title: Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism.
abstract: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a leukodystrophy characterized by early-onset macrocephaly and delayed-onset neurological deterioration. Recessive MLC1 mutations are observed in 75% of patients with MLC. Genetic-linkage studies failed to identify another gene. We recently showed that some patients without MLC1 mutations display the classical phenotype; others improve or become normal but retain macrocephaly. To find another MLC-related gene, we used quantitative proteomic analysis of affinity-purified MLC1 as an alternative approach and found that GlialCAM, an IgG-like cell adhesion molecule that is also called HepaCAM and is encoded by HEPACAM, is a direct MLC1-binding partner. Analysis of 40 MLC patients without MLC1 mutations revealed multiple different HEPACAM mutations. Ten patients with the classical, deteriorating phenotype had two mutations, and 18 patients with the improving phenotype had one mutation. Most parents with a single mutation had macrocephaly, indicating dominant inheritance. In some families with dominant HEPACAM mutations, the clinical picture and magnetic resonance imaging normalized, indicating that HEPACAM mutations can cause benign familial macrocephaly. In other families with dominant HEPACAM mutations, patients had macrocephaly and mental retardation with or without autism. Further experiments demonstrated that GlialCAM and MLC1 both localize in axons and colocalize in junctions between astrocytes. GlialCAM is additionally located in myelin. Mutant GlialCAM disrupts the localization of MLC1-GlialCAM complexes in astrocytic junctions in a manner reflecting the mode of inheritance. In conclusion, GlialCAM is required for proper localization of MLC1. HEPACAM is the second gene found to be mutated in MLC. Dominant HEPACAM mutations can cause either macrocephaly and mental retardation with or without autism or benign familial macrocephaly.
authors.affiliation: Sección de Fisiología, Departamento de Ciencias Fisiologicas II, University of Barcelona, 08907 Barcelona, Spain.
authors.forename: Tania
authors.initials: T
authors.lastname: López-Hernández
authors.forename: Margreet C
authors.initials: MC
authors.lastname: Ridder
authors.forename: Marisol
authors.initials: M
authors.lastname: Montolio
authors.forename: Xavier
authors.initials: X
authors.lastname: Capdevila-Nortes
authors.forename: Emiel
authors.initials: E
authors.lastname: Polder
authors.forename: Sònia
authors.initials: S
authors.lastname: Sirisi
authors.forename: Anna
authors.initials: A
authors.lastname: Duarri
authors.forename: Uwe
authors.initials: U
authors.lastname: Schulte
authors.forename: Bernd
authors.initials: B
authors.lastname: Fakler
authors.forename: Virginia
authors.initials: V
authors.lastname: Nunes
authors.forename: Gert C
authors.initials: GC
authors.lastname: Scheper
authors.forename: Albert
authors.initials: A
authors.lastname: Martínez
authors.forename: Raúl
authors.initials: R
authors.lastname: Estévez
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D003560:Cysts / Q000235:genetics / Q000378:metabolism; D005799:Genes, Dominant; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D058627:Megalencephaly / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017386:Sequence Homology, Amino Acid
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D018797:Cell Cycle Proteins; C487620:HEPACAM protein, human; C425069:MLC1 protein, human; D008565:Membrane Proteins; D011506:Proteins