EIF2B1 Human
Description
Molecular Function and Structure
The EIF2B1 gene produces the alpha subunit of the eIF2B complex, which consists of five subunits (α, β, γ, δ, ε). eIF2B acts as a guanine nucleotide exchange factor (GEF) for eIF2, facilitating the recycling of GDP to GTP during translation initiation . Key functions include:
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Regulation of protein synthesis: Under stress, eIF2B binds phosphorylated eIF2α, inhibiting GTP recycling and slowing translation .
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Stress response modulation: eIF2B integrates cellular stress signals (e.g., endoplasmic reticulum stress) to adjust protein production .
Table 1: EIF2B1 Protein Characteristics
Leukoencephalopathy with Vanishing White Matter (VWM)
Recessive loss-of-function mutations in EIF2B1 cause VWM, a fatal pediatric neurological disorder characterized by progressive white matter degeneration .
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Mechanism: Impaired eIF2B function disrupts stress adaptation in oligodendrocytes, leading to myelin loss .
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Notable Mutations: Missense variants (e.g., p.Leu49Arg) destabilize the eIF2B complex .
Neonatal Diabetes and Liver Dysfunction
Dominant de novo mutations (e.g., p.Gly44Val, p.Ser77Asn) are linked to permanent neonatal diabetes mellitus (PNDM) and transient hepatitis .
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Pathogenesis: Mutations disrupt eIF2B’s ability to sense phosphorylated eIF2α, causing unregulated endoplasmic reticulum (ER) stress and β-cell apoptosis .
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Clinical Features: Diabetes onset <2 years, episodic liver dysfunction, and mild neurodevelopmental issues .
Table 2: Disease Comparison of EIF2B1 Mutations
Therapeutic Targets
Small molecules like ISRIB rescue eIF2B activity in EIF2B1 mutants, suggesting potential treatments for VWM and diabetes .
Expression and Detection
EIF2B1 is widely expressed, with high levels in the brain, pancreas, and liver . Tools for study include:
Product Specs
Q&A
What is the normal function of EIF2B1 in human cells?
EIF2B1 encodes the alpha subunit of the eukaryotic initiation factor 2B (eIF2B) protein complex. This subunit works alongside four other subunits (β, γ, δ, and ε) to form the complete eIF2B complex. The primary function of eIF2B is to regulate protein synthesis by interacting with another protein called eIF2. Under normal conditions, eIF2B helps increase protein synthesis by recycling GTP molecules, which provide energy to the initiation factor. Under stress conditions, eIF2B can slow protein synthesis by binding tightly to the initiation factor, preventing GTP recycling and converting eIF2B into an inactive form. This regulation is vital for ensuring that cells produce appropriate protein levels in response to changing environmental conditions .
How does EIF2B1 interact with other subunits in the eIF2B complex?
The alpha subunit (encoded by EIF2B1) forms a trimeric subcomplex with the beta and delta subunits. This subcomplex directly interacts with the alpha subunit of eIF2, particularly when eIF2 is phosphorylated under stress conditions. The high sequence similarities between these three subunits (α, β, and δ) facilitate their association and function . The epsilon and gamma subunits form a separate binary subcomplex with its own catalytic function. Together, these subcomplexes constitute the complete eIF2B protein complex that regulates protein synthesis initiation .
What cellular processes depend on proper EIF2B1 function?
Proper EIF2B1 function is critical for multiple cellular processes:
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Protein synthesis regulation: eIF2B controls the rate of protein production, especially during stress conditions
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Cell growth and division: Cells must synthesize proteins much faster when multiplying than when in a resting state
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Stress response: eIF2B helps cells adapt to changing conditions by modulating protein synthesis
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White matter development and maintenance: Cells in the white matter appear particularly sensitive to disruptions in eIF2B function
What is the molecular pathophysiology of EIF2B1 mutations in leukoencephalopathy?
Mutations in EIF2B1 cause partial loss of eIF2B function, impairing the cell's ability to regulate protein synthesis and respond to cellular stress. White matter cells (oligodendrocytes and astrocytes) appear particularly vulnerable to this disruption. Research suggests that the abnormal stress response in these cells leads to the clinical manifestations of leukoencephalopathy with vanishing white matter (VWM). The exact mechanisms may involve:
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Impaired regulation of protein synthesis during cellular stress
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Abnormal unfolded protein response
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Dysregulation of glial cell maturation
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Increased vulnerability to environmental stressors like infections and head trauma
The severity spectrum appears to correlate with the degree of eIF2B functional impairment, with earlier-onset cases typically showing more severe clinical presentations and poorer outcomes .
How can eIF2B GEF activity be measured as a diagnostic tool?
