Compound heterozygous mutations of two eIF2B genes in early childhood onset form of vanishing white matter disease
Abstract Background Diagnoses of vanishing white matter disease (VWMD) were difficult due to variable clinical features, severity, age of onset and wide range of mutations in eIF2G genes which cause VWMD. This study reported two novel mutations in eIF2B genes associated with VWMD to and expand our understanding of VWMD. Case presentation Relevant data from clinical diagnoses and genetic mutational analyses in two Chinese female patients with sporadic VWMD were collected and analyzed. Protein structure/function was predicted. The identity of biological parents was confirmed based on variants called from the next-generation sequencing (NGS) data. Compound heterozygous mutations, c.254 T>A (p.Val85Glu), and c.597+2delT in the EIF2B2 gene, c.545C>T(p.Thr182Met) and c.1340C>T(p.Ser447Leu) in the EIF2B5 gene were detected in the two patients. Further phenotype investigation of both patients enables the diagnosis of the vanishing white matter disease .Three missense mutation c.254 T>A (p.Val85Glu) in the EIF2B2 gene, c.545C>T(p.Thr182Met) and c.1340C>T(p.Ser447Leu) in the EIF2B5 gene have been found and predicted to be deleterious. All the three mutation causes hydrophobicity and stability changes of proteins, and all the mutations were localized in conserved sequences. One novel mutation of c.1340C>T(p.Ser447Leu) in the EIF2B5 gene ,and two other known mutations. The iterative threading assembly refinement (I-TASSER) server generated three-dimensional (3D) atomic models based on protein sequences from the novel missense mutation of c.1340C>T(p.Ser447Leu) in the EIF2B5 gene, which showed that the protein structure changed . The novel mutation c.597+2delT in the EIF2B2 gene may cause the splice site to disappear. We also analyzed mutations in missense mutations that cause VWMD and found that most of the t Pathogenic sites are localized in conserved NT and I-patch homology regions and the catalytic domain of EIF2Bε. Conclusions This study expands the spectrum of genotypes and phenotypes of VWMD and provides new insights into the molecular mechanism of VWMD and aide the acute diagnosis and treatment of VWMD.
