{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:21:18Z","timestamp":1790356878877,"version":"4.1.0"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2020,1,21]],"date-time":"2020-01-21T00:00:00Z","timestamp":1579564800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["RTI2018-093493-B-I00"],"award-info":[{"award-number":["RTI2018-093493-B-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["BIO2016-79930-R"],"award-info":[{"award-number":["BIO2016-79930-R"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,5,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a type of leukodystrophy characterized by white matter edema, and it is caused mainly by recessive mutations in MLC1 and GLIALCAM genes. These variants are called MLC1 and MLC2A with both types of patients sharing the same clinical phenotype. In addition, dominant mutations in GLIALCAM have also been identified in a subtype of MLC patients with a remitting phenotype. This variant has been named MLC2B. GLIALCAM encodes for an adhesion protein containing two immunoglobulin (Ig) domains and it is needed for MLC1 targeting to astrocyte\u2013astrocyte junctions. Most mutations identified in GLIALCAM abolish GlialCAM targeting to junctions. However, it is unclear why some mutations behave as recessive or dominant. Here, we used a combination of biochemistry methods with a new developed anti-GlialCAM nanobody, double-mutants and cysteine cross-links experiments, together with computer docking, to create a structural model of GlialCAM homo-interactions. Using this model, we suggest that dominant mutations affect different GlialCAM\u2013GlialCAM interacting surfaces in the first Ig domain, which can occur between GlialCAM molecules present in the same cell (cis) or present in neighbouring cells (trans). Our results provide a framework that can be used to understand the molecular basis of pathogenesis of all identified GLIALCAM mutations.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa009","type":"journal-article","created":{"date-parts":[[2020,1,15]],"date-time":"2020-01-15T20:09:35Z","timestamp":1579118975000},"page":"1107-1120","source":"Crossref","is-referenced-by-count":16,"title":["Structural basis for the dominant or recessive character of GLIALCAM mutations found in leukodystrophies"],"prefix":"10.1093","volume":"29","author":[{"given":"Xabier","family":"Elorza-Vidal","sequence":"first","affiliation":[{"name":"Unitat de Fisiologia, Departament de Ci\u00e8ncies Fisiol\u00f2giques, Genes Disease and Therapy Program IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain"},{"name":"Centro de Investigaci\u00f3n en red de enfermedades raras (CIBERER), ISCIII, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Efren","family":"Xicoy-Espaulella","sequence":"first","affiliation":[{"name":"Unitat de Fisiologia, Departament de Ci\u00e8ncies Fisiol\u00f2giques, Genes Disease and Therapy Program IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adri\u00e0","family":"Pla-Casillanis","sequence":"first","affiliation":[{"name":"Unitat de Fisiologia, Departament de Ci\u00e8ncies Fisiol\u00f2giques, Genes Disease and Therapy Program IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Alonso-Gard\u00f3n","sequence":"first","affiliation":[{"name":"Unitat de Fisiologia, Departament de Ci\u00e8ncies Fisiol\u00f2giques, Genes Disease and Therapy Program IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9ctor","family":"Gait\u00e1n-Pe\u00f1as","sequence":"first","affiliation":[{"name":"Unitat de Fisiologia, Departament de Ci\u00e8ncies Fisiol\u00f2giques, Genes Disease and Therapy Program IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain"},{"name":"Centro de Investigaci\u00f3n en red de enfermedades raras (CIBERER), ISCIII, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn","family":"Engel-Pizcueta","sequence":"first","affiliation":[{"name":"Unitat de Fisiologia, Departament de Ci\u00e8ncies Fisiol\u00f2giques, Genes Disease and Therapy Program IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Fern\u00e1ndez-Recio","sequence":"first","affiliation":[{"name":"Barcelona Supercomputing Center (BSC), Barcelona, Spain"},{"name":"Institut de Biologia Molecular de Barcelona, CSIC, Barcelona, Spain"},{"name":"Instituto de Ciencias de la Vid y del Vino (ICVV), CSIC- Universidad de La Rioja- Gobierno de la Rioja, Logro\u00f1o, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ra\u00fal","family":"Est\u00e9vez","sequence":"first","affiliation":[{"name":"Unitat de Fisiologia, Departament de Ci\u00e8ncies Fisiol\u00f2giques, Genes Disease and Therapy Program IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, Spain"},{"name":"Centro de Investigaci\u00f3n en red de enfermedades raras (CIBERER), ISCIII, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,1,21]]},"reference":[{"key":"2020050805374800800_ref1","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/S1474-4422(19)30143-7","article-title":"Diagnosis, prognosis, and treatment of leukodystrophies","volume":"18","author":"van der Knaap","year":"2019","journal-title":"Lancet Neurol."