The guanine nucleotide exchange factor (GEF) activity of eIF2B can be measured in lymphoblastoid cell lines (LLBs) as a diagnostic marker for eIF2B-related disorders. This biochemical assay:
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Measures the ability of eIF2B to exchange GDP for GTP on the eIF2 protein
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Can identify functional impairment even when genetic testing is inconclusive
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Shows variations that correlate with disease severity
| Patient Group | Typical eIF2B GEF Activity Range | Utility |
|---|---|---|
| Normal controls | 80-120% of reference | Baseline comparison |
| Mild eIF2B-related disorders | 50-80% of normal | Less severe phenotypes |
| Severe eIF2B-related disorders | <50% of normal | Earlier onset, poorer prognosis |
This functional assay has shown high specificity and sensitivity for diagnosing eIF2B-related disorders and can help select patients eligible for EIF2B1-5 gene sequencing, enhancing the efficiency of molecular diagnosis .
What experimental models exist for studying EIF2B1 mutations?
Multiple experimental models have been developed to study EIF2B1 and related disorders:
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Patient-derived cells: Lymphoblastoid cell lines from patients show reduced eIF2B GEF activity and can be used to study disease mechanisms and potential therapies
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Yeast models: Studies in yeast have demonstrated that null mutations for eIF2B subunits are typically lethal, except for the alpha subunit (eIF2Bα), highlighting the essential nature of this complex
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Cellular stress assays: Models that apply various stressors (heat shock, endoplasmic reticulum stress) to cells with mutated EIF2B1 help understand the impaired stress response
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Mouse models: Engineered mice with specific eIF2B mutations can recapitulate aspects of VWM pathology
These models provide platforms for understanding pathophysiology and testing potential therapeutic approaches for eIF2B-related disorders.
What is the spectrum of known EIF2B1 mutations in disease?
Multiple mutations have been identified in EIF2B1 and other eIF2B subunit genes (EIF2B1-5) associated with leukoencephalopathy with vanishing white matter. In a comprehensive study of patients with diverse clinical phenotypes:
| Gene | Selected Mutations Identified | Protein Changes | Clinical Severity |
|---|---|---|---|
| EIF2B1 | Various novel mutations | Variable | Variable severity |
| EIF2B2 | 599G→T, 871C→T | G200V, P291S | Brain, lens, liver involvement |
| EIF2B3 | p.Ser14Phe/p.Ala87Val, p.Glu136Pro | Variable | Variable severity |
| EIF2B4 | 1447C→T, 1172C→A | R483W, A391D | Multiple organ involvement |
| EIF2B5 | p.Arg113His/p.Arg113His, p.Arg113His/p.Arg315Cys | Variable | Variable severity |
The spectrum of mutations is expanding as more patients undergo genetic testing. In one Chinese study, 15 novel mutations were identified in EIF2B1-5 genes, with 34 out of 36 clinically diagnosed children (94%) found to have pathogenic mutations .
What is the recommended genetic testing approach for suspected EIF2B1-related disorders?
For suspected eIF2B-related disorders, a comprehensive genetic testing approach is recommended:
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Initial screening: Measurement of eIF2B GEF activity in patient-derived lymphoblastoid cell lines to prioritize candidates for genetic testing
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Targeted sequencing: Sequencing of all five EIF2B1-5 genes, including exons and flanking splice junctions
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Primer design and coverage: Use of multiple primers (approximately 112 primers) to cover all 57 exons and flanking regions of EIF2B1-5 genes
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Sequencing technology: BigDye™ Terminator Ready Reaction chemistry or next-generation sequencing approaches
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Variant analysis: Comparison with reference sequences (e.g., NCBI accession numbers NM_001414.1 for EIF2B1) and checking variants against population databases
This comprehensive approach enables identification of both common and novel mutations in the eIF2B complex genes.
How do genotypes correlate with phenotypes in EIF2B1-related disorders?
The genotype-phenotype correlation in eIF2B-related disorders shows several patterns:
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Age of onset correlation: Generally, earlier disease onset correlates with more severe clinical course and poorer outcomes
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Mutation-specific effects: Some mutations consistently produce severe phenotypes, such as those seen in Cree leukoencephalopathy, suggesting direct genotype influence
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Variable expressivity: Identical genotypes can exhibit considerable variation in clinical presentations, indicating additional genetic or environmental modifiers
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Multi-organ involvement: Some mutations are associated with involvement of organs beyond the central nervous system, including ovaries, pancreas, liver, and kidneys
A study analyzing 15 patients with eIF2B-related disorders found a wide spectrum of clinical severity and disability, with risk of rapid disease progression higher in younger-onset cases .
What are the diagnostic criteria for eIF2B-related disorders?
