Details for: EIF2B2

Gene ID: 8892

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: EIF2B2

Ensembl ID: ENSG00000119718

Description: eukaryotic translation initiation factor 2B subunit beta

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • ciliated epithelial cell CL0000067
    CSI 5.26
    rCSI 4.63%
    PRS 76.8
  • CD4-positive, CD25-positive, alpha-beta regulatory T cell CL0000792
    CSI 5.01
    rCSI 4.92%
    PRS 95.74
  • double negative thymocyte CL0002489
    CSI 4.97
    rCSI 3.46%
    PRS 95.09
  • pro-B cell CL0000826
    CSI 4.73
    rCSI 3.92%
    PRS 88.23
  • type B pancreatic cell CL0000169
    CSI 4.55
    rCSI 10.07%
    PRS 86.18
  • effector CD8-positive, alpha-beta T cell CL0001050
    CSI 4.32
    rCSI 3.28%
    PRS 95.78
  • pulmonary ionocyte CL0017000
    CSI 4.28
    rCSI 5.21%
    PRS 91.04
  • neural crest cell CL0011012
    CSI 3.86
    rCSI 3.05%
    PRS 77.4
  • rod bipolar cell CL0000751
    CSI 3.78
    rCSI 6.8%
    PRS 80.68
  • perivascular cell CL4033054
    CSI 3.78
    rCSI 5.17%
    PRS 89.98
  • multi-ciliated epithelial cell CL0005012
    CSI 3.77
    rCSI 3.77%
    PRS 80.62
  • interneuron CL0000099
    CSI 3.73
    rCSI 7.49%
    PRS 78.75
  • granulocyte CL0000094
    CSI 3.72
    rCSI 5.68%
    PRS 91.55
  • precursor B cell CL0000817
    CSI 3.46
    rCSI 3.03%
    PRS 91.26
  • interstitial cell of Cajal CL0002088
    CSI 3.43
    rCSI 4.37%
    PRS 90.35
  • epithelial cell of lung CL0000082
    CSI 3.18
    rCSI 2.63%
    PRS 87.3
  • plasmacytoid dendritic cell, human CL0001058
    CSI 3.14
    rCSI 2.19%
    PRS 89.66
  • granulocyte monocyte progenitor cell CL0000557
    CSI 2.96
    rCSI 2.56%
    PRS 89.19
  • common myeloid progenitor CL0000049
    CSI 2.9
    rCSI 2.35%
    PRS 88.06
  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 2.89
    rCSI 2.61%
    PRS 84.88
  • hematopoietic stem cell CL0000037
    CSI 2.83
    rCSI 1.88%
    PRS 88.26
  • ionocyte CL0005006
    CSI 2.82
    rCSI 3.02%
    PRS 88.22
  • activated type II NK T cell CL0000931
    CSI 2.8
    rCSI 3.15%
    PRS 95.31
  • placental villous trophoblast CL2000060
    CSI 2.77
    rCSI 4.28%
    PRS 84.91
  • pulmonary capillary endothelial cell CL4028001
    CSI 2.71
    rCSI 5.17%
    PRS 93.23
  • stem cell CL0000034
    CSI 2.64
    rCSI 2.55%
    PRS 81.19
  • mesodermal cell CL0000222
    CSI 2.51
    rCSI 3.01%
    PRS 84.55
  • club cell CL0000158
    CSI 2.41
    rCSI 3.54%
    PRS 81.37
  • cerebral cortex endothelial cell CL1001602
    CSI 2.36
    rCSI 4.09%
    PRS 79.59
  • radial glial cell CL0000681
    CSI 2.35
    rCSI 3.26%
    PRS 84.65
  • early lymphoid progenitor CL0000936
    CSI 2.28
    rCSI 2.01%
    PRS 90.05
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 2.25
    rCSI 5.82%
    PRS 82.77
  • retinal bipolar neuron CL0000748
    CSI 2.18
    rCSI 4.09%
    PRS 76.47
  • colon epithelial cell CL0011108
    CSI 2.14
    rCSI 2.25%
    PRS 83.87
  • sst GABAergic cortical interneuron CL4023017
    CSI 2.09
    rCSI 2.7%
    PRS 72.04
  • peripheral nervous system neuron CL2000032
    CSI 2.02
    rCSI 2.75%
    PRS 78.98
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 1.92
    rCSI 3.38%
    PRS 70.35
  • neuroblast (sensu Vertebrata) CL0000031
    CSI 1.91
    rCSI 2.45%
    PRS 82.68
  • lung ciliated cell CL1000271
    CSI 1.89
    rCSI 2.18%
    PRS 79.96
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 1.81
    rCSI 2.26%
    PRS 68.68
  • promonocyte CL0000559
    CSI 1.69
    rCSI 2.9%
    PRS 89.88
  • dendritic cell, human CL0001056
    CSI 1.67
    rCSI 2.57%
    PRS 92.65
  • syncytiotrophoblast cell CL0000525
    CSI 1.66
    rCSI 4.78%
    PRS 89.31
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 1.62
    rCSI 2.72%
    PRS 70.88
  • mesenchymal cell CL0008019
    CSI 1.39
    rCSI 3.52%
    PRS 80.21
  • intermediate monocyte CL0002393
    CSI 1.33
    rCSI 2.01%
    PRS 90.78
  • retina horizontal cell CL0000745
    CSI 1.31
    rCSI 2%
    PRS 83.41
  • retinal cone cell CL0000573
    CSI 1.2
    rCSI 1.93%
    PRS 77.68
  • large pre-B-II cell CL0000957
    CSI 1.17
    rCSI 3.35%
    PRS 88.59
  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 1.16
    rCSI 1.41%
    PRS 66.57
  • helper T cell CL0000912
    CSI 1.14
    rCSI 1.61%
    PRS 83.31
  • platelet CL0000233
    CSI 0.96
    rCSI 3.96%
    PRS 83.23
  • endothelial cell of placenta CL0009092
    CSI 0.78
    rCSI 3.84%
    PRS 91.58
  • microcirculation associated smooth muscle cell CL0008035
    CSI 0.76
    rCSI 2.21%
    PRS 85.49
  • erythroid progenitor cell CL0000038
    CSI 0.56
    rCSI 3.2%
    PRS 89.59

