EIF2AK4 (GCN2) Gene: Function, Mutations, and Associated Diseases
Explore the EIF2AK4 gene, encoding the GCN2 kinase, its role in the integrated stress response, amino acid sensing, and its link to pulmonary veno-occlusive disease and other conditions.
Gene Information Card
| Symbol | EIF2AK4 |
|---|---|
| Full Name | Eukaryotic Translation Initiation Factor 2 Alpha Kinase 4 |
| Gene Type | protein-coding |
| Chromosomal Location | 15q15.1 |
| NCBI Gene ID | 440275 ncbi.nlm.nih.gov/gene/440275 |
| Ensembl ID | ENSG00000128833 |
| UniProt ID | Q9P2K8 |
| OMIM ID | 609937 |
| HGNC ID | 19675 |
| Aliases | GCN2, KIAA1338, PVOD2 |
Description
The EIF2AK4 gene encodes GCN2 (general control nonderepressible 2), a serine/threonine protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) in response to amino acid deprivation, UV irradiation, and other stress conditions. This phosphorylation attenuates global protein synthesis while selectively enhancing translation of stress-responsive mRNAs, such as ATF4, thereby mediating the integrated stress response (ISR). GCN2 is critical for cellular adaptation to nutrient availability and is implicated in metabolic regulation, immune responses, and tumor suppression. Biallelic loss-of-function mutations in EIF2AK4 cause pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH), which are rare forms of pulmonary arterial hypertension.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Pulmonary veno-occlusive disease (PVOD) | Biallelic loss-of-function mutations lead to impaired GCN2 kinase activity, disrupting the integrated stress response in pulmonary endothelial cells, resulting in progressive vascular remodeling and occlusion of pulmonary veins. | ClinVar, OMIM (OMIM: 609937; 234810) |
| Pulmonary capillary hemangiomatosis (PCH) | Same mechanism as PVOD; EIF2AK4 mutations cause abnormal proliferation of capillaries in the lung, often overlapping with PVOD phenotype. | ClinVar, OMIM (OMIM: 234810) |
| Hereditary pulmonary arterial hypertension (PAH) | EIF2AK4 mutations are the most common cause of heritable PVOD/PCH, which is a subgroup of PAH; biallelic mutations are associated with younger onset and poorer prognosis. | ClinVar, OMIM (OMIM: 609937) |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Lung | 12.4 | Medium |
| Liver | 9.8 | Medium |
| Kidney | 8.5 | Medium |
| Brain | 6.2 | Low |
| Heart | 5.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HUVEC (endothelial) | 15.2 | High expression relevant to vascular function |
| A549 (lung carcinoma) | 10.3 | Moderate expression |
| HepG2 (liver) | 9.1 | Moderate expression |
| K562 (leukemia) | 7.4 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1483C>T (p.Arg495Ter) | Nonsense | Rare (found in PVOD families) | Loss-of-function; truncates protein, abolishing kinase activity |
| c.2059C>T (p.Arg687Trp) | Missense | Rare (found in PVOD) | Likely loss-of-function; disrupts ATP-binding or catalytic activity |
| c.3124_3125del (p.Leu1042ValfsTer3) | Frameshift | Rare (found in PVOD) | Loss-of-function; premature stop codon, no functional protein |
| c.2200G>A (p.Asp734Asn) | Missense | Rare (found in PVOD) | Likely loss-of-function; affects kinase domain stability |
Mutation functional classification
Loss of Function (LOF)
Most EIF2AK4 mutations associated with PVOD/PCH are biallelic loss-of-function, leading to complete or partial loss of GCN2 kinase activity. This impairs eIF2α phosphorylation and the integrated stress response, causing endothelial dysfunction and vascular remodeling.
Gain of Function (GOF)
No gain-of-function mutations have been reported in EIF2AK4. The gene is not known to be oncogenic; rather, loss of GCN2 may promote tumor growth under metabolic stress.
Dominant Negative (DN)
No dominant-negative mutations have been described. PVOD/PCH inheritance is autosomal recessive, requiring biallelic mutations.
View complete mutation data：
Gene Ontology (GO)
| • protein serine/threonine kinase activity | • ATP binding |
| • eIF2alpha kinase activity | • translation initiation factor binding |
| • response to amino acid starvation | • integrated stress response signaling |
| • regulation of translation | • cellular response to UV |
Pathways
• Integrated stress response (ISR)
• Amino acid sensing and starvation response
• eIF2 alpha phosphorylation pathway
• ATF4-mediated gene expression
• Unfolded protein response (crosstalk)
Protein Summary
GCN2 is a 1649-amino acid protein kinase with a domain architecture including an N-terminal RWD domain, a pseudokinase domain, a catalytic kinase domain, a histidyl-tRNA synthetase (HisRS)-like domain, and a C-terminal ribosome-binding domain. Under amino acid starvation, uncharged tRNAs bind to the HisRS-like domain, activating the kinase domain to phosphorylate eIF2α at Ser51. This inhibits global translation but promotes translation of ATF4, which upregulates genes involved in amino acid synthesis and transport. GCN2 also plays roles in immune regulation, memory formation, and circadian rhythm. Mutations causing loss of function lead to PVOD/PCH, a fatal pulmonary vascular disease.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| EIF2AK4 Knockout HEK293 Cell Line | EDJ-KQ1936 | Human | 440275 | Details Get a Quote |
| EIF2AK4 Knockout A-549 Cell Line | EDJ-KQ21868 | Human | 440275 | Details Get a Quote |
| EIF2AK4 Knockout HCT 116 Cell Line | EDJ-KQ21869 | Human | 440275 | Details Get a Quote |
| EIF2AK4 Knockout HeLa Cell Line | EDJ-KQ21870 | Human | 440275 | Details Get a Quote |
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