title: EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy.
abstract: Vanishing white matter disease (VWM) is a heritable leukodystrophy linked to mutations in translation initiation factor 2B (eIF2B). Although the clinical course of this disease has been relatively well described, the cellular consequences of EIF2B mutations on neural cells are unknown. Here we have established cell cultures from the brain of an individual with VWM carrying mutations in subunit 5 of eIF2B (encoded by EIF2B5). Despite the extensive demyelination apparent in this VWM patient, normal-appearing oligodendrocytes were readily generated in vitro. In contrast, few GFAP-expressing (GFAP+) astrocytes were present in primary cultures, induction of astrocytes was severely compromised, and the few astrocytes generated showed abnormal morphologies and antigenic phenotypes. Lesions in vivo also lacked GFAP+ astrocytes. RNAi targeting of EIF2B5 severely compromised the induction of GFAP+ cells from normal human glial progenitors. This raises the possibility that a deficiency in astrocyte function may contribute to the loss of white matter in VWM leukodystrophy.
authors.affiliation: Department of Biomedical Genetics, Aab Institute, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642, USA.
authors.forename: Jörg
authors.initials: J
authors.lastname: Dietrich
authors.forename: Michelle
authors.initials: M
authors.lastname: Lacagnina
authors.forename: David
authors.initials: D
authors.lastname: Gass
authors.forename: Eric
authors.initials: E
authors.lastname: Richfield
authors.forename: Margot
authors.initials: M
authors.lastname: Mayer-Pröschel
authors.forename: Mark
authors.initials: M
authors.lastname: Noble
authors.forename: Carlos
authors.initials: C
authors.lastname: Torres
authors.forename: Christoph
authors.initials: C
authors.lastname: Pröschel
mesh_terms: D001253:Astrocytes / Q000166:cytology*; D001483:Base Sequence; D001927:Brain Diseases / Q000235:genetics* / Q000503:physiopathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D002648:Child; D003711:Demyelinating Diseases / Q000473:pathology; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics* / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis*; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000503:physiopathology
chemical_list: D020717:Eukaryotic Initiation Factor-2B; D005904:Glial Fibrillary Acidic Protein