Alternative titles; symbols
HGNC Approved Gene Symbol: EIF2B2
Cytogenetic location: 14q24.3 Genomic coordinates (GRCh38) : 14:75,002,921-75,012,366 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q24.3 | Leukoencephalopathy with vanishing white matter 2, with or without ovarian failure | 620312 | Autosomal recessive | 3 |
Eukaryotic initiation factor-2B (EIF2B) is a GTP exchange protein essential for protein synthesis. It consists of alpha (EIF2B1; 606686), beta (EIF2B2), gamma (EIF2B3; 606273), delta (EIF2B4; 606687), and epsilon (EIF2B5; 603945) subunits. EIF2B activates its EIF2 (see 603907) substrate by exchanging EIF2-bound GDP for GTP.
By sequence database analysis, Pavitt et al. (1997) obtained a full-length cDNA clone encoding EIF2B2.
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.
Leegwater et al. (2001) determined that the EIF2B2 gene contains 8 exons.
Cryoelectron Microscopy
Integrated stress response inhibitor (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 EIF2B2 gene to chromosome 14q24.3 based on an alignment of the EIF2B2 sequence (GenBank BC000494) with the genomic sequence (GRCh38).
In patients with leukoencephalopathy with vanishing white matter (VWM2; 620312), Leegwater et al. (2001) demonstrated mutations in the EIF2B2 gene (e.g., E213G, 606454.0001). Leegwater et al. (2001) noted that VWM is most often caused by mutations in the EIF2B5 gene (603945).
Fogli et al. (2003) identified mutations in the EIF2B2 (e.g., R183X, 606454.0003), EIF2B4, and EIF2B5 genes in patients with VWM with ovarian failure, which they referred to as ovarioleukodystrophy.
In 3 sisters with VWM2, van der Knaap et al. (2003) identified compound heterozygosity for 2 novel mutations in the EIF2B2 gene, G200V and P291S, each of which was inherited from an unaffected parent.
In a 56-year-old Japanese woman, born of consanguineous parents, with adult-onset VWM2, Matsukawa et al. (2011) identified a homozygous missense mutation in the EIF2B2 gene (V85E; 606454.0006).
In a 56-year-old Japanese woman, born of consanguineous parents, with adult-onset VWM (603896), Matsukawa et al. (2011) identified a homozygous missense mutation in the EIF2B2 gene (V85E; 606454.0006). In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing mutant EIF2B2 was significantly decreased (20% decrease) compared to wildtype, although the decrease was not as much as observed in mutations associated with childhood-onset VWM. The findings suggested that mutations that result in residual eIF2B activity may be associated with a later age at disease onset.
In 2 distantly related individuals (patients vwm63 and vwm203) with leukoencephalopathy with vanishing white matter (VWM2; 620312), Leegwater et al. (2001) found homozygosity for a c.638A-G transition (c.638A-G, NM_014239) in exon 5 of the EIF2B2 gene that resulted in an glu213-to-gly (E213G) amino acid substitution. Heterozygosity for the same mutation was found in a patient from the United States (vwm206) with VWM who shared a part of the haplotype on 14q24 with the homozygous patients observed in Europe, suggesting a familial relationship. The second mutation was a c.947T-A transversion in exon 8 that resulted in a V316D amino acid substitution (606454.0002). The Dutch patients with VWM due to the mutation in EIF2B2 came from the southern part of the Netherlands rather than the eastern part, where the patients with the T91A mutation in the EIF2B5 gene (603945.0001) lived.
In a 16-year-old girl (patient 992) with white matter abnormalities and primary amenorrhea who had slowly progressive neurologic disease in adolescence, Fogli et al. (2003) identified the E213G mutation in compound heterozygous state with a c.547C-T transition resulting in an arg183-to-ter substitution (R183X; 606454.0003)
For discussion of the c.947T-A transversion (c.947T-A, NM_014239) in exon 8 of the EIF2B2 gene that resulted in a val316-to-asp (V316D) amino acid substitution that was found in compound heterozygous state in a patient (vwm206) with leukoencephalopathy with vanishing white matter (VWM2; 620312) by Leegwater et al. (2001), see 606454.0001.
