Alternative titles; symbols
HGNC Approved Gene Symbol: EIF2AK2
Cytogenetic location: 2p22.2 Genomic coordinates (GRCh38): 2:37,099,210-37,156,980 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p22.2 | Dystonia 33 | 619687 | Autosomal dominant; Autosomal recessive | 3 |
| Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome | 618877 | Autosomal dominant | 3 |
The EIF2AK2 gene encodes a serine/threonine kinase that acquires enzymatic activity following autophosphorylation, a process mediated by double-stranded RNA (dsRNA). Activation of EIF2AK2 allows the kinase to phosphorylate its natural substrate, the alpha subunit of eukaryotic protein synthesis initiation factor-2 (EIF2-alpha; 603907), leading to the inhibition of protein synthesis (summary by Kuhen et al., 1996).
Members of the EIF2AK gene family inhibit protein synthesis in response to physiologic stress conditions by regulating the cytoprotective integrated stress response (ISR). EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation (summary by Mao et al., 2020).
Meurs et al. (1990) cloned EIF2AK2, which encodes a 550-amino acid protein with a predicted molecular mass of 62 kD. Immunoblot assay of interferon-treated human Daudi and murine L929 cells identified a 68-kD protein in human cells and a 65-kD protein in mouse cells. Transcription of EIF2AK2 was induced following exposure to interferon (IFNG; 147570) in a dose-dependent manner and was not affected by inhibition of protein synthesis.
Kuhen et al. (1996) isolated the EIF2AK2 gene, which they called PKR, as lambda phage and P1 phage clones from a human genomic library, and compared the structural organization of the mouse and human genes. The human and mouse proteins shared approximately 60% amino acid identity. Kuhen et al. (1996) determined the nucleotide sequence of the human EIF2AK2 gene, which encodes a 551-amino acid protein.
Jeon et al. (2012) reported that PKR contains 2 N-terminal dsRNA- binding motifs and a long C-terminal kinase domain.
Kuhen et al. (1996) determined that the EIF2AK2 gene contains 17 exons and spans approximately 50 kb.
Barber et al. (1993) mapped the EIF2AK2 gene to chromosome 2p21 by in situ hybridization. The corresponding mouse gene was mapped to chromosome 17 (band E2) by the same method. By FISH analysis, Squire et al. (1993) assigned the EIF2AK2 gene to the boundary between chromosome 2p22-p21.
Stumpf (2022) mapped the EIF2AK2 gene to chromosome 2p22.2 based on an alignment of the EIF2AK2 sequence (GenBank BC093676) with the genomic sequence (GRCh38).
Ben-Asouli et al. (2002) showed that human gamma-interferon mRNA uses local activation of PKR in the cell to control its own translation yield. IFNG mRNA was found to activate PKR through a pseudoknot in its 5-prime untranslated region. Mutations that impaired pseudoknot stability reduced the ability to activate PKR and strongly increased the translation efficiency of IFNG mRNA. Nonphosphorylatable mutant eIF2-alpha (eIF2A; 609234), knockout of PKR, and the PKR inhibitors 2-aminopurine, transdominant-negative PKR, or vaccinia E3L correspondingly enhanced translation of IFNG mRNA. The potential to form the pseudoknot was found to be phylogenetically conserved. Ben-Asouli et al. (2002) proposed that the RNA pseudoknot acts to adjust translation of IFNG mRNA to the PKR level expressed in the cell.
Taylor et al. (1999) studied the mechanism underlying the resistance of hepatitis C virus (HCV) to interferon. They demonstrated that the HCV envelope protein E2 contains a sequence identical with phosphorylation sites of the interferon-inducible protein kinase PKR and the translation initiation factor EIF2-alpha, a target of PKR. E2 inhibited the kinase activity of PKR and blocked its inhibitory effect on protein synthesis and cell growth. This interaction of E2 in PKR may be one mechanism by which HCV circumvents the antiviral effect of interferon. Taylor et al. (1999) hypothesized that another potential outcome of PKR inhibition is the promotion of cell growth which may contribute to HCV-associated hepatocellular carcinoma.
Huntington disease (143100) is a neurodegenerative disorder caused by a trinucleotide repeat expansion within the huntingtin gene (613004), resulting in generation of a polyglutamine tract in the protein product. Peel et al. (2001) showed that PKR preferentially bound mutant huntingtin RNA transcripts immobilized on streptavidin columns that had been incubated with human brain extracts. Immunohistochemical studies demonstrated that PKR was present in its activated form in both human Huntington autopsy material and brain tissue derived from Huntington yeast artificial chromosome transgenic mice. The increased immunolocalization of the activated kinase was more pronounced in areas most affected by the disease. The authors suggested a role for PKR activation in the Huntington disease process.