Diagnostic criteria for eIF2B-related disorders combine clinical, radiological, biochemical, and genetic elements:
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Clinical presentation:
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Progressive neurological deterioration often exacerbated by stressors
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Ataxia, spasticity, and cognitive decline
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In some cases, ovarian failure or other organ involvement
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MRI findings:
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Biochemical testing:
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Reduced eIF2B GEF activity in lymphoblastoid cell lines
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Genetic confirmation:
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Identification of biallelic pathogenic variants in any of the five EIF2B1-5 genes
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The combination of typical MRI findings with biochemical and genetic confirmation provides the most definitive diagnosis.
How can researchers differentiate eIF2B-related disorders from other leukodystrophies?
Differentiating eIF2B-related disorders from other leukodystrophies requires a systematic approach:
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MRI pattern recognition: eIF2B-related disorders have characteristic patterns distinct from other leukodystrophies like Pelizaeus-Merzbacher disease (PMD), Alexander disease (AD), and megalencephalic leukoencephalopathy with subcortical cysts (MLC)
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Biochemical testing: eIF2B GEF activity measurement can help distinguish eIF2B-related disorders:
| Disease | Mutated Gene | eIF2B GEF Activity (%) |
|---|---|---|
| eIF2B-related | EIF2B1-5 | Typically reduced (<80%) |
| PMD | PLP1 | Normal (86.2-108.6%) |
| AD | GFAP | Normal (103.8-133.6%) |
| MLC | MLC1 | Normal (109.6%) |
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Clinical features: The combination of leukoencephalopathy with ovarian failure is highly suggestive of eIF2B-related disorders
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Response to stress: Acute deterioration following febrile illness or minor head trauma is more characteristic of eIF2B-related disorders than other leukodystrophies
What therapeutic approaches are being explored for EIF2B1-related disorders?
While current management of EIF2B1-related disorders is largely supportive, several therapeutic approaches are being investigated:
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Stress management: Preventing or minimizing stressors that can trigger clinical deterioration
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Targeted molecular therapies: Developing compounds that could enhance residual eIF2B activity
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Gene therapy approaches: Exploring viral vector-mediated gene delivery to restore normal eIF2B function
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Cellular stress response modulators: Compounds that might stabilize the cellular response to stress despite impaired eIF2B function
These approaches are largely experimental, and translational research is needed to move them into clinical applications.
What are the current challenges in researching EIF2B1 function and pathology?
Researchers face several challenges in studying EIF2B1:
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Complex protein interactions: eIF2B functions as part of a multi-subunit complex with intricate interactions
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Essential cellular function: The essential nature of eIF2B makes it difficult to completely eliminate its function in experimental models
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Cell-type specificity: Understanding why certain cell types (particularly oligodendrocytes) are more vulnerable to eIF2B dysfunction
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Genotype-phenotype correlations: Elucidating why identical mutations can produce variable clinical phenotypes
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Developing relevant models: Creating animal and cellular models that accurately recapitulate the human disease
Addressing these challenges requires multidisciplinary approaches combining genetics, biochemistry, cell biology, and clinical research.
Product Science Overview
Eukaryotic Translation Initiation Factor 2B Subunit 1 Alpha (EIF2B1) is a crucial component of the eukaryotic translation initiation factor 2B (eIF2B) complex. This complex plays a pivotal role in the regulation of protein synthesis, a fundamental process in cellular biology. The human recombinant form of EIF2B1 is used in various research and therapeutic applications.
EIF2B1 is one of the five subunits of the eIF2B complex, which also includes EIF2B2, EIF2B3, EIF2B4, and EIF2B5 . The eIF2B complex functions as a guanine nucleotide exchange factor (GEF) for eukaryotic initiation factor 2 (eIF2). Specifically, EIF2B1 catalyzes the exchange of GDP for GTP on the eIF2 gamma subunit . This exchange is a critical step in the initiation of protein synthesis, as it allows the formation of the ternary complex consisting of eIF2, GTP, and methionyl-initiator methionine tRNA .
The activity of the eIF2B complex is tightly regulated and is essential for maintaining proper cellular function. When eIF2 is phosphorylated on its alpha subunit, the GEF activity of eIF2B is inhibited, leading to a reduction in global protein synthesis . This regulatory mechanism is crucial for cellular responses to stress, such as nutrient deprivation or viral infection .
Mutations in the EIF2B1 gene and other genes encoding eIF2B subunits have been associated with a rare genetic disorder known as leukoencephalopathy with vanishing white matter (VWM) . This disorder is characterized by the progressive loss of white matter in the brain, leading to neurological symptoms. Understanding the function and regulation of EIF2B1 is therefore important for developing potential therapeutic strategies for VWM and related conditions.
