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EIF2B4
eukaryotic translation initiation factor 2B subunit delta
The EIF2B4 gene provides instructions for a key subunit of the eIF2B protein, which plays a vital role in regulating protein production within cells. EIF2B4 encodes the delta subunit of the eukaryotic translation initiation factor 2B (eIF2B) protein complex.
EIF2B4 is located on the short (p) arm of chromosome 2, at band 2p23.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The EIF2B4 gene is responsible for producing one of the five components of the eukaryotic translation initiation factor 2B (eIF2B) protein. This specific component is known as the delta subunit. The eIF2B protein complex is fundamental to the cellular process of protein synthesis, acting as a crucial regulator.
Its function involves interacting with another protein, eIF2, to initiate protein production. Proper regulation of protein synthesis is essential for cells to adapt to changing conditions, such as rapid multiplication or resting states, by ensuring the correct supply of proteins.
What the gene does
The EIF2B4 gene provides the blueprint for the delta subunit of the eIF2B protein, an enzyme critical for initiating protein synthesis. The eIF2B complex works by helping to recycle molecules called guanosine triphosphate (GTP), which supply energy to the eIF2 initiation factor. This recycling process generally promotes increased protein synthesis.
Under specific cellular stress conditions, eIF2B can tightly bind to eIF2, which inactivates eIF2B and prevents GTP recycling. This mechanism allows the cell to slow down protein production when necessary. The precise control of protein synthesis by eIF2B is vital for cellular adaptation and survival, enabling cells to adjust protein levels to match their metabolic demands.
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Chromosome location
The EIF2B4 gene is located on chromosome 2, specifically at position 2p23.3. This chromosomal address indicates its precise position on the short (p) arm of chromosome 2.
Protein structure
The EIF2B4 protein, comprising 523 amino acids, includes distinct functional regions. There is a Disordered region spanning amino acids 1-147. Additionally, a specific area within the protein, amino acids 170-179, has been identified as a region that may bind the chemical integrated stress response (ISR) inhibitor ISRIB.
Key variants
Variants within the EIF2B4 gene can impact the function of the eIF2B delta subunit, potentially disrupting the intricate regulation of protein synthesis. These genetic changes can lead to a range of effects on protein activity, from partial loss of function to more significant impairments.
Sample of pathogenic variants
9 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.104_108del | p.Glu35fs | Pathogenic | ★☆☆☆ | not provided |
c.325del | p.Glu109fs | Pathogenic | ★☆☆☆ | not provided |
c.481A>T | p.Lys161Ter | Pathogenic | ★☆☆☆ | not provided |
c.508C>T | p.Arg170Ter | Pathogenic | ★☆☆☆ | not provided |
c.625C>T | p.Arg209Ter | Pathogenic | ★☆☆☆ | not provided |
c.637C>T | p.Gln213Ter | Pathogenic | ★☆☆☆ | not provided |
c.84dup | p.Arg29fs | Pathogenic | ★☆☆☆ | not provided |
c.620T>C | p.Met207Thr | Pathogenic | - | Leukoencephalopathy with vanishing white matter 4 |
c.683C>T | p.Ala228Val | Pathogenic | - | Leukoencephalopathy with vanishing white matter 4 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Mutations in the EIF2B4 gene have been associated with various inherited conditions, primarily affecting the nervous system. Notably, variants have been identified in individuals with leukoencephalopathy with vanishing white matter, an inherited disorder affecting the brain's white matter. In some instances, this condition can present with additional features such as ovarian failure, a variation referred to as ovarioleukodystrophy.
No disease links recorded for this gene in our reference set.
UK clinical status
The EIF2B4 gene is included in several expert-curated panels within the NHS Genomic Medicine Service's PanelApp. This indicates its recognised role in various neurological conditions. It is part of panels for conditions such as Ataxia and cerebellar anomalies - childhood onset, Early onset or syndromic epilepsy, Hereditary ataxia, Inherited white matter disorders, and Neurodegenerative disorders, adult onset. It is also listed on the DDG2P panel and the Leukodystrophy, adult onset panel (R62).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the EIF2B4 gene?
The EIF2B4 gene provides instructions for the delta subunit of the eIF2B protein, which is essential for regulating protein synthesis in cells by initiating the process and adapting to changing cellular conditions.
What health conditions are associated with EIF2B4 gene variants?
Variants in the EIF2B4 gene are primarily associated with leukoencephalopathy with vanishing white matter, a condition affecting the brain's white matter. Some individuals may also experience ovarian failure, known as ovarioleukodystrophy.
How does the EIF2B4 protein regulate protein production?
The EIF2B4 protein, as part of the eIF2B complex, helps recycle GTP molecules to initiate protein synthesis. It can also slow protein production by binding to the eIF2 initiation factor, which inactivates eIF2B and stops GTP recycling.
References
- Fogli A, Boespflug-Tanguy O. The large spectrum of eIF2B-related diseases. Biochemical Society transactions. 2006. PMID: 16246171
- Scheper GC, Proud CG, van der Knaap MS. Defective translation initiation causes vanishing of cerebral white matter. Trends in molecular medicine. 2006. PMID: 16545608
- Pronk JC, van Kollenburg B, Scheper GC. Vanishing white matter disease: a review with focus on its genetics. Mental retardation and developmental disabilities research reviews. 2006. PMID: 16807905
- van Kollenburg B, van Dijk J, Garbern J. Glia-specific activation of all pathways of the unfolded protein response in vanishing white matter disease. Journal of neuropathology and experimental neurology. 2006. PMID: 16825957
- Scali O, Di Perri C, Federico A. The spectrum of mutations for the diagnosis of vanishing white matter disease. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2006. PMID: 16998732
- Dietrich J, Lacagnina M, Gass D. EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy. Nature medicine. 2005. PMID: 15723074
- van der Voorn JP, van Kollenburg B, Bertrand G. The unfolded protein response in vanishing white matter disease. Journal of neuropathology and experimental neurology. 2005. PMID: 16141786
- Pavitt GD. eIF2B, a mediator of general and gene-specific translational control. Biochemical Society transactions. 2005. PMID: 16246152
- Fogli A, Schiffmann R, Hugendubler L. Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients. European journal of human genetics : EJHG. 2004. PMID: 15054402
- Li W, Wang X, Van Der Knaap MS. Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways. Molecular and cellular biology. 2004. PMID: 15060152