A point mutation in translation initiation factor eIF2B leads to function--and time-specific changes in brain gene expression.

PloS One
Liraz MaromOrna Elroy-Stein

Abstract

Mutations in eukaryotic translation initiation factor 2B (eIF2B) cause Childhood Ataxia with CNS Hypomyelination (CACH), also known as Vanishing White Matter disease (VWM), which is associated with a clinical pathology of brain myelin loss upon physiological stress. eIF2B is the guanine nucleotide exchange factor (GEF) of eIF2, which delivers the initiator tRNA(Met) to the ribosome. We recently reported that a R132H mutation in the catalytic subunit of this GEF, causing a 20% reduction in its activity, leads under normal conditions to delayed brain development in a mouse model for CACH/VWM. To further explore the effect of the mutation on global gene expression in the brain, we conducted a wide-scale transcriptome analysis of the first three critical postnatal weeks. Genome-wide mRNA expression of wild-type and mutant mice was profiled at postnatal (P) days 1, 18 and 21 to reflect the early proliferative stage prior to white matter establishment (P1) and the peak of oligodendrocye differentiation and myelin synthesis (P18 and P21). At each developmental stage, between 441 and 818 genes were differentially expressed in the mutant brain with minimal overlap, generating unique time point-specific gene expression signatures. The cu...Continue Reading

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Citations

Mar 15, 2016·The Journal of Clinical Investigation·Stephanie DoovesMarjo S van der Knaap
Sep 21, 2012·Journal of Child Neurology·Ozlem UnalH Serap Kalkanoglu-Sivri
May 28, 2019·Neuromolecular Medicine·Melisa HerreroOrna Elroy-Stein
Oct 4, 2018·Frontiers in Molecular Neuroscience·Andrea AtzmonOrna Elroy-Stein
Jan 20, 2017·Frontiers in Molecular Neuroscience·Vera G VolpiMaurizio D'Antonio

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Datasets Mentioned

BETA
GSE9566
GSE13379
GSE32201

Methods Mentioned

BETA
nucleotide exchange
flow cytometry
FACS
dissection
chips
genotyping
PCR
electrophoresis
chip
Assay

Software Mentioned

BioMart
CellQuest
CLICK
Affymetrix

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