title: Heightened stress response in primary fibroblasts expressing mutant eIF2B genes from CACH/VWM leukodystrophy patients.
abstract: Childhood ataxia with central nervous system hypomyelination (CACH), also called vanishing white matter (VWM) leukoencephalopathy, is a fatal genetic disease caused by mutations in eukaryotic initiation factor 2B (eIF2B) genes. The five subunits eIF2B factor is critical for translation initiation under normal conditions and regulates protein synthesis in response to cellular stresses. Primary fibroblasts from CACH/VWM patients and normal individuals were used to measure basal eIF2B activity as well as global protein synthesis and ATF4 induction in response to stress in the endoplasmic reticulum. We show that although the cells expressing mutant eIF2B genes respond normally to stress conditions by reduced global translation rates, they exhibit significantly greater increase in ATF4 induction compared to normal controls despite equal levels of stress and activity of the upstream eIF2alpha kinase. This heightened stress response observed in primary fibroblasts that suffer from minor loss of basal eIF2B activity may be employed as an initial screening tool for CACH/VWM leukodystrophy.
authors.affiliation: Department of Cell Research & Immunology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, 69978, Israel.
authors.forename: Liraz
authors.initials: L
authors.lastname: Kantor
authors.forename: Heather P
authors.initials: HP
authors.lastname: Harding
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.forename: Raphael
authors.initials: R
authors.lastname: Schiffmann
authors.forename: Christine R
authors.initials: CR
authors.lastname: Kaneski
authors.forename: Scot R
authors.initials: SR
authors.lastname: Kimball
authors.forename: Orna
authors.initials: O
authors.lastname: Elroy-Stein
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation
chemical_list: C497109:ATF4 protein, human; D017931:DNA Primers; D020717:Eukaryotic Initiation Factor-2B; D051701:Activating Transcription Factor 4