title: Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients.
abstract: Mutations in each of the five eucaryotic initiation factor 2B (eIF2B) subunits have been found in leukodystrophies of various severity: Cree leukoencephalopathy, childhood ataxia with central hypomyelination/leukodystrophy with vanishing white matter and ovarioleukodystrophy. A continuum was observed from fatal infantile forms to adult forms without neurological deterioration. Disease severity was found to correlate with the age at disease onset and the specific amino-acid substitution. In order to analyze the functional consequences of eIF2B mutations, we measured the guanine nucleotide exchange factor (GEF) activity of eIF2B in transformed lymphocytes from 30 affected patients carrying mutations in eIF2B compared to 10 unaffected heterozygotes and 22 controls without eIF2B mutations. A significant decrease of 20-70% in GEF activity was observed in all mutated cells. The severity of this decrement of GEF activity correlated with age at onset of the disease. These results suggest that a deficiency in GEF activity underlies the encephalopathy associated eIF2B-related disease. Our study demonstrates that the evaluation of the GEF activity in transformed lymphocytes represents an interesting alternative test to the systematic screening of the five EIF2B genes. This relevant cellular model may also be used to test the functional impact of different molecules on the GEF activity for future therapeutic strategies.
authors.affiliation: INSERM UMR 384, Faculté de Médecine, 28 place Henri Dunant, Clermont-Ferrand, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Fogli
authors.forename: Raphael
authors.initials: R
authors.lastname: Schiffmann
authors.forename: Lynne
authors.initials: L
authors.lastname: Hugendubler
authors.forename: Patricia
authors.initials: P
authors.lastname: Combes
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Diana
authors.initials: D
authors.lastname: Rodriguez
authors.forename: Scot R
authors.initials: SR
authors.lastname: Kimball
authors.forename: Odile
authors.initials: O
authors.lastname: Boespflug-Tanguy
mesh_terms: D000293:Adolescent; D001927:Brain Diseases / Q000235:genetics* / Q000378:metabolism; D002461:Cell Line, Transformed; D002648:Child; D002675:Child, Preschool; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics
chemical_list: D020717:Eukaryotic Initiation Factor-2B