Alternative titles; symbols
HGNC Approved Gene Symbol: EIF2B3
Cytogenetic location: 1p34.1 Genomic coordinates (GRCh38) : 1:44,850,522-44,986,595 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p34.1 | Leukoencephalopathy with vanishing white matter 3, with or without ovarian failure | 620313 | Autosomal recessive | 3 |
The EIF2B3 gene contains a subunit of eIF2B, a heteropentameric guanine nucleotide exchange factor necessary for the proper function of the translation initiation factor eIF2 (see 603907). EIF2B catalyzes the exchange of GDP for GTP (summary by Fogli et al., 2004).
Translation of mRNA usually requires modification of the 5-prime cap, but some viral and cellular mRNAs use a cap-independent mechanism of ribosome binding mediated by an internal ribosomal entry site (IRES). The 5-prime untranslated region of hepatitis C virus (HCV) is highly conserved in all strains and folds into an IRES that binds directly to 40S ribosome subunits. Among the relatively limited number of cellular cofactors binding to the HCV IRES/40S subunit is EIF2 (see 603907). Using a ribozyme-based selection system to identify cellular factors involved in HCV IRES function, followed by database searches and 5-prime RACE with ribozyme-binding sequences as primers, Kruger et al. (2000) isolated a cDNA encoding EIF2B3, which they called EIF2B-gamma. The deduced 452-amino acid protein is 91% identical to rat Eif2b-gamma.
Using human EST database searching and PCR, followed by screening of a rat cDNA library, Price et al. (1996) obtained a partial cDNA encoding human EIF2B3 and a full-length rat clone encoding Eif2b3. Northern blot analysis revealed wide expression of an approximately 1.8-kb Eif2b3 transcript in rat tissues.
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 (606454), EIF2B3, EIF2B4 (606687), and EIF2B5 (603945) 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.
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.
Gross (2015) mapped the EIF2B3 gene to chromosome 1p34.1 based on an alignment of the EIF2B3 sequence (GenBank BC018728) with the genomic sequence (GRCh38).
Leukoencephalopathy with vanishing white matter (VWM3; 620313) is an autosomal recessive disorder characterized by a chronic and 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 the translation initiation factor eIF2B can cause the disorder. Two mutations were found in the EIF2B3 gene in compound heterozygous state (606273.0001, 606273.0002); 1 was found in homozygosity (606273.0003).
In 5 of 11 unrelated Chinese patients with leukoencephalopathy with vanishing white matter, Wu et al. (2009) identified mutations in the EIF2B3 gene, including 4 patients with the same mutation (I346T; 606273.0004), of whom 2 were homozygotes.
In a 66-year old woman with adult-onset vanishing white matter disease, Ghezzi et al. (2012) identified a homozygous missense mutation (A87V; 606273.0003) in EIF2B3.
Variant Function
Using molecular modeling, Lee et al. (2021) found that 6 mutations in EIF2B3 in patients with VWM all caused misfolding and steric hindrance in the EIF2B3 protein, consistent with the altered unfolded protein response (UPR) pathway found in eif2b3 -/- zebrafish (see ANIMAL MODEL). Furthermore, none of 19 missense mutations in EIF2B3 associated with VWM in humans could rescue the morphologic phenotype of eif2b3 -/- zebrafish, validating the pathogenicity of the mutations.
In a 30-year-old Japanese woman, born of consanguineous parents, with adult-onset VWM, Matsukawa et al. (2011) identified a homozygous missense mutation in the EIF2B3 gene (L27Q; 606273.0005). In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing mutant EIF2B3 was significantly decreased (40% 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 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 EIF2B3 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
By RT-PCR and situ hybridization analyses, Lee et al. (2021) showed that eif2b3 was primarily expressed both maternally and zygotically in proliferating cells during early development of zebrafish. Lee et al. (2021) found that eif2b3 -/- and wildtype zebrafish had similar gross morphology until 3 days postfertilization (dpf). At 5 dpf, mutant fish had small eyes and heart edema, resulting in lethality by 8 dpf. Development of early nervous system was normal in mutant fish, as indicated by tail coiling movements, but myelin development and glial cell differentiation were defective. Moreover, expression of genes in the UPR pathway was increased in eif2b3 -/- fish, and mutant fish exhibited endoplasmic reticulum stress and ectopic angiogenesis.
In a patient (vwm91) with leukoencephalopathy with vanishing white matter (VWM3; 620313), van der Knaap et al. (2002) found compound heterozygosity for 2 mutations in the EIF2B3 gene: arg225 to gln (R225Q) and c.1295_1296delTG (606273.0002). The R225Q substitution was caused by a G-to-A transition in exon 6.
