Alternative titles; symbols
HGNC Approved Gene Symbol: EIF2B1
Cytogenetic location: 12q24.31 Genomic coordinates (GRCh38) : 12:123,620,406-123,633,686 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.31 | Leukoencephalopathy with vanishing white matter 1, with or without ovarian failure | 603896 | Autosomal recessive | 3 |
The EIF2B1 gene encodes EIF2B-alpha, the smallest subunit of the eukaryotic translation initiation factor eIF2B, which is a heterodecameric complex comprising 5 subunits: alpha (EIF2B1), beta (EIF2B2; 606454), gamma (EIF2B3; 606273), delta (EIF2B4; 606687), and epsilon (EIF2B5; 603945). EIF2B is a GTP exchange factor that is essential for protein synthesis: its substrate is eIF2 (see 603907). GTP-bound eIF2 is responsible for loading the initiator methionyl-tRNA onto the ribosome to allow initiation of protein synthesis to take place. EIF2B-alpha, -beta, and -delta form the regulatory subcomplex, whereas EIF2B-gamma and -epsilon form the catalytic subcomplex (summary by Wortham and Proud, 2015).
Flowers et al. (1995) cloned a rat cDNA encoding Eif2b1. The deduced 305-amino acid rat protein (GenBank AAA91276) is 92% identical to the human protein (Converse, 2002). By Northern blot analysis, Flowers et al. (1995) detected equivalent expression of rat Eif2b1 in all tissues tested; in contrast, Eif2b5 is predominantly expressed in testis.
By genomic sequence analysis, Flowers et al. (1995) determined that the rat Eif2b1 gene has 9 exons and spans 8.5 kb.
Cryoelectron Microscopy
Kenner et al. (2019) reported cryoelectron microscopy structures of eIF2 bound to eIF2B in the dephosphorylated state. The structures revealed that the eIF2B decamer is a static platform upon which 1 or 2 flexible eIF2 trimers bind and align with eIF2B's bipartite catalytic centers to catalyze nucleotide exchange. Phosphorylation refolds eIF2-alpha (603907), allowing it to contact eIF2B at a different interface and, the authors surmised, thereby sequestering it into a nonproductive complex.
To elucidate how eIF2 phosphorylation status regulates the eIF2B activity, Kashiwagi et al. (2019) determined cryoelectron microscopic and crystallographic structures of eIF2B in complex with unphosphorylated or phosphorylated eIF2. The unphosphorylated and phosphorylated forms of eIF2 bind to eIF2B in completely different manners: the nucleotide exchange-active and -inactive modes, respectively. Kashiwagi et al. (2019) concluded that these structures explained how phosphorylated eIF2 dominantly inhibits the nucleotide exchange activity of eIF2B.
Gross (2015) mapped the EIF2B1 gene to chromosome 12q24.31 based on an alignment of the EIF2B1 sequence (GenBank BC103763) with the genomic sequence (GRCh38).
Leukoencephalopathy with vanishing white matter (VWM1; 603896) 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. In a patient with VWM1, van der Knaap et al. (2002) found compound heterozygosity for 2 mutations in the EIF2B1 gene (606686.0001 and 606686.0002).
In 2 sisters with a moderate form of VWM1, Ohlenbusch et al. (2005) identified a homozygous missense mutation in the EIF2B1 gene (V183F; 606686.0003). These patients were reported to have ovarian failure. Functional studies of the variant were not performed.
In a patient with leukoencephalopathy with vanishing white matter, Maletkovic et al. (2008) identified compound heterozygous mutations in the EIF2B1 gene (606686.0005 and 606686.0006). Functional studies of the variants were not performed. The patient was 1 of 15 VWM patients with mutations in 1 of the EIF2B genes. The authors noted that mutations in the EIF2B1 gene account for only approximately 4% of all reported mutations and are found in approximately 1% of patients reported with EIF2B-related disorders.
Variant Function
In in vitro functional expression studies, Wortham and Proud (2015) found that the V183F (606686.0003), gly204del (606686.0005), and Y275C (606686.0006) EIF2B1 mutations affected formation of the EIF2B complex. Gly204del was unable to interact with any of the other subunits in the complex, whereas V183F and Y275C led to a 50% reduction in binding to the rest of the complex, which was presumed to result in decreased catalytic activity of the overall complex. Further activity studies showed a 30% decrease in EIF2B GEF activity for the V183F mutant. The N208Y mutation (606686.0002) resulted in a 40% increase in EIF2B GEF activity compared to wildtype, whereas P278R (606686.0004) had no effect on GEF activity. The results indicated that different mutations in the EIF2B1 gene have a wide variety of effects on the EIF2B complex, rendering it difficult to interpret pathogenic effects.
