title: Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts.
abstract: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy caused by mutations in MLC1 or GLIALCAM. The GLIALCAM gene product functions as an MLC1 beta-subunit. We aim to further clarify the molecular mechanisms of MLC caused by mutations in MLC1 or GLIALCAM. For this purpose, we analyzed a human post-mortem brain obtained from an MLC patient, who was homozygous for a missense mutation (S69L) in MLC1. We showed that this mutation affects the stability of MLC1 in vitro and reduces MLC1 protein levels in the brain to almost undetectable. However, the amount of GlialCAM and its localization were nearly unaffected, indicating that MLC1 is not necessary for GlialCAM expression or targeting. These findings were supported by experiments in primary astrocytes and in heterologous cells. In addition, we demonstrated that MLC1 and GlialCAM form homo- and hetero-complexes and that MLC-causing mutations in GLIALCAM mainly reduce the formation of GlialCAM homo-complexes, leading to a defect in the trafficking of GlialCAM alone to cell junctions. GLIALCAM mutations also affect the trafficking of its associated molecule MLC1, explaining why GLIALCAM and MLC1 mutations lead to the same disease: MLC.
authors.affiliation: Sección de Fisiología, Idibell-Hospital Universitari de Bellvitge, Hospitalet de LLobregat, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Tania
authors.initials: T
authors.lastname: López-Hernández
authors.forename: Sònia
authors.initials: S
authors.lastname: Sirisi
authors.forename: Xavier
authors.initials: X
authors.lastname: Capdevila-Nortes
authors.forename: Marisol
authors.initials: M
authors.lastname: Montolio
authors.forename: Victor
authors.initials: V
authors.lastname: Fernández-Dueñas
authors.forename: Gert C
authors.initials: GC
authors.lastname: Scheper
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
authors.forename: Pilar
authors.initials: P
authors.lastname: Casquero
authors.forename: Francisco
authors.initials: F
authors.lastname: Ciruela
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.forename: Virginia
authors.initials: V
authors.lastname: Nunes
authors.forename: Raúl
authors.initials: R
authors.lastname: Estévez
mesh_terms: D000328:Adult; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D003560:Cysts / Q000235:genetics* / Q000473:pathology; D017809:Fatal Outcome; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D021381:Protein Transport; D011506:Proteins / Q000235:genetics*; D034622:RNA Interference; D051381:Rats; D014162:Transfection
chemical_list: D018797:Cell Cycle Proteins; C487620:HEPACAM protein, human; C425069:MLC1 protein, human; D008565:Membrane Proteins; D050505:Mutant Proteins; D011506:Proteins