For discussion of the 2-bp deletion in the EIF2B3 gene (c.1295_1296delTG) that was found in compound heterozygous state in a patient with leukoencephalopathy with vanishing white matter (VWM3; 620313) by van der Knaap et al. (2002), see 606273.0001.
In a patient (vwm47) with leukoencephalopathy with vanishing white matter (VWM3; 620313), van der Knaap et al. (2002) found homozygosity for an ala87-to-val (A87V) substitution in the EIF2B3 gene, which resulted from a C-to-T transition at nucleotide 362 (c.362C-T) in exon 2.
Ghezzi et al. (2012) identified homozygosity for an A87V mutation in a 66-year-old woman with adult-onset VWM disease and a history of premature ovarian failure at 24 years. She had a 5-year history of progressive gait impairment and behavioral and cognitive disturbances and had experienced a rapid worsening of her clinical condition 10 days prior to evaluation.
In 4 of 11 unrelated Chinese patients with leukoencephalopathy with vanishing white matter (VWM3; 620313), Wu et al. (2009) identified a c.1037T-C transition in exon 9 of the EIF2B3 gene, resulting in an ile346-to-thr (I346T) substitution. The mutation was not observed in 100 control samples. Two patients (8 and 11) were homozygous for the mutation, 1 (7) was compound heterozygous with another pathogenic EIF2B3 mutation, and the second mutation could not be identified in the fourth patient (10).
In a 30-year-old Japanese woman (patient 3), born of consanguineous parents, with adult-onset leukoencephalopathy with vanishing white matter (VWM3; 620313), Matsukawa et al. (2011) identified a homozygous c.80T-A transversion in the EIF2B3 gene, resulting in a leu27-to-gln (L27Q) substitution. She developed secondary amenorrhea at age 28 years, left hemianopia at age 29, and weakness in her left leg after a fall. In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing mutant EIF2B was significantly decreased (40% 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.
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
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]
Ghezzi, L., Scarpini, E., Rango, M., Arighi, A., Bassi, M. T., Tenderini, E., De Riz, M., Jacini, F., Fumagalli, G. G., Pietroboni, A. M., Galimberti, D., Bresolin, N. A 66-year-old patient with vanishing white matter disease due to the p.Ala87Val EIF2B3 mutation. Neurology 79: 2077-2078, 2012. [PubMed: 23115207] [Full Text: https://doi.org/10.1212/WNL.0b013e3182749edc]
Gross, M. B. Personal Communication. Baltimore, Md. 5/28/2015.
Kruger, M., Beger, C., Li, Q.-X., Welch, P. J., Tritz, R., Leavitt, M., Barber, J. R., Wong-Staal, F. Identification of eIF2B-gamma and eIF2-gamma as cofactors of hepatitis C virus internal ribosome entry site-mediated translation using a functional genomics approach. Proc. Nat. Acad. Sci. 97: 8566-8571, 2000. [PubMed: 10900014] [Full Text: https://doi.org/10.1073/pnas.97.15.8566]
Lee, Y. R., Kim, S. H., Ben-Mahmoud, A., Kim, O. H., Choi, T. I., Lee, K. H., Ku, B., Eum, J., Kee, Y., Lee, S., Cha, J., Won, D., Lee, S. T., Choi, J. R., Lee, J. S., Kim, H. D., Kim, H. G., Bonkowsky, J. L., Kang, H. C., Kim, C. H. Eif2b3 mutants recapitulate phenotypes of vanishing white matter disease and validate novel disease alleles in zebrafish. Hum. Molec. Genet. 30: 331-342, 2021. [PubMed: 33517449] [Full Text: https://doi.org/10.1093/hmg/ddab033]
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]
Price, N. T., Kimball, S. R., Jefferson, L. S., Proud, C. G. Cloning of cDNA for the gamma-subunit of mammalian translation initiation factor 2B, the guanine nucleotide-exchange factor for eukaryotic initiation factor 2. Biochem. J. 318: 631-636, 1996. [PubMed: 8809057] [Full Text: https://doi.org/10.1042/bj3180631]
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. Note: Electronic Article. [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]
Wu, Y., Pan, Y., Du, L., Wang, J., Gu, Q., Gao, Z., Li, J., Leng, X., Qin, J., Wu, X., Jiang, Y. Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease. J. Hum. Genet. 54: 74-77, 2009. [PubMed: 19158808] [Full Text: https://doi.org/10.1038/jhg.2008.10]