In a patient with leukoencephalopathy with vanishing white matter (VWM1; 603896), van der Knaap et al. (2002) found compound heterozygosity for 2 mutations in the EIF2B1 gene: IVS2+1G-A and a 622A-T transversion in exon 6, causing an asn208-to-tyr (N208Y) missense change in the polypeptide (606686.0002).
For discussion of the asn208-to-tyr (N208Y) mutation in the EIF2B1 gene that was found in compound heterozygous state in a patient with leukoencephalopathy with vanishing white matter (VWM1; 603896) by van der Knaap et al. (2002), see 606686.0001.
In in vitro functional studies, Wortham and Proud (2015) found that the N208Y mutation resulted in a 40% increase in EIF2B GEF activity.
In 2 sisters (patients 3252 and 3253) with leukoencephalopathy with vanishing white matter (VWM1; 603896), Ohlenbusch et al. (2005) identified a homozygous c.547G-T transversion (c.547G-T, NM_001414.1) in the EIF2B1 gene, resulting in a val183-to-phe (V183F) substitution at a highly conserved residue. The unaffected parents were heterozygous for the mutation, which was not found in 100 controls. The girls presented at ages 10 and 17 years, respectively, with a history of mental retardation and cognitive and behavioral signs. They had a stable disease course, with brain and ovarian involvement; they were moderately disabled. Functional studies of the variant were not performed.
In in vitro functional expression studies, Wortham and Proud (2015) found that the V183F mutation affected formation of the EIF2B complex and led to a 50% reduction in binding to the rest of the complex, which was presumed to result in decreased catalytic activity of the overall complex. Further activity studies showed a 30% decrease in EIF2B GEF activity for the V183F mutant.
In a review of leukoencephalopathy with vanishing white matter (VWM1; 603896), Pronk et al. (2006) reported a patient with a c.833C-G transversion in the EIF2B1 gene, resulting in a pro278-to-arg (P278R) substitution. Clinical details and functional studies of the variant were not provided. (In the article by Pronk et al. (2006), this mutation is incorrectly given as P287R.)
In in vitro functional expression studies, Wortham and Proud (2015) found that the P278R mutation had no effect on GEF activity.
In a patient with leukoencephalopathy with vanishing white matter (VWM1; 603896), Maletkovic et al. (2008) identified compound heterozygous mutations in the EIF2B1 gene: an in-frame 3-bp deletion (c.610_612), resulting in the deletion of residue gly204, and a c.824A-G transition, resulting in a tyr275-to-cys (Y275C; 606686.0006) substitution at a conserved residue. The mutations were not found in 48 control chromosomes. Clinical details of the patient and functional studies of the variants were not provided.
In in vitro functional expression studies, Wortham and Proud (2015) found that the gly204del mutation affected formation of the EIF2B complex; the mutant protein was unable to interact with any of the other subunits in the complex.
For discussion of the c.824A-G transition in the EIF2B1 gene, resulting in a tyr275-to-cys (Y275C) substitution that was found in compound heterozygous state in a patient with leukoencephalopathy with vanishing white matter (VWM1; 603896) by Maletkovic et al. (2008), see 606686.0005.
In a 61-year-old Japanese woman, born of consanguineous parents, with leukoencephalopathy with vanishing white matter (VWM1; 603896), Shimada et al. (2015) identified a homozygous c.715T-G transversion in exon 8 of the EIF2B1 gene, resulting in a phe239-to-val (F239V) substitution. The mutation was not present in the dbSNP (build 138) database; segregation of the mutation in the family was not confirmed, and functional studies were not performed. The patient presented with neurologic symptoms with gait disturbances at age 29 years. She also had mild cognitive impairment (IQ of 66), motor incoordination, spasticity, and seizures. Brain imaging showed nonspecific white matter abnormalities. The disorder was progressive, and she was bedridden at the time of the report.
