Alternative titles; symbols
HGNC Approved Gene Symbol: EIF2B4
Cytogenetic location: 2p23.3 Genomic coordinates (GRCh38) : 2:27,364,352-27,370,338 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p23.3 | Leukoencephalopathy with vanishing white matter 4, with or without ovarian failure | 620314 | Autosomal recessive | 3 |
EIF2B is a GTP exchange factor that is essential for protein synthesis. Its substrate is EIF2 (see 603907). EIF2B consists of alpha (EIF2B1; 606686), beta (EIF2B2; 606454), gamma (EIF2B3; 606273), delta (EIF2B4), and epsilon (EIF2B5; 603945) subunits.
By screening human genomic and cDNA libraries, followed by probing mouse cDNA libraries, Henderson et al. (1994) cloned cDNAs encoding 2 isoforms of mouse Eif2b4, one containing 544 amino acids and the other containing 524 amino acids. The isoforms differ at their N termini. Henderson et al. (1994) stated that the shorter isoform is present in rabbit and human cells. Northern blot analysis revealed wide expression of a 1.9-kb Eif2b4 transcript in mouse. Western blot analysis showed expression of an approximately 60-kD protein, close to the predicted size. Price et al. (1996) cloned a cDNA encoding rat Eif2b4. The 525-amino acid rat protein is 96% identical to the 524-amino acid mouse isoform.
Fogli et al. (2004) measured the guanine nucleotide exchange factor (GEF) activity of EIF2B in transformed lymphocytes from 30 patients with leukoencephalopathies (603896) with homozygous or compound heterozygous mutations in EIF2B2, EIF2B3, EIF2B4, and EIF2B5 compared to 10 unaffected heterozygotes and 22 controls with no EIF2B mutation. A significant decrease of 20 to 70% in GEF activity was observed in all mutated cells, and the extent of the decrease correlated with age at onset of disease. Fogli et al. (2004) suggested that a deficiency in GEF activity underlies the encephalopathy in EIF2B-related disease.
The integrated stress response (ISR) modulates mRNA translation to regulate the mammalian unfolded protein response (UPR), immunity, and memory formation. A chemical ISR inhibitor, ISRIB, enhances cognitive function and modulates the UPR in vivo. To explore mechanisms involved in ISRIB action, Sekine et al. (2015) screened cultured mammalian cells for somatic mutations that reversed its effect on the ISR. Clustered missense mutations were found at the amino-terminal portion of the delta subunit of GEF EIF2B (EIF2B4). When reintroduced by CRISPR-Cas9 gene editing of wildtype cells, these mutations reversed both ISRIB-mediated inhibition of the ISR and its stimulatory effect on EIF2B GEF activity toward its substrate, the translation initiation factor EIF2 (see EIF2A, 609234), in vitro. Sekine et al. (2015) concluded that ISRIB targets an interaction between EIF2 and EIF2B that lies at the core of the ISR.
Cryoelectron Microscopy
ISRIB is a drug-like eIF2B activator that reverses the effects of eIF2 phosphorylation. In rodents, it enhances cognition and corrects cognitive deficits after brain injury. To determine its mechanism of action, Tsai et al. (2018) solved an atomic-resolution structure of ISRIB bound in a deep cleft within decameric human eIF2B by cryoelectron microscopy. Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of 2 identical tetrameric subcomplexes involving EIF2B-beta (EIF2B2), -gamma (EIF2B3), -delta (EIF2B4), and -epsilon (EIF2B5), and ISRIB promoted this step by cross-bridging a central symmetry interface. Tsai et al. (2018) concluded that thus, regulation of eIF2B assembly emerges as a rheostat for eIF2B activity that tunes translation during the ISR and that can be further modulated by ISRIB.
Zyryanova et al. (2018) described a 4.1-angstrom resolution cryoelectron microscopy structure of human eIF2B with an ISRIB molecule bound at the interface between the beta and delta regulatory subunits. Mutagenesis of residues lining this pocket altered the hierarchic cellular response to ISRIB analogs in vivo and ISRIB binding in vitro. Zyryanova et al. (2018) concluded that their findings pointed to a site in eIF2B that can be exploited by ISRIB to regulate translation.
Gross (2015) mapped the EIF2B4 gene to chromosome 2p23.3 based on an alignment of the EIF2B4 sequence (GenBank BC091502) with the genomic sequence (GRCh38).
Leukoencephalopathy with vanishing white matter (VWM4; 620314) is an autosomal recessive disorder characterized by a chronic progressive course with additional episodes of rapid deterioration provoked by fever and minor head trauma. Van der Knaap et al. (2002) demonstrated that mutations in each of the 5 subunits of translation initiation factor eIF2B can cause this disorder, including mutations in the EIF2B4 gene.
Fogli et al. (2003) identified mutations in the EIF2B2, EIF2B4, and EIF2B5 genes in patients with VWM4 with ovarian failure, which they referred to as ovarioleukodystrophy.
In 3 patients with antenatal-onset encephalopathy, van der Knaap et al. (2003) performed mutational analysis of the EIF2B1-EIF2B5 genes and detected different novel homozygous missense mutations in EIF2B4: R483W (606687.0007) in sib patients 4 and 5, and A391D (606687.0008) in patient 6.
In a 12-month old Turkish boy with intractable seizures and VWM disease, Gungor et al. (2015) detected a homozygous missense mutation (R374C; 606687.0002) in exon 11 in the EIF2B4 gene.
