EIF2B4

EIF2B4

Introduction

Eif2B4 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-gene"> [@eifb2010]
<table> [@therapeutic2020]
<tr><th>Gene Symbol</th><td>EIF2B4</td></tr> [@eifb2019]
<tr><th>Full Name</th><td>Eukaryotic Translation Initiation Factor 2B Subunit Delta</td></tr> [@vwm2017]
<tr><th>Chromosomal Location</th><td>2p23.3</td></tr> [@integrated2021]
<tr><th>NCBI Gene ID</th><td><a href="https://www.ncbi.nlm.nih.gov/gene/8715" target="_blank">8715</a></td></tr>
<tr><th>OMIM</th><td><a href="https://www.omim.org/entry/606080" target="_blank">606080</a></td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000109771</td></tr>
<tr><th>UniProt ID</th><td><a href="https://www.uniprot.org/uniprot/P35228" target="_blank">P35228</a></td></tr>
<tr><th>Associated Diseases</th><td>[Vanishing White Matter Disease](/diseases/vanishing-white-matter-disease), [Leukoencephalopathy](/diseases/leukoencephalopathy)</td></tr>
</table>
</div>

Overview

EIF2B4 (Eukaryotic Translation Initiation Factor 2B Subunit Delta) is a critical gene encoding one of the five subunits of eIF2B, the guanine nucleotide exchange factor that recycles eIF2-GDP to eIF2-GTP. This process is essential for translational initiation in all eukaryotic cells.

...

EIF2B4

Introduction

Eif2B4 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-gene"> [@eifb2010]
<table> [@therapeutic2020]
<tr><th>Gene Symbol</th><td>EIF2B4</td></tr> [@eifb2019]
<tr><th>Full Name</th><td>Eukaryotic Translation Initiation Factor 2B Subunit Delta</td></tr> [@vwm2017]
<tr><th>Chromosomal Location</th><td>2p23.3</td></tr> [@integrated2021]
<tr><th>NCBI Gene ID</th><td><a href="https://www.ncbi.nlm.nih.gov/gene/8715" target="_blank">8715</a></td></tr>
<tr><th>OMIM</th><td><a href="https://www.omim.org/entry/606080" target="_blank">606080</a></td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000109771</td></tr>
<tr><th>UniProt ID</th><td><a href="https://www.uniprot.org/uniprot/P35228" target="_blank">P35228</a></td></tr>
<tr><th>Associated Diseases</th><td>[Vanishing White Matter Disease](/diseases/vanishing-white-matter-disease), [Leukoencephalopathy](/diseases/leukoencephalopathy)</td></tr>
</table>
</div>

Overview

EIF2B4 (Eukaryotic Translation Initiation Factor 2B Subunit Delta) is a critical gene encoding one of the five subunits of eIF2B, the guanine nucleotide exchange factor that recycles eIF2-GDP to eIF2-GTP. This process is essential for translational initiation in all eukaryotic cells.

EIF2B4 mutations are associated with vanishing white matter disease (VWM), an autosomal recessive leukoencephalopathy. The gene is ubiquitously expressed with high levels in brain white matter.

Function

EIF2B4 encodes the delta subunit of eukaryotic translation initiation factor 2B (eIF2B), the guanine nucleotide exchange factor (GEF) that recycles eIF2-GDP to eIF2-GTP. This reaction is essential for translation initiation as it generates the active ternary complex (eIF2-GTP-Met-tRNAi) required for start codon recognition[@structure2015].

The eIF2B complex is a heterodecamer composed of two copies each of five subunits (alpha, beta, gamma, delta, epsilon). The delta subunit plays a structural role in maintaining complex integrity. eIF2B serves as the master regulator of the integrated stress response (ISR), where phosphorylation of eIF2alpha at Ser51 inhibits eIF2B activity, leading to translational attenuation while selectively enhancing expression of stress-response genes such as ATF4[@eifb2010].

Disease Associations

Vanishing White Matter Disease (VWM)

Mutations in EIF2B4 are a well-established cause of vanishing white matter disease (VWM), accounting for a significant portion of cases. VWM is characterized by progressive cerebellar ataxia, spasticity, and cognitive decline, with characteristic MRI findings of diffuse white matter rarefaction[@therapeutic2020].

The pathophysiology involves impaired eIF2B function leading to defective stress response in oligodendrocytes. This compromises the ability of these myelinating cells to handle various cellular stresses, ultimately resulting in myelin vacuolization and loss[@eifb2019].

Expression

EIF2B4 shows ubiquitous expression with high levels in brain tissue. Within the central nervous system, the protein is expressed in oligodendrocytes, [astrocytes](/entities/astrocytes), and [neurons](/entities/neurons). The cytoplasmic localization is essential for its function in translation initiation regulation[@vwm2017].

Key Publications

[Structure of the eIF2B decameric GEF complex (2015)](https://doi.org/10.1038/nature14888)

[EIF2B4 mutations in VWM: clinical spectrum (2010)](https://pubmed.ncbi.nlm.nih.gov/20401335/)

[Therapeutic approaches to VWM disease (2020)](https://doi.org/10.1016/j.pharmthera.2020.107684)

[eIF2B and translational control in stress (2019)](https://pubmed.ncbi.nlm.nih.gov/31122098/)

[VWM pathology: oligodendrocyte dysfunction (2017)](https://pubmed.ncbi.nlm.nih.gov/28347059/)

[Integrated stress response in neurodegeneration (2021)](https://doi.org/10.1016/j.neuropharm.2021.108444)

Background

The study of Eif2B4 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

Cross-References

• [eIF2B4 Protein](/proteins/eif2b4-protein)
• [Vanishing White Matter Disease](/diseases/vanishing-white-matter-disease)
• [ER Stress Pathway](/mechanisms/er-stress-pathway)
• [Integrated Stress Response](/mechanisms/integrated-stress-response)

See Also

• [Genes Index](/genes)
• eIF2B Complex
• Translation Initiation
• [Integrated Stress Response](/mechanisms/integrated-stress-response)

External Links

• [UniProt: EIF2B4](https://www.uniprot.org/)
• [PubMed: EIF2B4](https://pubmed.ncbi.nlm.nih.gov/?term=EIF2B4+translation)
• [OMIM: EIF2B4](https://www.omim.org/)

References

[Unknown, Structure of the eIF2B decameric GEF complex (2015) (2015)](https://doi.org/10.1038/nature14888)

[Unknown, EIF2B4 mutations in VWM: clinical spectrum (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20401335/)

[Unknown, Therapeutic approaches to VWM disease (2020) (2020)](https://doi.org/10.1016/j.pharmthera.2020.107684)

[Unknown, eIF2B and translational control in stress (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31122098/)

[Unknown, VWM pathology: oligodendrocyte dysfunction (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28347059/)

[Unknown, Integrated stress response in neurodegeneration (2021) (2021)](https://doi.org/10.1016/j.neuropharm.2021.108444)