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EIF2B4
eukaryotic translation initiation factor 2B subunit delta
The EIF2B4 gene provides instructions for a subunit of the eIF2B protein, which is crucial for regulating protein synthesis in cells and is associated with certain neurological conditions. EIF2B4 codes for the delta subunit of the eukaryotic translation initiation factor 2B (eIF2B) protein.
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, also known as eukaryotic translation initiation factor 2B subunit delta, contains the genetic blueprint for a component of the eIF2B protein complex. This complex is fundamental for the intricate process of protein synthesis, ensuring cells can produce the necessary proteins to function correctly and adapt to various physiological conditions.
Proper regulation of protein production is essential for cellular health and development. The eIF2B protein helps manage this by initiating protein synthesis and adjusting its rate based on the cell's requirements, such as during growth or stress responses.
What the gene does
The EIF2B4 gene directs the production of the delta subunit, one of five components that form the eIF2B protein. This multi-subunit protein complex is a key regulator of protein synthesis, specifically by interacting with another protein called eIF2, which initiates the protein-building process.
Under normal conditions, eIF2B facilitates protein synthesis by helping to recycle GTP molecules, which are essential energy carriers for the initiation factor. However, under certain cellular stresses, eIF2B can slow down protein synthesis by binding tightly to eIF2, making eIF2B inactive and preventing GTP recycling. This dynamic regulation ensures that cells can adjust protein production levels to cope with changing environments, such as rapid cell division or periods of rest.
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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 place within the human genome, where it carries the instructions for making the delta subunit of the eIF2B protein.
Protein structure
The EIF2B4 gene encodes a protein comprising 523 amino acids. A notable feature of this protein is a Disordered region spanning amino acids 1-147. Additionally, a specific region from amino acids 170-179 May bind the chemical integrated stress response (ISR) inhibitor ISRIB, suggesting potential pharmacological interactions.
Key variants
Genetic variations within the EIF2B4 gene can alter the protein's function, potentially leading to health implications. These changes, known as variants, can range from single nucleotide changes to larger alterations within the gene sequence. Research into these variants helps to understand their impact on the eIF2B protein and its role in cellular processes.
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
Variations in the EIF2B4 gene have been associated with Leukoencephalopathy with vanishing white matter. This condition affects the brain's white matter, which is crucial for nerve signal transmission. Some affected individuals, particularly females, may also experience ovarian failure, a presentation known as ovarioleukodystrophy. These conditions typically arise when variants lead to a partial reduction in the eIF2B protein's function.
No disease links recorded for this gene in our reference set.
UK clinical status
The EIF2B4 gene is included in several NHS Genomic Medicine Service national testing panels, reflecting its clinical significance within the UK. It is part of panels for conditions such as Ataxia and cerebellar anomalies - childhood onset, Early onset or syndromic epilepsy, Hereditary ataxia (both general and adult onset), Inherited white matter disorders, Leukodystrophy, adult onset, Neurodegenerative disorders, adult onset, and White matter disorders and cerebral calcification - childhood onset. It is also listed within the Developmental Disorders Gene Panel (DDG2P).
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, the process by which cells make proteins. It helps manage the rate of protein production based on cellular needs.
What health conditions are associated with EIF2B4 gene variants?
Variants in the EIF2B4 gene are primarily associated with Leukoencephalopathy with vanishing white matter. Some individuals, especially females, may also experience ovarioleukodystrophy, a variant of the disorder involving ovarian failure.
How does EIF2B4 relate to protein synthesis?
EIF2B4 is part of the eIF2B protein, which interacts with the eIF2 protein to initiate and regulate protein synthesis. It helps recycle energy molecules (GTP) for protein initiation and can slow down protein production under certain cellular stress conditions.
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