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [EIF2B2](/details-gene/8892) encodes the beta subunit of the eukaryotic translation initiation factor 2B (eIF2B), a crucial guanyl-nucleotide exchange factor that recycles eIF2-GDP to its active, GTP-bound form. This function places [EIF2B2](/details-gene/8892) at a central control point for global protein synthesis. Its significance is highlighted in a wide range of metabolically active or proliferating cell types, including various immune cells, ciliated epithelia, and specialized secretory cells. Clinically, mutations in [EIF2B2](/details-gene/8892) are a primary cause of leukoencephalopathy with vanishing white matter (VWM), a severe, progressive neurological disorder, underscoring its indispensable role in central nervous system homeostasis, particularly in myelin-producing cells ([Link](https://doi.org/10.1038/ng764)). ## Cellular Roles and Expression Landscape The expression profile of [EIF2B2](/details-gene/8892) reflects its fundamental role in protein synthesis, showing high significance in cells with demanding translational requirements. **Overall**, its role as a key cellular component is most prominent in several distinct functional groups. First, it is highly significant in various epithelial populations, including [ciliated epithelial cell](/details-cell/CL0000067) (CSI: 5.26), [pulmonary ionocyte](/details-cell/CL0017000) (CSI: 4.28), and [multi-ciliated epithelial cell](/details-cell/CL0005012) (CSI: 3.77). This pattern suggests that cells responsible for barrier function, secretion, and motility rely heavily on the robust translational machinery in which [EIF2B2](/details-gene/8892) participates. Second, the gene is a key factor across multiple stages of lymphocyte development and function. High CSI values are observed in developing lymphocytes such as [double negative thymocyte](/details-cell/CL0002489) (CSI: 4.97) and [pro-B cell](/details-cell/CL0000826) (CSI: 4.73), as well as mature, functional populations like [CD4-positive, CD25-positive, alpha-beta regulatory T cell](/details-cell/CL0000792) (CSI: 5.01) and [effector CD8-positive, alpha-beta T cell](/details-cell/CL0001050) (CSI: 4.32). This is consistent with the high rates of protein synthesis required for immune cell proliferation, differentiation, and effector molecule production. Third, its importance is noted in specialized cell types with high metabolic or secretory activity, such as [type B pancreatic cell](/details-cell/CL0000169) (CSI: 4.55), and in developing or active neural cells like [neural crest cell](/details-cell/CL0011012) (CSI: 3.86) and [interneuron](/details-cell/CL0000099) (CSI: 3.73). This broad but significant expression pattern underscores its role as a ubiquitous and essential component for maintaining cellular function across diverse tissues. ## Pathways and Molecular Function Functionally, [EIF2B2](/details-gene/8892) is integral to the eIF2B complex, which exhibits `Guanyl-nucleotide exchange factor activity` ([GO:0005085](https://www.ebi.ac.uk/QuickGO/term/GO:0005085)). This activity is central to the process of `Translational initiation` ([GO:0006413](https://www.ebi.ac.uk/QuickGO/term/GO:0006413)) and is a rate-limiting step in `Cap-dependent translation initiation` ([R-HSA-72737](https://reactome.org/content/detail/R-HSA-72737)). The complex catalyzes the exchange of GDP for GTP on the eIF2 factor, a prerequisite for the delivery of initiator Met-tRNA to the ribosome, as detailed in the `Recycling of eif2:gdp` pathway ([R-HSA-72731](https://reactome.org/content/detail/R-HSA-72731)). The gene's annotations strongly link it to neurological function and disease. Its involvement in `Central nervous system development` ([GO:0007417](https://www.ebi.ac.uk/QuickGO/term/GO:0007417)), `Myelination` ([GO:0042552](https://www.ebi.ac.uk/QuickGO/term/GO:0042552)), and `Oligodendrocyte development` ([GO:0014003](https://www.ebi.ac.uk/QuickGO/term/GO:0014003)) provides a direct molecular basis for the severe leukoencephalopathy observed in patients with [EIF2B2](/details-gene/8892) mutations ([Link](https://doi.org/10.1002/humu.9325), [Link](https://doi.org/10.1016/j.gene.2011.12.047)). Furthermore, its annotation in the `T cell receptor signaling pathway` ([GO:0050852](https://www.ebi.ac.uk/QuickGO/term/GO:0050852)) aligns with its high significance in T cell populations, where rapid protein synthesis is required upon antigen recognition. ## Research Directions While [EIF2B2](/details-gene/8892) is a ubiquitously expressed housekeeping gene, its mutations result in a surprisingly tissue-specific pathology, primarily affecting the white matter of the brain. This discrepancy suggests a unique vulnerability of certain cell types, particularly oligodendrocytes, to perturbations in translational control. Based on the available data, several testable hypotheses can be proposed: 1. The high and sustained rate of protein synthesis required for myelin production and maintenance renders oligodendrocytes uniquely susceptible to hypomorphic mutations in [EIF2B2](/details-gene/8892). This vulnerability may be exacerbated by cellular stress, which further inhibits the eIF2B complex, leading to apoptosis and the 'vanishing white matter' phenotype. 2. Given its high significance in developing lymphocytes, such as [pro-B cell](/details-cell/CL0000826) and [double negative thymocyte](/details-cell/CL0002489), mutations in [EIF2B2](/details-gene/8892) may lead to subtle, yet clinically relevant, immune dysregulation that could contribute to disease progression or secondary complications in patients with VWM. A key experiment to test the first hypothesis would be to use patient-derived induced pluripotent stem cells (iPSCs) harboring known [EIF2B2](/details-gene/8892) mutations and differentiate them into oligodendrocytes. By comparing these patient-derived cells to isogenic, CRISPR-corrected controls, one could quantify differences in myelination capacity (e.g., in co-culture with neurons), overall protein synthesis rates using metabolic labeling (e.g., puromycin incorporation), and the activation of the integrated stress response pathway upon exposure to stressors like heat shock or tunicamycin. From a therapeutic perspective, [EIF2B2](/details-gene/8892) is a challenging target. As the associated diseases are caused by loss-of-function, therapeutic strategies should aim for **activation** or functional rescue rather than inhibition. The gene's essential, ubiquitous nature makes systemic modulation risky. However, approaches such as CNS-directed gene therapy to deliver a functional copy of the gene to neural progenitors or oligodendrocytes could be a viable long-term strategy. Additionally, the identification of small-molecule compounds that can enhance the activity of the eIF2B complex, as has been shown in the context of memory enhancement ([Link](https://doi.org/10.1126/science.aaa6986)), suggests that pharmacological potentiation of the remaining mutant eIF2B complex activity could be a promising avenue for treating VWM and related disorders.