},{"key":"2020050805374800800_ref2","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/S1474-4422(12)70192-8","article-title":"Megalencephalic leukoencephalopathy with subcortical cysts: chronic white matter oedema due to a defect in brain ion and water homoeostasis","volume":"11","author":"van der Knaap","year":"2012","journal-title":"Lancet Neurol."},{"key":"2020050805374800800_ref3","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1086\/319519","article-title":"Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts","volume":"68","author":"Leegwater","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"2020050805374800800_ref4","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.ajhg.2011.02.009","article-title":"Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism","volume":"88","author":"L\u00f3pez-Hern\u00e1ndez","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"2020050805374800800_ref5","doi-asserted-by":"crossref","first-page":"E1395","DOI":"10.1212\/WNL.0000000000005334","article-title":"Megalencephalic leukoencephalopathy with subcortical cysts: characterization of disease variants","volume":"90","author":"Hamilton","year":"2018","journal-title":"Neurology"},{"key":"2020050805374800800_ref6","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.ejmg.2017.10.013","article-title":"Megalencephalic leukoencephalopathy with subcortical cysts: a personal biochemical retrospective","volume":"61","author":"Est\u00e9vez","year":"2018","journal-title":"Eur. J. Med. Genet."},{"key":"2020050805374800800_ref7","first-page":"4111","article-title":"Regulatory-auxiliary subunits of CLC chloride channel-transport proteins","volume":"593","author":"Barrallo-Gimeno","year":"2015","journal-title":"Austral. J. Phys."},{"key":"2020050805374800800_ref8","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1002\/acn3.405","article-title":"Megalencephalic leukoencephalopathy with cysts: the Glialcam -null mouse model","volume":"4","author":"Bugiani","year":"2017","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"2020050805374800800_ref9","doi-asserted-by":"crossref","first-page":"3475","DOI":"10.1038\/ncomms4475","article-title":"Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction","volume":"5","author":"Hoegg-Beiler","year":"2014","journal-title":"Nat. Commun."},{"key":"2020050805374800800_ref10","doi-asserted-by":"crossref","first-page":"4405","DOI":"10.1093\/hmg\/ddt290","article-title":"Insights into MLC pathogenesis: GlialCAM is an MLC1 chaperone required for proper activation of volume-regulated anion currents","volume":"22","author":"Capdevila-Nortes","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"2020050805374800800_ref11","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/j.neuron.2011.12.039","article-title":"GlialCAM, a protein defective in a Leukodystrophy, serves as a ClC-2 cl - channel auxiliary subunit","volume":"73","author":"Jeworutzki","year":"2012","journal-title":"Neuron"},{"key":"2020050805374800800_ref12","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1016\/j.bpj.2014.07.040","article-title":"GlialCAM, a CLC-2 cl(\u2212) channel subunit, activates the slow gate of CLC chloride channels","volume":"107","author":"Jeworutzki","year":"2014","journal-title":"Biophys. J."},{"key":"2020050805374800800_ref13","first-page":"4165","article-title":"Structural determinants of interaction, trafficking and function in the ClC-2\/MLC1 subunit GlialCAM involved in leukodystrophy","volume":"593","author":"Capdevila-Nortes","year":"2015","journal-title":"Austral. J. Phys."},{"key":"2020050805374800800_ref14","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1002\/humu.22622","article-title":"Functional analyses of mutations in HEPACAM causing megalencephalic leukoencephalopathy","volume":"35","author":"Arnedo","year":"2014","journal-title":"Hum. Mutat."},{"key":"2020050805374800800_ref15","doi-asserted-by":"crossref","first-page":"3266","DOI":"10.1093\/hmg\/ddr238","article-title":"Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts","volume":"20","author":"L\u00f3pez-Hern\u00e1ndez","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"2020050805374800800_ref16","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s10048-013-0381-x","article-title":"Expanding the spectrum of megalencephalic leukoencephalopathy with subcortical cysts in two patients with GLIALCAM mutations","volume":"15","author":"Arnedo","year":"2014","journal-title":"Neurogenetics"},{"key":"2020050805374800800_ref17","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1073\/pnas.0911235107","article-title":"The protein tyrosine phosphatases PTPRZ and PTPRG bind to distinct members of the contactin family of neural recognition molecules","volume":"107","author":"Bouyain","year":"2010","journal-title":"Proc. Nat. Acad. Sci. U.S.A."