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EIF2AK4
eukaryotic translation initiation factor 2 alpha kinase 4
The EIF2AK4 gene provides instructions for a protein that helps cells respond to various stressors by regulating protein production and gene activity. EIF2AK4 encodes a protein crucial for cellular stress responses, particularly when nutrient levels are low.
EIF2AK4 is located on the long (q) arm of chromosome 15, at band 15q15.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The EIF2AK4 gene, also known as eukaryotic translation initiation factor 2 alpha kinase 4, plays a vital role in cellular adaptation to stress. It produces a protein that acts as a sensor for changes within the cell, particularly those that could lead to damage or nutrient deprivation. This protein is present in various tissues throughout the body, including the walls of blood vessels.
What the gene does
The protein encoded by EIF2AK4 is a kinase, meaning it adds phosphate groups to other proteins, thereby altering their activity. A key target of EIF2AK4 is another protein called eIF2 alpha (eIF2α). When cells experience stress, such as a shortage of amino acids (the building blocks of proteins), EIF2AK4 activates eIF2α. This activation leads to a reduction in overall protein synthesis, which helps to conserve amino acids and other resources. Additionally, activated eIF2α can stimulate the production of specific transcription factors. These transcription factors, in turn, regulate the activity of genes involved in cellular processes that aim to alleviate the stress and restore cellular balance.
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Chromosome location
The EIF2AK4 gene is located on chromosome 15 at position 15q15.1. This specifies its precise address on the long (q) arm of chromosome 15.
Protein structure
The EIF2AK4 protein is composed of 1649 amino acids and features several distinct regions and domains. Near the N-terminus, it includes a Disordered region (amino acids 1-25) followed by an RWD domain (amino acids 25-137). Further along, there are additional Disordered regions (amino acids 138-158 and 227-256) and a Coiled coil region (amino acids 146-205). The protein's kinase activity is mediated by two key catalytic domains: Protein kinase 1 (amino acids 296-539) and Protein kinase 2 (amino acids 590-1001). Other Disordered regions are present within and around these kinase domains (amino acids 660-750 and 766-788). A large Histidyl-tRNA synthetase-like region (amino acids 1022-1493) is also a prominent feature of the protein's C-terminal half.
Key variants
Genetic variations within the EIF2AK4 gene include different types of changes, such as single nucleotide variants, small insertions, and deletions. Some of these variants are benign, meaning they do not affect gene function or health, while others are pathogenic or likely pathogenic, contributing to disease development. The inheritance pattern for conditions associated with EIF2AK4 can vary.
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 | ★★☆☆ | Familial pulmonary capillary hemangiomatosis |
c.3766C>T | p.Arg1256Ter | Pathogenic | ★★☆☆ | Familial pulmonary capillary hemangiomatosis |
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.2310_2313del | p.Ser770fs | Pathogenic | ★☆☆☆ | not provided |
c.2521G>T | p.Glu841Ter | Pathogenic | ★☆☆☆ | not provided |
c.3856C>T | p.Gln1286Ter | Pathogenic | ★☆☆☆ | not provided |
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 EIF2AK4 gene are primarily associated with pulmonary veno-occlusive disease (PVOD). In PVOD, an excess of fibrous tissue develops in the small pulmonary veins, which are responsible for carrying oxygenated blood from the lungs to the heart. This build-up narrows the vessels, impairing blood flow. Research has identified EIF2AK4 variants as the primary genetic cause of PVOD, with at least 22 mutations in this gene documented in affected individuals. Additionally, the gene has connections to pulmonary arterial hypertension.
- Pulmonary veno-occlusive disease Dedicated page coming soon
UK clinical status
In the UK, the EIF2AK4 gene is part of the NHS Genomic Medicine Service. It is included as a green-listed gene on the 'Pulmonary arterial hypertension' panel (R188) on PanelApp.
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 making a protein that helps cells respond to various types of stress. It primarily does this by regulating protein production and controlling the activity of other genes involved in stress reduction.
What health condition is most commonly associated with EIF2AK4 variants?
Variants in the EIF2AK4 gene are most commonly associated with pulmonary veno-occlusive disease (PVOD). This condition involves the narrowing of small blood vessels in the lungs due to fibrous tissue build-up.
Where is the EIF2AK4 gene located?
The EIF2AK4 gene is located on chromosome 15. More specifically, its precise location is at band 15q15.1 on the long arm of chromosome 15.
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