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EIF2B5
eukaryotic translation initiation factor 2B subunit epsilon
The EIF2B5 gene provides instructions for a subunit of the eIF2B protein, which plays a crucial role in regulating protein production within cells. EIF2B5 is essential for cellular function, as its encoded protein helps manage how and when proteins are made.
EIF2B5 is located on the long (q) arm of chromosome 3, at band 3q27.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The EIF2B5 gene, also known as eukaryotic translation initiation factor 2B subunit epsilon, encodes one of five subunits of the eIF2B protein. This protein complex is vital for controlling the rate of protein synthesis, a fundamental cellular process. Proper regulation of protein production is critical for cells to adapt to various conditions, such as growth or stress.
Changes in the EIF2B5 gene can affect the eIF2B protein's function, leading to conditions that impact neurological development and function.
What the gene does
The EIF2B5 gene provides the blueprint for the epsilon subunit of the eukaryotic translation initiation factor 2B (eIF2B) protein. The eIF2B protein is a guanine nucleotide exchange factor, meaning it facilitates the exchange of GDP for GTP on another protein called eIF2. This exchange is a key step in initiating protein synthesis, ensuring that the cellular machinery is ready to start building new proteins.
Under certain cellular conditions, eIF2B promotes protein synthesis by helping to recycle GTP molecules, which provide energy for the initiation process. In other scenarios, eIF2B can slow down protein production by binding tightly to eIF2, making it inactive and preventing GTP recycling. This precise regulation ensures cells can adjust protein levels to cope with changing demands, such as during cell division or periods of rest.
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Chromosome location
The EIF2B5 gene is located on chromosome 3 at position q27.1. This specific location on the long arm (q) of chromosome 3 helps pinpoint its genomic address within the human genome.
Protein structure
The EIF2B5 gene encodes a protein consisting of 721 amino acids. The protein structure includes several notable regions. There are three disordered regions: one spanning amino acids 1-40, another from amino acids 444-483, and a third from amino acids 523-547. Additionally, a distinct W2 domain is present, encompassing amino acids 543-720, which is likely important for the protein's function.
Key variants
Genetic variations within the EIF2B5 gene can range from single nucleotide changes to larger deletions or insertions. These variants may alter the structure or function of the resulting eIF2B5 protein subunit, affecting its role in regulating protein synthesis. Different types of variants can have varying impacts on protein activity and cellular processes.
Sample of pathogenic variants
10 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.1289T>C | p.Val430Ala | Pathogenic/Likely pathogenic | ★★☆☆ | Vanishing white matter disease |
c.1694delinsTTTCTTGTGCATCTCCACTACAGAGGAGCGGGGCATCTCCACTAC | p.Lys565fs | Pathogenic | ★★☆☆ | Vanishing white matter disease |
c.1813del | p.Leu605fs | Pathogenic | ★★☆☆ | Vanishing white matter disease |
c.1960del | p.Phe653_Leu654insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Leukoencephalopathy with vanishing white matter 5 |
c.203T>C | p.Leu68Ser | Pathogenic/Likely pathogenic | ★★☆☆ | EIF2B5-related disorder |
c.406C>T | p.Arg136Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Leukoencephalopathy with vanishing white matter 5 |
c.439_442del | p.Asp147fs | Pathogenic/Likely pathogenic | ★★☆☆ | Vanishing white matter disease |
c.721C>T | p.Arg241Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Vanishing white matter disease |
c.799C>T | p.Gln267Ter | Pathogenic | ★★☆☆ | Vanishing white matter disease |
c.805C>T | p.Arg269Ter | Pathogenic | ★★☆☆ | Vanishing white matter disease |
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
Variants in the EIF2B5 gene are primarily associated with leukoencephalopathy with vanishing white matter. This condition is characterised by the progressive loss of white matter in the brain, which can lead to a range of neurological symptoms. EIF2B5 variants are found in a significant proportion of individuals with this disorder, including specific forms observed in certain populations.
No disease links recorded for this gene in our reference set.
UK clinical status
The EIF2B5 gene is recognised within several UK NHS Genomic Medicine Service national test directories, as indicated by its 'green' status on PanelApp. It is included in panels related to 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 primary ovarian insufficiency. It is also listed within the DDG2P (Deciphering Developmental Disorders) panel.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the EIF2B5 gene?
The EIF2B5 gene provides instructions for the epsilon subunit of the eIF2B protein, which is essential for regulating the initiation of protein synthesis within cells. It helps control the rate at which new proteins are produced, allowing cells to adapt to different conditions.
What condition is most commonly associated with EIF2B5 gene variants?
Variants in the EIF2B5 gene are most commonly associated with leukoencephalopathy with vanishing white matter. This is a neurological disorder characterised by the progressive degeneration of the brain's white matter.
How does the eIF2B protein regulate protein synthesis?
The eIF2B protein regulates protein synthesis by facilitating the exchange of GDP for GTP on the eIF2 protein, a crucial step in initiating protein production. It can either promote synthesis by recycling energy-carrying molecules or slow it down by binding to eIF2, thus controlling cellular protein levels.
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