Functional analysis of recently identified mutations in eukaryotic translation initiation factor 2Bε (eIF2Bε) 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 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