By Sanger sequencing of all 5 EIF2B subunit genes, Kanbayashi et al. (2015) found compound heterozygosity for novel missense mutations in the EIF2B4 gene (M206T, 606687.0009 and I318V, 606687.0010) in a 59-year-old Japanese woman with adult-onset VWM disease. Amino acid ile318 is highly conserved through zebrafish, and met206 is highly conserved among mammals.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human EIF2B4 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a patient (vwm239) with leukoencephalopathy with vanishing white matter (VWM4; 620314), van der Knaap et al. (2002) found compound heterozygosity for 2 mutations in the EIF2B4 gene: an arg357 to gln (R357Q) mutation and an arg374 to cys (R374C; 606687.0002) mutation, both in exon 11.
For discussion of the arg374-to-cys (R374C) mutation in the EIF2B4 gene that was found in compound heterozygous state in patient vwm239 with leukoencephalopathy with vanishing white matter (VWM4; 620314) by van der Knaap et al. (2002), see 606687.0001.
In a 12-month old Turkish boy with intractable seizures and vanishing white matter disease, Gungor et al. (2015) detected a homozygous c.1091G-A substitution in exon 11 in the EIF2B4 gene resulting in a R374C substitution. The mutation was identified by next-generation sequencing and confirmed by Sanger sequencing.
In a patient (vwm244) with leukoencephalopathy with vanishing white matter (VWM4; 620314), van der Knaap et al. (2002) found compound heterozygosity for 2 mutations in the EIF2B4 gene: a splice site mutation, IVS11+1G-A, which resulted in the insertion of 11 amino acids following glu397; and an ala228-to-val (A228V) mutation in exon 7 (606687.0004).
For discussion of the ala228-to-val (A228V) mutation in the EIF2B4 gene that was found in compound heterozygous state in patient vwm244 with leukoencephalopathy with vanishing white matter (VWM4; 620314) by van der Knaap et al. (2002), see 606687.0003.
In 2 sisters (941-1 and 941-2) with vanishing white matter leukodystrophy and ovarian failure (VWM4; 620314), Fogli et al. (2003) found compound heterozygosity for a c.1393C-T transition in the EIF2B4 gene, resulting in a cys465-to-arg (C465R) mutation, and a c.1465C-T transition resulting in a tyr489-to-his mutation (Y489H; 606687.0006). They were examined at 23 and 24 years of age, respectively. Both had had difficulties in school. In both there was spasticity of gait and gait instability having begun at ages 10 and 15 years, respectively; 1 required the use of a walker at age 16 years. Optic atrophy was present in both. Cognitive function was mildly to moderately reduced.
For discussion of the tyr489-to-his (Y489H) mutation in the EIF2B4 gene that was found in compound heterozygous state in 2 sisters with vanishing white matter leukodystrophy and ovarian failure (VWM4; 620314) by Fogli et al. (2003), see 606687.0005.
In sibs (patients 4 and 5) with antenatal-onset leukoencephalopathy (VWM4; 620314), van der Knaap et al. (2003) detected a novel homozygous c.1447C-T transition in the EIF2B4 gene resulting in an arg483-to-trp (R483W) substitution. The brother and sister had fetal growth retardation, oligohydramnios, and microcephaly noted at birth. Their clinical course deteriorated with feeding difficulties, vomiting, apathy, axial hypotonia, hypertonia and hyperreflexia of the extremities, seizures, and ultimately apneic events. The patients died at 3.5 and 4 months of age, respectively. Arginine-483 is conserved in mammals only but the mutation to tryptophan is likely to result in a substantial alteration in the 3-dimensional structure of the protein, since tryptophan is a more bulky amino acid.
In an infant girl (patient 6) with antenatal-onset leukoencephalopathy (VWM4; 620314), van der Knaap et al. (2003) detected a novel homozygous c.1172C-A transversion in the EIF2B4 gene resulting in an ala391-to-asp (A391D) substitution. She had a history of growth retardation and oligohydramnios noted at 31 weeks' gestation. She was born at 38 weeks' gestation with microcephaly, bilateral cataracts, and mild contractures. Her clinical course was significant for impaired swallowing, failure to thrive, myoclonic convulsions, and absence of psychomotor development. Aspiration pneumonia led to death at 10 months of age.
In a 59-year old Japanese woman with adult-onset vanishing white matter disease (VWM4; 620314), Kanbayashi et al. (2015) detected compound heterozygosity for mutations in the EIF2B4 gene: a c.617T-C transition in exon 7 resulting in a met206-to-thr (M206T) substitution, and a c.952A-G transition in exon 10 resulting in an ile318-to-val (I318V; 606687.0008) substitution. The mutation was identified by Sanger sequencing of all 5 EIF2B subunit genes. She presented with gait unsteadiness and forgetfulness at age 56 years. She had no history of episodic neurologic deterioration evoked by stresses. Her childhood development was described as normal and she had no history of ovarian failure.
For discussion of the ile318-to-val (I318V) mutation in the EIF2B4 gene that was found in compound heterozygous state in a 59-year old Japanese woman with adult-onset vanishing white matter leukodystrophy (VWM4; 620314) by Kanbayashi et al. (2015), see 606687.0009.
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Gross, M. B. Personal Communication. Baltimore, Md. 5/28/2015.
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Tsai, J. C., Miller-Vedam, L. E., Anand, A. A., Jaishankar, P., Nguyen, H. C., Renslo, A. R., Frost, A., Walter, P. Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule. Science 359: eaaq0939, 2018. [PubMed: 29599213] [Full Text: https://doi.org/10.1126/science.aaq0939]
van der Knaap, M. S., Leegwater, P. A. J., Konst, A. A. M., Visser, A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C. Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann. Neurol. 51: 264-270, 2002. [PubMed: 11835386] [Full Text: https://doi.org/10.1002/ana.10112]
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