For discussion of the c.547C-T transition in the EIF2B2 gene that resulted in an arg183-to-ter (R183X) amino acid substitution that was found in compound heterozygous state in a 16-year-old girl (patient 992) with primary amenorrhea and white matter abnormalities confirmed by MRI (VWM2; 620312) by Fogli et al. (2003), see 606454.0001.
In a 33-year old woman (patient 944) with vanishing white matter and ovarian failure (VWM2; 620312), Fogli et al. (2003) identified compound heterozygosity for a c.512C-T transition in the EIF2B2 gene resulting in a ser171-to-phe amino acid substitution (S171F), and a 6-bp deletion (ATGGCT)/2-bp insertion (TG) at nucleotide 607, resulting in a frameshift at met203 (606454.0005). Secondary amenorrhea occurred at age 26 years in the patient.
For discussion of the 6-bp deletion (ATGGCT)/2-bp insertion (TG) in the EIF2B2 gene that was found in compound heterozygous state in a 33-year-old woman (patient 944) with white matter leukodystrophy and ovarian failure (VWM2; 620312) by Fogli et al. (2003), see 606454.0004.
In a 56-year-old Japanese woman (case 1), born of consanguineous parents, with adult-onset leukoencephalopathy with vanishing white matter (VWM2; 620312), Matsukawa et al. (2011) identified a homozygous c.375T-A transversion in the EIF2B2 gene, resulting in a val85-to-glu (V85E) substitution. She had a history of amenorrhea and juvenile cataracts in her twenties, and developed progressive unsteadiness of the upper and lower limbs at age 43. Forgetfulness appeared at age 54. In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing mutant EIF2B2 was significantly decreased (20% decrease) compared to wildtype, although the decrease was not as much as observed in mutations associated with childhood-onset VWM. The findings suggested that mutations that result in residual eIF2B activity may be associated with a later age at disease onset.
Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O. Ovarian failure related to eukaryotic initiation factor 2B mutations. Am. J. Hum. Genet. 72: 1544-1550, 2003. [PubMed: 12707859] [Full Text: https://doi.org/10.1086/375404]
Fogli, A., Schiffmann, R., Hugendubler, L., Combes, P., Bertini, E., Rodriguez, D., Kimball, S. R., Boespflug-Tanguy, O. Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients. Europ. J. Hum. Genet. 12: 561-566, 2004. [PubMed: 15054402] [Full Text: https://doi.org/10.1038/sj.ejhg.5201189]
Gross, M. B. Personal Communication. Baltimore, Md. 5/28/2015.
Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nature Genet. 29: 383-388, 2001. [PubMed: 11704758] [Full Text: https://doi.org/10.1038/ng764]
Matsukawa, T., Wang, X., Liu, R., Wortham, N. C., Onuki, Y., Kubota, A., Hida, A., Kowa, H., Fukuda, Y., Ishiura, H., Mitsui, J., Takahashi, Y., Aoki, S., Takizawa, S., Shimizu, J., Goto, J., Proud, C. G., Tsuji, S. Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5. Neurogenetics 12: 259-261, 2011. [PubMed: 21484434] [Full Text: https://doi.org/10.1007/s10048-011-0284-7]
Pavitt, G. D., Yang, W., Hinnebusch, A. G. Homologous segments in three subunits of the guanine nucleotide exchange factor eIF2B mediate translational regulation by phosphorylation of eIF2. Molec. Cell. Biol. 17: 1298-1313, 1997. [PubMed: 9032257] [Full Text: https://doi.org/10.1128/MCB.17.3.1298]
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., van Berkel, C. G. M., Herms, J., van Coster, R., Baethmann, M., Naidu, S., Boltshauser, E., Willemsen, M. A. A. P., Plecko, B., Hoffmann, G. F., Proud, C. G., Scheper, G. C., Pronk, J. C. eIF2B-related disorders: antenatal onset and involvement of multiple organs. Am. J. Hum. Genet. 73: 1199-1207, 2003. [PubMed: 14566705] [Full Text: https://doi.org/10.1086/379524]
Zyryanova, A. F., Weis, F., Faille, A., Alard, A. A., Crespillo-Casado, A., Sekine, Y., Harding, H. P., Allen, F., Parts, L., Fromont, C., Fischer, P. M., Warren, A. J., Ron, D. Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science 359: 1533-1536, 2018. [PubMed: 29599245] [Full Text: https://doi.org/10.1126/science.aar5129]