We also generated zebrafish <jats:italic>glialcama<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup><jats:italic>mlc1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> and mice double KO for both genes and performed magnetic resonance imaging, histological studies and biochemical analyses.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>glialcama<jats:sup>\u2212\/\u2212<\/jats:sup> shows megalencephaly and increased fluid accumulation. In both zebrafish and mice, this phenotype is not aggravated by additional elimination of <jats:italic>mlc1<\/jats:italic>. Unlike mice, mlc1 protein expression and localization are unaltered in <jats:italic>glialcama<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> zebrafish, possibly because there is an up-regulation of <jats:italic>mlc1<\/jats:italic> mRNA. In line with these results, MLC1 overexpressed in <jats:italic>Glialcam<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mouse primary astrocytes is located at cell-cell junctions.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>This work indicates that the two proteins involved in the pathogenesis of MLC, GlialCAM and MLC1, form a functional unit, and thus, that loss-of-function mutations in these genes cause leukodystrophy through a common pathway.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s13023-019-1248-5","type":"journal-article","created":{"date-parts":[[2019,11,21]],"date-time":"2019-11-21T13:02:33Z","timestamp":1574341353000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Comparison of zebrafish and mice knockouts for Megalencephalic Leukoencephalopathy proteins indicates that GlialCAM\/MLC1 forms a functional unit"],"prefix":"10.1186","volume":"14","author":[{"given":"Carla","family":"P\u00e9rez-Rius","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00f3nica","family":"Folgueira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xabier","family":"Elorza-Vidal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Alia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maja B.","family":"Hoegg-Beiler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhamed N. 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