Terumitsu-Tsujita M1,2,3, Kitaura H1,4, Miura I5, Kiyama Y2, Goto F2, Muraki Y1, Ominato S1, Hara N6, Simankova A7, Bizen N7, Kashiwagi K8, Ito T8, Toyoshima Y4, Kakita A4, Manabe T2, Wakana S5, Takebayashi H7,9, Igarashi H1.
1Center for Integrated Human Brain Science, Brain Research Institute, Niigata University
2Division of Neuronal Network, The Institute of Medical Science, The University of Tokyo
3Administrative Section of Radiation Protection, National Institute of Neuroscience, National Center of Neurology and Psychiatry
4Department of Pathology, Brain Research Institute, Niigata University
5Technology and Development Team for Mouse Phenotype Analysis, The Japan Mouse Clinic, RIKEN BioResource Research Center
6Department of Molecular Genetics, Brain Research Institute, Niigata University
7Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University
8Laboratory for Translation Structural Biology, RIKEN Center for Biosystems Dynamics Research
9Center for Coordination of Research Facilities, Niigata University
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 Eif2b5I98M 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 Eif2b5I98M 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 Eif2b5I98M brain. Histological analyses indicated up-regulated glial fibrillary acidic protein immunoreactivity in the astrocytes of the Eif2b5I98M forebrain and translocation of Bergmann glia in the Eif2b5I98M 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 Eif2b5I98M spinal cord at 8 months old. Our data show that Eif2b5I98M mutants are a good model for understanding VWM pathogenesis and therapy development.