EIF2B5
Eukaryotic Translation Initiation Factor 2B Subunit Epsilon
Gene Information Card
| Symbol | EIF2B5 |
|---|---|
| Full Name | Eukaryotic Translation Initiation Factor 2B Subunit Epsilon |
| Gene Type | protein-coding |
| Chromosomal Location | 3q27.1 |
| NCBI Gene ID | 8893 ncbi.nlm.nih.gov/gene/8893 |
| Ensembl ID | ENSG00000114520 |
| UniProt ID | Q13144 |
| OMIM ID | 603945 |
| HGNC ID | 3261 |
| Aliases | EIF2Bepsilon, eIF-2B epsilon subunit, CACH, VWM |
Description
EIF2B5 encodes the epsilon (catalytic) subunit of eukaryotic translation initiation factor 2B (eIF2B). eIF2B is a heteropentameric guanine nucleotide exchange factor (GEF) that converts inactive eIF2-GDP to active eIF2-GTP, a critical step in translation initiation. Mutations in EIF2B5 are a major cause of childhood ataxia with central nervous system hypomyelination (CACH) / vanishing white matter disease (VWM), an autosomal recessive leukodystrophy.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Leukoencephalopathy with vanishing white matter (VWM) / Childhood ataxia with central nervous system hypomyelination (CACH) | Loss-of-function mutations impair eIF2B GEF activity, reducing translation initiation and triggering chronic integrated stress response (ISR), leading to oligodendrocyte dysfunction and white matter degeneration. | OMIM #603896; ClinVar; multiple case reports |
| Ovarioleukodystrophy | Same EIF2B5 mutations cause ovarian failure in females with VWM due to impaired translation in germ cells. | OMIM #603896; literature review |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.5 | Medium |
| Ovary | 8.3 | Medium |
| Testis | 7.1 | Medium |
| Liver | 6.8 | Low |
| Kidney | 5.9 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 14.2 | High expression |
| HeLa | 11.0 | Medium expression |
| SH-SY5Y | 9.5 | Medium expression |
| HepG2 | 7.3 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.338G>A (p.Arg113His) | Missense | Common in VWM | Reduced eIF2B GEF activity; dominant-negative effect in some studies |
| c.584G>A (p.Arg195His) | Missense | Recurrent | Impaired eIF2B complex assembly and catalytic activity |
| c.1016G>A (p.Arg339Gln) | Missense | Reported | Decreased GEF activity; associated with milder phenotype |
| c.1340T>C (p.Leu447Pro) | Missense | Rare | Severe loss of function; early-onset VWM |
Mutation functional classification
Loss of Function (LOF)
Most missense mutations reduce eIF2B GEF activity, impairing translation initiation.
Gain of Function (GOF)
Not reported for EIF2B5.
Dominant Negative (DN)
Some mutations (e.g., p.Arg113His) exert dominant-negative effects by disrupting the pentameric complex.
View complete mutation data：
Gene Ontology (GO)
| • GTPase activator activity | • translation initiation factor activity |
| • guanyl-nucleotide exchange factor activity | • eIF2B complex |
| • cytoplasm | • regulation of translational initiation |
| • response to stress |
Pathways
• Eukaryotic translation initiation (Reactome: R-HSA-72613)
• Regulation of eIF2 activity by eIF2B (Reactome: R-HSA-72731)
• Integrated stress response (ISR)
Protein Summary
EIF2B5 encodes the epsilon subunit (catalytic) of the eIF2B complex. This 721-amino acid protein contains a catalytic domain responsible for guanine nucleotide exchange on eIF2. It is essential for recycling eIF2-GDP to eIF2-GTP during translation initiation. Mutations in EIF2B5 disrupt this exchange, leading to reduced global protein synthesis and activation of the integrated stress response, particularly affecting oligodendrocytes and causing leukodystrophy.
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