| Title | Functional analysis of recently identified mutations in eukaryotic translation initiation factor 2B epsilon (eIF2B epsilon) identified in Chinese patients with vanishing white matter disease |
| Authors | Leng, Xuerong Wu, Ye Wang, Xuemin Pan, Yanxia Wang, Jingmin Li, Jiao Du, Li Dai, Lifang Wu, Xiru Proud, Christopher G. Jiang, Yuwu |
| Affiliation | Univ Southampton, Div Human Genet, Southampton Gen Hosp, Southampton SO16 6YD, Hants, England. Peking Univ, Dept Pediat, Hosp 1, Beijing 100034, Peoples R China. Shan Xi Med Univ, Dept Neurol, Taiyuan, Peoples R China. Univ Southampton, Div Human Genet, Southampton Gen Hosp, Duthie Bldg,Tremona Rd, Southampton SO16 6YD, Hants, England. |
| Keywords | Chinese childhood ataxia with central nervous system hypomyelination (CACH) eukaryotic translation initiation factor 2B (eIF2B) mutation vanishing white matter disease (VWM) FACTOR 2B COMPLEX PROTEIN-SYNTHESIS FACTOR EIF2B LEUKOENCEPHALOPATHY SUBUNIT LEUKODYSTROPHIES ACTIVATION SPECTRUM MUTANT GENES |
| Issue Date | 2011 |
| Publisher | journal of human genetics |
| Citation | JOURNAL OF HUMAN GENETICS.2011,56,(4),300-305. |
| 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 alpha-beta) are responsible for the disease, although the mechanism of the pathogenesis is not well understood. In our previous study, four novel eIF2B epsilon 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 epsilon, leading to almost complete loss-of-function. No evidence was obtained for the three missense mutations in changes in eIF2B epsilon protein level or eIF2B epsilon 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. Journal of Human Genetics (2011) 56, 300-305; doi:10.1038/jhg.2011.9; published online 10 February 2011 |
| URI | http://hdl.handle.net/20.500.11897/304469 |
| ISSN | 1434-5161 |
| DOI | 10.1038/jhg.2011.9 |
| Indexed | SCI(E) PubMed |
| Appears in Collections: | 第一医院 |
