期刊论文详细信息
BMC Medical Genetics
Biochemical effects of mutations in the gene encoding the alpha subunit of eukaryotic initiation factor (eIF) 2B associated with Vanishing White Matter disease
Christopher G. Proud1  Noel C. Wortham2 
[1]South Australian Health and Medical Research Institute, Adelaide, SA5001, Australia
[2]Centre for Biological Sciences, University of Southampton, Life Sciences Building 85, Highfield Campus, Southampton SO17 1BJ, UK
关键词: VWM;    EIF2B1;    eIF2B;    Leukodystrophy;    CACH;   
Others  :  1223158
DOI  :  10.1186/s12881-015-0204-z
 received in 2015-03-18, accepted in 2015-07-14, published in 16
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【 摘 要 】

Background

Leukoencephalopathy with Vanishing White Matter (VWM) is an autosomal recessive disorder caused by germline mutations in the genes EIF2B1-5, which encode the 5 subunits of the eukaryotic translation initiation factor eIF2B. To date, analysis of the biochemical effects of mutations in the EIF2B2-5 genes has been carried out, but no study has been performed on mutations in the EIF2B1 gene. This gene encodes eIF2Bα, the smallest subunit in eIF2B which has an important role in both the structure and regulation of the eIF2B complex.

Methods

eIF2B subunits were overexpressed in HEK293 cells and isolated from the resulting cell lysates by affinity chromatography. Formation of the eIF2B complex and binding of its substrate, eIF2, was assessed by western blot. Assays of the guanine nucleotide exchange (GEF) activity were also carried out.

Results

Of the 5 eIF2Bα mutations studied, we found 3 that showed loss or reduction of binding of eIF2Bα to the rest of the complex, one with increased GEF activity, and one where no effects on activity or complex formation were observed.

Conclusions

This is the first study on eIF2Bα VWM mutations. We show that some mutations cause expected decreases in GEF activity or complex formation, similar to a majority of observed VWM mutations. However, we also observe some unexpected changes which hint at other effects of these mutations on as yet undescribed functions of eIF2B.

【 授权许可】

   
2015 Wortham and Proud.

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