On this page
EIF2AK4
eukaryotic translation initiation factor 2 alpha kinase 4
The EIF2AK4 gene encodes a protein that plays a key role in cellular stress responses, helping cells adapt to challenging conditions, and is primarily associated with pulmonary veno-occlusive disease. The EIF2AK4 gene provides instructions for a protein vital for directing a cell's response to conditions that could cause damage, such as low amino acid levels.
EIF2AK4 is located on the long (q) arm of chromosome 15, at band 15q15.1. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 15 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The EIF2AK4 gene, also known as eukaryotic translation initiation factor 2 alpha kinase 4, is integral to how cells manage and respond to various stressors. The protein it produces is found in multiple tissues, including the walls of blood vessels, and plays a key role in pulmonary veno-occlusive disease.
What the gene does
The EIF2AK4 gene provides instructions for creating a protein crucial in directing a cell's response to potentially damaging changes. This protein functions by activating another protein, eIF2 alpha (eIF2α), a key regulator of protein synthesis. When cells experience stress, such as insufficient amino acids, EIF2AK4 activates eIF2α [PMID:24077189]. This activation helps to reduce overall protein production, thereby conserving cellular resources. Additionally, activated eIF2α can stimulate the production of certain transcription factors, which are proteins that control the activity of other genes [PMID:28704229]. These transcription factors manage genes involved in processes that alleviate cellular stress, allowing the cell to adapt and survive adverse conditions [PMID:22095977].
Video: Genetics 101
Chromosome location
The EIF2AK4 gene is located on chromosome 15 at position 15q15.1. This specific genomic location provides the physical address for the gene within the human genome.
Protein structure
The EIF2AK4 protein is composed of 1649 amino acids and features several distinct regions and domains. It contains multiple disordered regions, including one at amino acids 1-25, another from 138-158, and further regions from 227-256, 660-750, and 766-788. Notable structured domains include an RWD domain (amino acids 25-137), a coiled-coil region (amino acids 146-205), and two protein kinase domains (Protein kinase 1 from 296-539 and Protein kinase 2 from 590-1001). A large Histidyl-tRNA synthetase-like region spans amino acids 1022-1493.
Key variants
Genetic variations within the EIF2AK4 gene can influence its function, potentially leading to altered cellular stress responses. These variations, which may include changes in the DNA sequence, are studied to understand their impact on protein activity and associated health outcomes. At least 22 pathogenic variants in EIF2AK4 have been identified in individuals with pulmonary veno-occlusive disease.
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.1387C>T | p.Arg463Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial pulmonary capillary hemangiomatosis |
c.1392del | p.Arg465fs | Pathogenic | ★★☆☆ | EIF2AK4-related disorders |
c.2061_2076dup | p.Leu693fs | Pathogenic | ★★☆☆ | EIF2AK4-related disorder |
c.249T>A | p.Tyr83Ter | Pathogenic/Likely pathogenic | ★★☆☆ | EIF2AK4-related disorders |
c.3766C>T | p.Arg1256Ter | Pathogenic | ★★☆☆ | EIF2AK4-related disorders |
c.4009C>T | p.Arg1337Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial pulmonary capillary hemangiomatosis |
c.4065+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Familial pulmonary capillary hemangiomatosis |
c.4205dup | p.Ser1403fs | Pathogenic | ★★☆☆ | Familial pulmonary capillary hemangiomatosis |
c.560_564del | p.Lys187fs | Pathogenic | ★★☆☆ | Familial pulmonary capillary hemangiomatosis |
c.1672C>T | p.Gln558Ter | Pathogenic | ★☆☆☆ | EIF2AK4-related disorders |
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
Pathogenic variants in the EIF2AK4 gene are primarily associated with pulmonary veno-occlusive disease, which typically follows an autosomal recessive inheritance pattern. This condition is characterised by the build-up of excess fibrous tissue within the small pulmonary vessels that transport oxygenated blood [PMID:24077189]. These variants are recognised as a significant genetic cause for pulmonary veno-occlusive disease.
- Pulmonary veno-occlusive disease Dedicated page coming soon
UK clinical status
The EIF2AK4 gene is part of the UK National Genomic Test Directory. It is listed on the 'Pulmonary arterial hypertension' panel, which is currently categorised as green, indicating that it is routinely considered for testing within the NHS Genomic Medicine Service.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the EIF2AK4 gene?
The EIF2AK4 gene provides instructions for a protein that helps cells respond to stressful conditions. It does this by activating eIF2 alpha, which then helps regulate protein production and gene activity to mitigate cellular stress.
Which medical condition is most associated with variants in EIF2AK4?
Variants in the EIF2AK4 gene are primarily associated with pulmonary veno-occlusive disease (PVOD). PVOD is a rare and severe lung disorder.
How does EIF2AK4 activate eIF2 alpha?
The EIF2AK4 protein acts as a kinase, meaning it adds a phosphate group to eIF2 alpha. This phosphorylation activates eIF2 alpha, leading to a reduction in protein synthesis and the activation of stress-response genes.
References
- Eyries M, Montani D, Girerd B. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nature genetics. 2014. PMID: 24292273
- Donnelly N, Gorman AM, Gupta S. The eIF2α kinases: their structures and functions. Cellular and molecular life sciences : CMLS. 2013. PMID: 23354059
- Murguía JR, Serrano R. New functions of protein kinase Gcn2 in yeast and mammals. IUBMB life. 2012. PMID: 23129244
- Deval C, Chaveroux C, Maurin AC. Amino acid limitation regulates the expression of genes involved in several specific biological processes through GCN2-dependent and GCN2-independent pathways. The FEBS journal. 2009. PMID: 19120448