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EIF2AK3
eukaryotic translation initiation factor 2 alpha kinase 3
EIF2AK3 is located on the short (p) arm of chromosome 2, at band 2p11.2. Arm ratio per GRCh38 - banding schematic.
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Overview
EIF2AK3 (eukaryotic translation initiation factor 2 alpha kinase 3) encodes a specialised protein kinase involved in the cellular stress response pathway known as the unfolded protein response. This pathway helps cells adapt when misfolded or unfolded proteins accumulate in the endoplasmic reticulum, a situation that can arise during rapid growth, infection, or metabolic disruption. The enzyme produced by EIF2AK3 phosphorylates translation initiation factors to temporarily reduce protein synthesis, giving the cell time to restore normal function.
Pathogenic variants in EIF2AK3 are associated with Wolcott-Rallison syndrome, a rare autosomal recessive disorder typically presenting in infancy with diabetes mellitus and skeletal dysplasia. The gene is located on chromosome 2p11.2 and is monitored within several NHS clinical genomics pathways relating to neonatal diabetes, skeletal abnormalities, and endocrine disorders.
What the gene does
The EIF2AK3 protein functions as a stress-sensing kinase anchored in the endoplasmic reticulum membrane. When unfolded proteins accumulate in the endoplasmic reticulum lumen, the kinase domain becomes activated and phosphorylates the alpha subunit of eukaryotic translation initiation factor 2. This phosphorylation event reduces global protein synthesis, alleviating the burden on the protein-folding machinery and allowing the cell to clear misfolded proteins.
The enzyme is particularly important in secretory cells such as pancreatic beta cells, which produce large quantities of insulin and rely heavily on efficient endoplasmic reticulum function. By modulating translation in response to cellular stress, EIF2AK3 helps maintain protein homeostasis and prevents cell death. The protein kinase domain spans a substantial portion of the enzyme and contains a large insert loop, which is characteristic of this kinase family and contributes to substrate recognition and regulatory interactions.
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Chromosome location
EIF2AK3 is located on the short arm of chromosome 2 at position 11.2 (2p11.2). The gene encodes a protein of 1,116 amino acids. The chromosomal region 2p11.2 contains several genes involved in cellular metabolism and signalling, though EIF2AK3 is the primary gene in this locus associated with inherited endocrine disorders.
Protein structure
The EIF2AK3 protein is organised into several functional regions across its 1,116 amino acids. The protein kinase domain extends from amino acids 593 to 1,077, forming the catalytic core responsible for phosphorylating translation initiation factors. Within this kinase domain lies a notably large insert loop spanning amino acids 647 to 888, a structural feature that distinguishes EIF2AK3 from other kinases and likely influences substrate specificity and regulatory mechanisms. Several disordered regions are present, including segments at amino acids 77-101, 550-571, 841-863, and 1,090-1,116, which may provide flexibility for protein-protein interactions and conformational changes during activation.
Key variants
Pathogenic variants in EIF2AK3 are typically loss-of-function changes that impair the kinase's ability to phosphorylate its target or to sense endoplasmic reticulum stress appropriately. Most reported pathogenic variants are inherited in an autosomal recessive manner, meaning both gene copies must carry variants for disease to manifest. Missense variants, nonsense variants, and frameshift changes have all been documented in individuals with Wolcott-Rallison syndrome.
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.1192C>T | p.Gln398Ter | Pathogenic | ★★☆☆ | Wolcott-Rallison dysplasia |
c.1564_1565del | p.Trp522fs | Pathogenic | ★★☆☆ | Wolcott-Rallison dysplasia |
c.1570_1573del | p.Lys523_Glu524insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Wolcott-Rallison dysplasia |
c.1578dup | p.Ala527fs | Pathogenic/Likely pathogenic | ★★☆☆ | Wolcott-Rallison dysplasia |
c.1762C>T | p.Arg588Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Wolcott-Rallison dysplasia |
c.1897C>T | p.Arg633Trp | Pathogenic/Likely pathogenic | ★★☆☆ | Wolcott-Rallison dysplasia |
c.1912C>T | p.Arg638Ter | Pathogenic | ★★☆☆ | Wolcott-Rallison dysplasia |
c.1199C>G | p.Ser400Ter | Pathogenic | ★☆☆☆ | not provided |
c.1262del | p.Asn421fs | Pathogenic | ★☆☆☆ | Syndromic Monogenic Diabetes |
c.1409C>A | p.Ser470Ter | Pathogenic | ★☆☆☆ | Syndromic Monogenic Diabetes |
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 EIF2AK3 cause Wolcott-Rallison syndrome, a rare autosomal recessive disorder characterised by permanent neonatal or early-infancy diabetes mellitus and skeletal dysplasia. Affected infants typically present with insulin-requiring diabetes within the first months of life, along with bone abnormalities such as osteoporosis and growth retardation. Additional features may include liver dysfunction, intellectual disability, and renal abnormalities, though the clinical spectrum varies. The condition reflects the critical role of EIF2AK3 in pancreatic beta-cell survival and skeletal development.
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UK clinical status
EIF2AK3 is classified on multiple NHS Genomic Medicine Service gene panels, reflecting its relevance to several clinical pathways. The gene holds green classification on the DDG2P panel, the Diabetes with additional phenotypes suggestive of a monogenic aetiology panel, the Familial diabetes panel, the Neonatal diabetes panel, and the Skeletal dysplasia panel. It is also listed on the Fetal anomalies panel and the Intellectual disability panel. These classifications indicate that EIF2AK3 variants are considered in the diagnostic evaluation of individuals presenting with neonatal diabetes, skeletal abnormalities, or multisystem phenotypes consistent with Wolcott-Rallison syndrome.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is Wolcott-Rallison syndrome?
Wolcott-Rallison syndrome is a rare autosomal recessive condition caused by pathogenic variants in EIF2AK3. It typically presents in infancy with permanent diabetes mellitus and skeletal abnormalities such as bone fragility and growth delay. Additional features may include liver and kidney complications.
How is EIF2AK3 inherited?
EIF2AK3-related conditions follow an autosomal recessive inheritance pattern. An individual must inherit a pathogenic variant from both parents to develop Wolcott-Rallison syndrome. Carriers with one variant typically do not show symptoms.
Can EIF2AK3 variants be identified through genetic testing?
Yes, pathogenic variants in EIF2AK3 can be identified through clinical genetic testing, including targeted gene panels for neonatal diabetes or broader genomic sequencing approaches. Testing is typically considered when an infant presents with diabetes and skeletal abnormalities or other features consistent with Wolcott-Rallison syndrome.