title: Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter.
abstract: Leukoencephalopathy with vanishing white matter (VWM) is an inherited brain disease that occurs mainly in children. The course is chronic-progressive with additional episodes of rapid deterioration following febrile infection or minor head trauma. We have identified mutations in EIF2B5 and EIF2B2, encoding the epsilon- and beta-subunits of the translation initiation factor eIF2B and located on chromosomes 3q27 and 14q24, respectively, as causing VWM. We found 16 different mutations in EIF2B5 in 29 patients from 23 families. We also found two distantly related individuals who were homozygous with respect to a missense mutation in EIF2B2, affecting a conserved amino acid. Three other patients also had mutations in EIF2B2. As eIF2B has an essential role in the regulation of translation under different conditions, including stress, this may explain the rapid deterioration of people with VWM under stress. Mutant translation initiation factors have not previously been implicated in disease.
authors.affiliation: Department of Child Neurology, Free University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: P A
authors.initials: PA
authors.lastname: Leegwater
authors.forename: G
authors.initials: G
authors.lastname: Vermeulen
authors.forename: A A
authors.initials: AA
authors.lastname: Könst
authors.forename: S
authors.initials: S
authors.lastname: Naidu
authors.forename: J
authors.initials: J
authors.lastname: Mulders
authors.forename: A
authors.initials: A
authors.lastname: Visser
authors.forename: P
authors.initials: P
authors.lastname: Kersbergen
authors.forename: D
authors.initials: D
authors.lastname: Mobach
authors.forename: D
authors.initials: D
authors.lastname: Fonds
authors.forename: C G
authors.initials: CG
authors.lastname: van Berkel
authors.forename: R J
authors.initials: RJ
authors.lastname: Lemmers
authors.forename: R R
authors.initials: RR
authors.lastname: Frants
authors.forename: C B
authors.initials: CB
authors.lastname: Oudejans
authors.forename: R B
authors.initials: RB
authors.lastname: Schutgens
authors.forename: J C
authors.initials: JC
authors.lastname: Pronk
authors.forename: M S
authors.initials: MS
authors.lastname: van der Knaap
mesh_terms: D001483:Base Sequence; D001927:Brain Diseases / Q000235:genetics* / Q000473:pathology; D002883:Chromosomes, Human, Pair 14; D002893:Chromosomes, Human, Pair 3; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis / Q000502:physiology*
chemical_list: D020717:Eukaryotic Initiation Factor-2B