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Severity of vanishing white matter disease does not correlate with deficits in eIF2B activity or the integrity of eIF2B complexes

Severity of vanishing white matter disease does not correlate with deficits in eIF2B activity or the integrity of eIF2B complexes
Severity of vanishing white matter disease does not correlate with deficits in eIF2B activity or the integrity of eIF2B complexes
Autosomal recessive mutations in eukaryotic initiation factor 2B (eIF2B) cause leukoencephalopathy vanishing white matter with a wide clinical spectrum. eIF2B comprises five subunits (?-?; genes EIF2B1, 2, 3, 4 and 5) and is the guanine nucleotide-exchange factor (GEF) for eIF2. It plays a key role in protein synthesis. Here, we have studied the functional effects of selected VWM mutations in EIF2B2-5 by co-expressing mutated and wildtype subunits in human cells. The observed functional effects are very diverse, including defects in eIF2B complex integrity; binding to the regulatory ?-subunit; substrate binding; and GEF activity. Activity data for recombinant eIF2B complexes agree closely with those for patient-derived cells with the same mutations. Some mutations do not affect these parameters even though they cause severe disease. These findings are important for three reasons; they demonstrate that measuring eIF2B activity in patients' cells has limited value as a diagnostic test; they imply that severe disease can result from alterations in eIF2B function other than defects in complex integrity, substrate binding or GEF activity and, lastly, the diversity of functional effects of VWM mutations implies that seeking agents to manage or treat VWM should focus on downstream effectors of eIF2B, not restoring eIF2B activity.
vwm, cach, childhood ataxia with central nervous system hypomyelination, translation initiation factor
1059-7794
1036-1045
Liu, Rui
f6ba8ec9-4057-4dd9-a960-d63f660eee09
van der Lei, Hannemieke D.W.
5286fd52-6846-47e1-a517-c66cb14b8703
Wang, Xuemin
d6bb4eb2-5687-46ed-b770-cceb22fd792e
Wortham, Noel C.
9b0a219d-41fa-4f83-9621-6ffd60f44c8f
Tang, Hua
32c33df0-02af-4e5d-8e45-0e1fd1efc10a
van Berkel, Carola G.M.
7603a118-68a1-4cc4-ad07-82af63ff4205
Mufunde, Tsitsi Arikana
42966447-0ac8-442e-a021-ae3300e1b5d9
Huang, Weida
a8b7a725-8c4e-4b92-9881-821d0f5dde50
van der Knaap, Marjo S.
b46a8973-a464-464c-a35d-5e0c600749c3
Scheper, Gert C.
1ed78a31-c592-4ea4-8256-a75ad241d802
Proud, Christopher G.
59dabfc8-4b44-4be8-a17f-578a58550cb3
Liu, Rui
f6ba8ec9-4057-4dd9-a960-d63f660eee09
van der Lei, Hannemieke D.W.
5286fd52-6846-47e1-a517-c66cb14b8703
Wang, Xuemin
d6bb4eb2-5687-46ed-b770-cceb22fd792e
Wortham, Noel C.
9b0a219d-41fa-4f83-9621-6ffd60f44c8f
Tang, Hua
32c33df0-02af-4e5d-8e45-0e1fd1efc10a
van Berkel, Carola G.M.
7603a118-68a1-4cc4-ad07-82af63ff4205
Mufunde, Tsitsi Arikana
42966447-0ac8-442e-a021-ae3300e1b5d9
Huang, Weida
a8b7a725-8c4e-4b92-9881-821d0f5dde50
van der Knaap, Marjo S.
b46a8973-a464-464c-a35d-5e0c600749c3
Scheper, Gert C.
1ed78a31-c592-4ea4-8256-a75ad241d802
Proud, Christopher G.
59dabfc8-4b44-4be8-a17f-578a58550cb3

Liu, Rui, van der Lei, Hannemieke D.W., Wang, Xuemin, Wortham, Noel C., Tang, Hua, van Berkel, Carola G.M., Mufunde, Tsitsi Arikana, Huang, Weida, van der Knaap, Marjo S., Scheper, Gert C. and Proud, Christopher G. (2011) Severity of vanishing white matter disease does not correlate with deficits in eIF2B activity or the integrity of eIF2B complexes. Human Mutation, 32 (9), 1036-1045. (doi:10.1002/humu.21535). (PMID:21560189)

Record type: Article

Abstract

Autosomal recessive mutations in eukaryotic initiation factor 2B (eIF2B) cause leukoencephalopathy vanishing white matter with a wide clinical spectrum. eIF2B comprises five subunits (?-?; genes EIF2B1, 2, 3, 4 and 5) and is the guanine nucleotide-exchange factor (GEF) for eIF2. It plays a key role in protein synthesis. Here, we have studied the functional effects of selected VWM mutations in EIF2B2-5 by co-expressing mutated and wildtype subunits in human cells. The observed functional effects are very diverse, including defects in eIF2B complex integrity; binding to the regulatory ?-subunit; substrate binding; and GEF activity. Activity data for recombinant eIF2B complexes agree closely with those for patient-derived cells with the same mutations. Some mutations do not affect these parameters even though they cause severe disease. These findings are important for three reasons; they demonstrate that measuring eIF2B activity in patients' cells has limited value as a diagnostic test; they imply that severe disease can result from alterations in eIF2B function other than defects in complex integrity, substrate binding or GEF activity and, lastly, the diversity of functional effects of VWM mutations implies that seeking agents to manage or treat VWM should focus on downstream effectors of eIF2B, not restoring eIF2B activity.

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e-pub ahead of print date: 16 August 2011
Published date: September 2011
Keywords: vwm, cach, childhood ataxia with central nervous system hypomyelination, translation initiation factor
Organisations: Centre for Biological Sciences

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Local EPrints ID: 350235
URI: http://eprints.soton.ac.uk/id/eprint/350235
ISSN: 1059-7794
PURE UUID: f17a7134-bef2-4606-870c-4c3729a9903b

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Date deposited: 20 Mar 2013 11:50
Last modified: 16 Jul 2019 21:40

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Contributors

Author: Rui Liu
Author: Hannemieke D.W. van der Lei
Author: Xuemin Wang
Author: Noel C. Wortham
Author: Hua Tang
Author: Carola G.M. van Berkel
Author: Tsitsi Arikana Mufunde
Author: Weida Huang
Author: Marjo S. van der Knaap
Author: Gert C. Scheper
Author: Christopher G. Proud

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