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Functional analysis of recently identified mutations in eukaryotic translation initiation factor 2B? (eIF2B?) identified in Chinese patients with vanishing white matter disease

Functional analysis of recently identified mutations in eukaryotic translation initiation factor 2B? (eIF2B?) identified in Chinese patients with vanishing white matter disease
Functional analysis of recently identified mutations in eukaryotic translation initiation factor 2B? (eIF2B?) identified in Chinese patients with vanishing white matter disease
Vanishing white matter disease (VWM) is the first human hereditary disease known to be caused by defects in initiation of protein synthesis. Gene defects in each of the five subunits of eukaryotic translation initiation factor 2B (eIF2B ?-?) are responsible for the disease, although the mechanism of the pathogenesis is not well understood. In our previous study, four novel eIF2B? mutations were found in Chinese patients: p.Asp62Val, p.Cys335Ser, p.Asn376Asp and p.Ser610-Asp613del. Functional analysis was performed on these mutations and the recently reported p.Arg269X. Our data showed that all resulted in a decrease in the guanine nucleotide exchange (GEF) activity of the eIF2B complex. p.Arg269X and p.Ser610-Asp613del mutants displayed the lowest activity, followed by p.Cys335Ser, p.Asn376Asp and p.Asp62Val. p.Arg269X and p.Ser610-Asp613del could not produce stable eIF2B?, leading to almost complete loss-of-function. No evidence was obtained for the three missense mutations in changes in eIF2B? protein level or eIF2B?Ser(540) phosphorylation, and disruption of holocomplex assembly, or binding to eIF2. All patients in our study had the classical phenotype. p.Asp62Val and p.Asn376Asp mutations caused only mildly decreased GEF activity, were probably responsible for relatively mild phenotype in cases of classical VWM.
1434-5161
300-305
Leng, Xuerong
2a47ece4-7d3a-4af6-b41a-aec2d4cefe10
Wu, Ye
a29944dd-3a13-4a9d-a54b-4d752e0fa2b4
Wang, Xuemin
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Pan, Yanxia
340edba5-452c-4510-be59-0af80a5f743a
Wang, Jingmin
55b3e04d-c8c8-4db6-82d2-fe23af3d3571
Li, Jiao
f7e2e620-cbc4-4861-b515-64346ef8ec10
Du, Li
0b64ebb7-7727-46e3-966d-1b8f8061b265
Dai, Lifang
9c56a048-20bc-4a29-8fd4-baf132e60212
Wu, Xiru
3b7e36fc-00e4-45cb-a7fe-d5948514b4fd
Proud, Christopher G
5832db56-9069-4617-a80d-08b069093dba
Jiang, Yuwu
8954763a-045d-48bc-b786-099072c02e58
Leng, Xuerong
2a47ece4-7d3a-4af6-b41a-aec2d4cefe10
Wu, Ye
a29944dd-3a13-4a9d-a54b-4d752e0fa2b4
Wang, Xuemin
d6bb4eb2-5687-46ed-b770-cceb22fd792e
Pan, Yanxia
340edba5-452c-4510-be59-0af80a5f743a
Wang, Jingmin
55b3e04d-c8c8-4db6-82d2-fe23af3d3571
Li, Jiao
f7e2e620-cbc4-4861-b515-64346ef8ec10
Du, Li
0b64ebb7-7727-46e3-966d-1b8f8061b265
Dai, Lifang
9c56a048-20bc-4a29-8fd4-baf132e60212
Wu, Xiru
3b7e36fc-00e4-45cb-a7fe-d5948514b4fd
Proud, Christopher G
5832db56-9069-4617-a80d-08b069093dba
Jiang, Yuwu
8954763a-045d-48bc-b786-099072c02e58

Leng, Xuerong, Wu, Ye, Wang, Xuemin, Pan, Yanxia, Wang, Jingmin, Li, Jiao, Du, Li, Dai, Lifang, Wu, Xiru, Proud, Christopher G and Jiang, Yuwu (2011) Functional analysis of recently identified mutations in eukaryotic translation initiation factor 2B? (eIF2B?) identified in Chinese patients with vanishing white matter disease. Journal of Human Genetics, 56 (4), 300-305. (doi:10.1038/jhg.2011.9). (PMID:21307862)

Record type: Article

Abstract

Vanishing white matter disease (VWM) is the first human hereditary disease known to be caused by defects in initiation of protein synthesis. Gene defects in each of the five subunits of eukaryotic translation initiation factor 2B (eIF2B ?-?) are responsible for the disease, although the mechanism of the pathogenesis is not well understood. In our previous study, four novel eIF2B? mutations were found in Chinese patients: p.Asp62Val, p.Cys335Ser, p.Asn376Asp and p.Ser610-Asp613del. Functional analysis was performed on these mutations and the recently reported p.Arg269X. Our data showed that all resulted in a decrease in the guanine nucleotide exchange (GEF) activity of the eIF2B complex. p.Arg269X and p.Ser610-Asp613del mutants displayed the lowest activity, followed by p.Cys335Ser, p.Asn376Asp and p.Asp62Val. p.Arg269X and p.Ser610-Asp613del could not produce stable eIF2B?, leading to almost complete loss-of-function. No evidence was obtained for the three missense mutations in changes in eIF2B? protein level or eIF2B?Ser(540) phosphorylation, and disruption of holocomplex assembly, or binding to eIF2. All patients in our study had the classical phenotype. p.Asp62Val and p.Asn376Asp mutations caused only mildly decreased GEF activity, were probably responsible for relatively mild phenotype in cases of classical VWM.

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Published date: April 2011
Organisations: Centre for Biological Sciences

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Local EPrints ID: 350228
URI: http://eprints.soton.ac.uk/id/eprint/350228
ISSN: 1434-5161
PURE UUID: e6e1b193-07e3-4cd7-ad43-29b06497e580

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Date deposited: 20 Mar 2013 11:33
Last modified: 16 Jul 2019 21:40

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Contributors

Author: Xuerong Leng
Author: Ye Wu
Author: Xuemin Wang
Author: Yanxia Pan
Author: Jingmin Wang
Author: Jiao Li
Author: Li Du
Author: Lifang Dai
Author: Xiru Wu
Author: Christopher G Proud
Author: Yuwu Jiang

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