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Glial pathology in a novel spontaneous mutant mouse of the Eif2b5 gene: a vanishing white matter disease model
Author(s) -
TerumitsuTsujita Mika,
Kitaura Hiroki,
Miura Ikuo,
Kiyama Yuji,
Goto Fumiko,
Muraki Yoshiko,
Ominato Shiho,
Hara Norikazu,
Simankova Anna,
Bizen Norihisa,
Kashiwagi Kazuhiro,
Ito Takuhiro,
Toyoshima Yasuko,
Kakita Akiyoshi,
Manabe Toshiya,
Wakana Shigeharu,
Takebayashi Hirohide,
Igarashi Hironaka
Publication year - 2020
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.14887
Subject(s) - biology , endoplasmic reticulum , mutant , microbiology and biotechnology , unfolded protein response , mutation , genetics , gene
Vanishing white matter disease (VWM) is an autosomal recessive neurological disorder caused by mutation(s) in any subunit of eukaryotic translation initiation factor 2B (eIF2B), an activator of translation initiation factor eIF2. VWM occurs with mutation of the genes encoding eIF2B subunits ( EIF2B1 , EIF2B2 , EIF2B3 , EIF2B4 , and EIF2B5 ). However, little is known regarding the underlying pathogenetic mechanisms or how to treat patients with VWM. Here we describe the identification and detailed analysis of a new spontaneous mutant mouse harboring a point mutation in the Eif2b5 gene (p.Ile98Met). Homozygous Eif2b5 I98M mutant mice exhibited a small body, abnormal gait, male and female infertility, epileptic seizures, and a shortened lifespan. Biochemical analyses indicated that the mutant eIF2B protein with the Eif2b5 I98M mutation decreased guanine nucleotide exchange activity on eIF2, and the level of the endoplasmic reticulum stress marker activating transcription factor 4 was elevated in the 1‐month‐old Eif2b5 I98M brain. Histological analyses indicated up‐regulated glial fibrillary acidic protein immunoreactivity in the astrocytes of the Eif2b5 I98M forebrain and translocation of Bergmann glia in the Eif2b5 I98M cerebellum, as well as increased mRNA expression of an endoplasmic reticulum stress marker, C/EBP homologous protein. Disruption of myelin and clustering of oligodendrocyte progenitor cells were also indicated in the white matter of the Eif2b5 I98M spinal cord at 8 months old. Our data show that Eif2b5 I98M mutants are a good model for understanding VWM pathogenesis and therapy development.Cover Image for this issue: doi: 10.1111/jnc.14751 .