},{"key":"2020050805374800800_ref18","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/S0959-440X(02)00358-5","article-title":"CLC chloride channels: correlating structure with function","volume":"12","author":"Est\u00e9vez","year":"2002","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2020050805374800800_ref19","doi-asserted-by":"crossref","first-page":"12659","DOI":"10.1074\/jbc.M110.197368","article-title":"Crystal structure of the cis-dimer of Nectin-1","volume":"286","author":"Narita","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2020050805374800800_ref20","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/S0955-0674(00)00138-1","article-title":"IgCAMs: bidirectional signals underlying neurite growth","volume":"12","author":"Kamiguchi","year":"2000","journal-title":"Curr. Opin. Cell Biol."},{"key":"2020050805374800800_ref21","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.mcn.2016.11.009","article-title":"Cell-cell communication mediated by the CAR subgroup of immunoglobulin cell adhesion molecules in health and disease","volume":"81","author":"Matth\u00e4us","year":"2017","journal-title":"Mol. Cell. 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Genet."},{"key":"2020050805374800800_ref24","first-page":"17","article-title":"Structure of the human ClC-1 chloride channel","volume":"e3000218","author":"Wang","year":"2019","journal-title":"PLOS Biol."},{"key":"2020050805374800800_ref25","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.nbd.2007.01.016","article-title":"Expression patterns of MLC1 protein in the central and peripheral nervous systems","volume":"26","author":"Teijido","year":"2007","journal-title":"Neurobiol. Dis."},{"key":"2020050805374800800_ref26","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.1093\/hmg\/ddh291","article-title":"Localization and functional analyses of the MLC1 protein involved in megalencephalic leukoencephalopathy with subcortical cysts","volume":"13","author":"Teijido","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"2020050805374800800_ref27","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nprot.2014.039","article-title":"A general protocol for the generation of Nanobodies for structural biology","volume":"9","author":"Pardon","year":"2014","journal-title":"Nat. Protoc."},{"key":"2020050805374800800_ref28","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1038\/s41467-019-09837-z","article-title":"L amino acid transporter structure and molecular bases for the asymmetry of substrate interaction","volume":"10","author":"Errasti-Murugarren","year":"2019","journal-title":"Nat. Commun."},{"key":"2020050805374800800_ref29","doi-asserted-by":"crossref","first-page":"W244","DOI":"10.1093\/nar\/gki408","article-title":"The HHpred interactive server for protein homology detection and structure prediction","volume":"33","author":"Soding","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"2020050805374800800_ref30","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1002\/prot.21419","article-title":"pyDock: electrostatics and desolvation for effective scoring of rigid-body protein-protein docking","volume":"68","author":"Cheng","year":"2007","journal-title":"Proteins"},{"key":"2020050805374800800_ref31","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1093\/bioinformatics\/btt262","article-title":"pyDockWEB: a web server for rigid-body protein\u2013protein docking using electrostatics and desolvation scoring","volume":"29","author":"Jim\u00e9nez-Garc\u00eda","year":"2013","journal-title":"Bioinformatics"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddaa009\/32905933\/ddaa009.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/29\/7\/1107\/33192102\/ddaa009.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/29\/7\/1107\/33192102\/ddaa009.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,5,8]],"date-time":"2020-05-08T09:38:03Z","timestamp":1588930683000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/29\/7\/1107\/5709832"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,21]]},"references-count":31,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,1,21]]},"published-print":{"date-parts":[[2020,5,8]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddaa009","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,4,1]]},"published":{"date-parts":[[2020,1,21]]}}}