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Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways

Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways
Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways
Leukoencephalopathy with vanishing white matter (VWM) is a severe inherited human neurodegenerative disorder that is caused by mutations in the genes for the subunits of eukaryotic initiation factor 2B (eIF2B), a heteropentameric guanine nucleotide exchange factor that regulates both global and mRNA-specific translation. Marked variability is evident in the clinical severity and time course of VWM in patients. Here we have studied the effects of VWM mutations on the function of human eIF2B. All the mutations tested cause partial loss of activity. Frameshift mutations in genes for eIF2B{varepsilon} or eIF2Bß lead to truncated polypeptides that fail to form complexes with the other subunits and are effectively null mutations. Certain point mutations also impair the ability of eIF2Bß or -{varepsilon} to form eIF2B holocomplexes and also diminish the intrinsic nucleotide exchange activity of eIF2B. A point mutation in the catalytic domain of eIF2B{varepsilon} impairs its ability to bind the substrate, while two mutations in eIF2Bß actually enhance eIF2 binding. We provide evidence that expression of VWM mutant eIF2B may enhance the translation of specific mRNAs. The variability of the clinical phenotype in VWM may reflect the multiple ways in which VWM mutations affect eIF2B function.
guanine-nucleotide-exchange, nervous-system hypomyelination, translation initiation, factor EIF-2B, factor-ll, in-vivo2
0270-7306
3295-3306
Li, Wei
ab5e097b-b347-4edf-95dd-2b245edf0f81
Wang, Xuemin
530099a8-90dc-47de-8315-9c2f6f11a569
Van der Knaap, Marjo S.
b46a8973-a464-464c-a35d-5e0c600749c3
Proud, Christopher G.
59dabfc8-4b44-4be8-a17f-578a58550cb3
Li, Wei
ab5e097b-b347-4edf-95dd-2b245edf0f81
Wang, Xuemin
530099a8-90dc-47de-8315-9c2f6f11a569
Van der Knaap, Marjo S.
b46a8973-a464-464c-a35d-5e0c600749c3
Proud, Christopher G.
59dabfc8-4b44-4be8-a17f-578a58550cb3

Li, Wei, Wang, Xuemin, Van der Knaap, Marjo S. and Proud, Christopher G. (2004) Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways. Molecular and Cellular Biology, 24 (8), 3295-3306. (doi:10.1128/MCB.24.8.3295-3306.2004).

Record type: Article

Abstract

Leukoencephalopathy with vanishing white matter (VWM) is a severe inherited human neurodegenerative disorder that is caused by mutations in the genes for the subunits of eukaryotic initiation factor 2B (eIF2B), a heteropentameric guanine nucleotide exchange factor that regulates both global and mRNA-specific translation. Marked variability is evident in the clinical severity and time course of VWM in patients. Here we have studied the effects of VWM mutations on the function of human eIF2B. All the mutations tested cause partial loss of activity. Frameshift mutations in genes for eIF2B{varepsilon} or eIF2Bß lead to truncated polypeptides that fail to form complexes with the other subunits and are effectively null mutations. Certain point mutations also impair the ability of eIF2Bß or -{varepsilon} to form eIF2B holocomplexes and also diminish the intrinsic nucleotide exchange activity of eIF2B. A point mutation in the catalytic domain of eIF2B{varepsilon} impairs its ability to bind the substrate, while two mutations in eIF2Bß actually enhance eIF2 binding. We provide evidence that expression of VWM mutant eIF2B may enhance the translation of specific mRNAs. The variability of the clinical phenotype in VWM may reflect the multiple ways in which VWM mutations affect eIF2B function.

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More information

Submitted date: 8 September 2003
Published date: April 2004
Keywords: guanine-nucleotide-exchange, nervous-system hypomyelination, translation initiation, factor EIF-2B, factor-ll, in-vivo2

Identifiers

Local EPrints ID: 48778
URI: http://eprints.soton.ac.uk/id/eprint/48778
ISSN: 0270-7306
PURE UUID: 7a84fd79-0259-4b79-b2cd-aac019715bfd

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Date deposited: 12 Oct 2007
Last modified: 15 Mar 2024 09:49

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Contributors

Author: Wei Li
Author: Xuemin Wang
Author: Marjo S. Van der Knaap
Author: Christopher G. Proud

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