In a 2-year-old Chinese girl (case 29) with early-childhood onset of leukoencephalopathy with vanishing white matter (VWM1; 603896), Zhang et al. (2015) identified a homozygous c.328A-G transition (c.328A-G, NM_001414) in exon 4 of the EIF2B1 gene, resulting in a lys110-to-glu (KL110E) substitution. Functional studies of the variant were not performed. The patient had seizures, episodic aggravation, and progressive significant loss of motor function on follow-up about a year later. The patient was 1 (3%) of a cohort of 34 patients with the disorder who underwent sequencing of EIF2B genes, and was the only patient who carried an EIF2B1 mutation.
Converse, P. J. Personal Communication. Baltimore, Md. 2/12/2002.
Flowers, K. M., Mellor, H., Kimball, S. R., Jefferson, L. S. Structure and sequence of the gene encoding the alpha-subunit of rat translation initiation factor-2B. Biochim. Biophys. Acta 1264: 163-167, 1995. [PubMed: 7495858] [Full Text: https://doi.org/10.1016/0167-4781(95)00160-i]
Gross, M. B. Personal Communication. Baltimore, Md. 5/28/2015.
Kashiwagi, K., Yokoyama, T., Nishimoto, M., Takahashi, M., Sakamoto, A., Yonemochi, M., Shirouzu, M., Ito, T. Structural basis for eIF2B inhibition in integrated stress response. Science 364: 495-499, 2019. [PubMed: 31048492] [Full Text: https://doi.org/10.1126/science.aaw4104]
Kenner, L. R., Anand, A. A., Nguyen, H. C., Myasnikov, A. G., Klose, C. J., McGeever, L. A., Tsai, J. C., Miller-Vedam, L. E., Walter, P., Frost, A. eIF2B-catalyzed nucleotide exchange and phosphoregulation by the integrated stress response. Science 364: 491-495, 2019. [PubMed: 31048491] [Full Text: https://doi.org/10.1126/science.aaw2922]
Maletkovic, J., Schiffmann, R., Gorospe, J. R., Gordon, E. S., Mintz, M., Hoffman, E. P., Alper, G., Lynch, D. R., Singhal, B. S., Harding, C., Amartino, H., Brown, C. M., and 12 others. Genetic and clinical heterogeneity in eIF2B-related disorder. J. Child Neurol. 23: 205-215, 2008. [PubMed: 18263758] [Full Text: https://doi.org/10.1177/0883073807308705]
Ohlenbusch, A., Henneke, M., Brockmann, K., Goerg, M., Hanefeld, F., Kohlschutter, A., Gartner, J. Identification of ten novel mutations in patients with eIF2B-related disorders. Hum. Mutat. 25: 411, 2005. [PubMed: 15776425] [Full Text: https://doi.org/10.1002/humu.9325]
Pronk, J. C., van Kollenburg, B., Scheper, G. C., van der Knaap, M. S. Vanishing white matter disease: a review with focus on its genetics. Ment. Retard. Dev. Disabil. Res. Rev. 12: 123-128, 2006. [PubMed: 16807905] [Full Text: https://doi.org/10.1002/mrdd.20104]
Shimada, S., Shimojima, K., Sangu, N., Hoshino, A., Hachiya, Y., Ohto, T., Hashi, Y., Nishida, K., Mitani, M., Kinjo, S., Tsurusaki, Y., Matsumoto, N., Morimoto, M., Yamamoto, T. Mutations in the genes encoding eukaryotic translation initiation factor 2B in Japanese patients with vanishing white matter disease. Brain Dev. 37: 960-966, 2015. [PubMed: 25843247] [Full Text: https://doi.org/10.1016/j.braindev.2015.03.003]
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]
Wortham, N. C., Proud, C. G. Biochemical effects of mutations in the gene encoding the alpha subunit of eukaryotic initiation factor (EIF) 2B associated with vanishing white matter disease. BMC Med. Genet. 16: 64, 2015. Note: Electronic Article. [PubMed: 26285592] [Full Text: https://doi.org/10.1186/s12881-015-0204-z]
Zhang, H., Dai, L., Chen, N., Zang, L., Leng, X., Du, L., Wang, J., Jiang, Y., Zhang, F., Wu, X., Wu, Y. Fifteen novel EIF2B1-5 mutations identified in Chinese children with leukoencephalopathy with vanishing white matter and a long term follow-up. PLoS One 10: e0118001, 2015. Note: Electronic Article. [PubMed: 25761052] [Full Text: https://doi.org/10.1371/journal.pone.0118001]