Genular Protein ID: 4160899864

Symbol: EI2BB_HUMAN

Name: Translation initiation factor eIF2B subunit beta

UniProtKB Accession Codes:

P49770 O43201

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CORUM 1 CTD 1 ChiTaRS 1 ComplexPortal 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 4 EMDB 21 Ensembl 1 ExpressionAtlas 1 GO 18 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 5 OrthoDB 1 PANTHER 2 PDB 22 PDBsum 22 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 Reactome 1 RefSeq 1 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 SwissPalm 1 TreeFam 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 7596406

Title: Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.

PubMed ID: 7596406

DOI: 10.1038/375754a0

PubMed ID: 12508121

Title: The DNA sequence and analysis of human chromosome 14.

PubMed ID: 12508121

DOI: 10.1038/nature01348

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 22814378

Title: N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB.

PubMed ID: 22814378

DOI: 10.1073/pnas.1210303109

PubMed ID: 25858979

Title: Stress responses. Mutations in a translation initiation factor identify the target of a memory-enhancing compound.

PubMed ID: 25858979

DOI: 10.1126/science.aaa6986

PubMed ID: 27023709

Title: Expression, purification, and crystallization of Schizosaccharomyces pombe eIF2B.

PubMed ID: 27023709

DOI: 10.1007/s10969-016-9203-3

PubMed ID: 31048492

Title: Structural basis for eIF2B inhibition in integrated stress response.

PubMed ID: 31048492

DOI: 10.1126/science.aaw4104

PubMed ID: 11704758

Title: Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter.

PubMed ID: 11704758

DOI: 10.1038/ng764

PubMed ID: 12707859

Title: Ovarian failure related to eukaryotic initiation factor 2B mutations.

PubMed ID: 12707859

DOI: 10.1086/375404

PubMed ID: 15776425

Title: Identification of ten novel mutations in patients with eIF2B-related disorders.

PubMed ID: 15776425

DOI: 10.1002/humu.9325

PubMed ID: 21484434

Title: Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5.

PubMed ID: 21484434

DOI: 10.1007/s10048-011-0284-7

PubMed ID: 22285377

Title: Vanishing white matter disease caused by EIF2B2 mutation with the presentation of an adrenoleukodystrophy phenotype.

PubMed ID: 22285377

DOI: 10.1016/j.gene.2011.12.047

PubMed ID: 22729508

Title: Vanishing white matter disease: an Italian case with A638G mutation in exon 5 of EIF2B2 gene, an unusual early onset and a long course.

PubMed ID: 22729508

DOI: 10.1007/s10072-012-1129-3

PubMed ID: 26740508

Title: Identification of novel genetic causes of Rett syndrome-like phenotypes.

PubMed ID: 26740508

DOI: 10.1136/jmedgenet-2015-103568

Sequence Information:

  • Length: 351
  • Mass: 38990
  • Checksum: C29FE477143F545A
  • Sequence:
    • MPGSAAKGSE LSERIESFVE TLKRGGGPRS SEEMARETLG LLRQIITDHR WSNAGELMEL 
IRREGRRMTA AQPSETTVGN MVRRVLKIIR EEYGRLHGRS DESDQQESLH KLLTSGGLNE 
DFSFHYAQLQ SNIIEAINEL LVELEGTMEN IAAQALEHIH SNEVIMTIGF SRTVEAFLKE 
AARKRKFHVI VAECAPFCQG HEMAVNLSKA GIETTVMTDA AIFAVMSRVN KVIIGTKTIL 
ANGALRAVTG THTLALAAKH HSTPLIVCAP MFKLSPQFPN EEDSFHKFVA PEEVLPFTEG 
DILEKVSVHC PVFDYVPPEL ITLFISNIGG NAPSYIYRLM SELYHPDDHV L