Gale et al. (1998) showed that P58(IPK) (601184) is inhibited through a direct interaction with P52(rIPK) (607374), which in turn results in upregulation of PKR activity. Gale et al. (1998) concluded that their data described a protein kinase-regulatory system that encompasses an intersection of interferon-, stress-, and growth-regulatory pathways.
Yin et al. (2003) found that mouse Prkrip1 (617458) bound to dsRNA-activated PKR via the dsRNA binding domain of PKR and the N-terminal region of Prkrip1. In vitro kinase assays showed that Prkrip1 inhibited PKR activation via a dsRNA-independent mechanism. Overexpression of Prkrip1 inhibited induction of eIF2a phosphorylation following poly(I:C) treatment.
PKR, which is involved in TLR signaling and mediates apoptosis in fibroblasts in response to viral infection and inflammatory cytokines, also activates IKK (see 600664) and NFKB (see 164011), thereby suppressing apoptosis. To determine the role of PKR in macrophage apoptosis, Hsu et al. (2004) examined its regulation and found that both lipopolysaccharide (LPS) and poly(IC) activate PKR dependent on the presence of TRIF (607601). Macrophages lacking PKR had normal activation of p38 (MAPK14; 600289) and IKK as well as other NFKB target genes in response to LPS, but exhibited defective STAT1 (600555) phosphorylation and failed to undergo apoptosis, independent of the presence of IFNB (147640). They observed that apoptosis induced by live pathogenic gram-positive and gram-negative bacteria required both TLR4 (603030) and PKR, possibly representing a major mechanism for pathogenic bacteria that use specific virulence factors to avoid detection and destruction by the innate immune system. Hsu et al. (2004) proposed that TLR4 activates PKR and triggers apoptosis through TRIF and TRAM (608321) adaptor proteins and that inhibition of PKR may augment macrophage-mediated antibacterial responses.
Zhang et al. (2004) used immunoprecipitation and reconstituted kinase assays to show that the FANCC (227645), FANCA (607139), and FANCG (602956) proteins functionally interacted with and inhibited PKR in bone marrow cells. PKR showed strongest binding to the FANCC protein. PKR activity was increased in bone marrow cells of patients with Fanconi anemia (FA; 227650) with mutations in the FANCC, FANCA, or FANCG genes. All 3 of these cell lines showed significant increases in PKR bound to the FANCC protein, which correlated with increased PKR activation. The cells also showed hypersensitivity to growth repression mediated by IFN-gamma and TNF-alpha (191160). Forced expression of a patient-derived FANCC mutation increased PKR activation and cell death. Zhang et al. (2004) concluded that FA mutations cause increased binding of PKR to FANCC and increased PKR activation, leading to growth inhibition of hematopoietic progenitors and bone marrow failure in Fanconi anemia.
Nallagatla et al. (2007) reported that RNAs with very limited secondary structures activate PKR in a 5-prime-triphosphate-dependent fashion in vitro and in vivo. Activation of PKR by 5-prime-triphosphate RNA is independent of RIG1 (ROBO3; 608630) and is enhanced by treatment with type I interferon (IFNA; 147660). Surveillance of molecular features at the 5-prime end of transcripts by PKR presents a means of allowing pathogenic RNA to be distinguished from self-RNA. Nallagatla et al. (2007) concluded that this form of RNA-based discrimination may be a critical step in mounting an early immune response.
To be effective, PKR must recognize a conserved substrate (eIF2A; 609234) while avoiding rapidly evolving substrate mimics such as the poxvirus-encoded K3L. Using the PKR-K3L system and a combination of phylogenetic and functional analyses, Elde et al. (2009) uncovered evolutionary strategies by which host proteins can overcome viral mimicry. Elde et al. (2009) found that PKR has evolved under intense episodes of positive selection in primates. The ability of PKR to evade viral mimics is partly due to positive selection at sites most intimately involved in eIF2A recognition. They also found that adaptive changes on multiple surfaces of PKR produce combinations of substitutions that increase the odds of defeating mimicry. Elde et al. (2009) concluded that, although it can seem that pathogens gain insurmountable advantages by mimicking cellular components, host factors such as PKR can compete in molecular 'arms races' with mimics because of evolutionary flexibility at protein interaction interfaces challenged by mimicry.
Using HCT116 human colon carcinoma cells and mouse embryo fibroblasts, Yoon et al. (2009) found PKR mRNA and protein were upregulated by p53 (TP53; 191170) and by genotoxic stress, which induces p53 expression. Deletion analysis and DNase footprinting revealed 2 half-sites for p53 binding within the PKR promoter. Electrophoretic mobility shift assays, chromatin immunoprecipitation, and reporter gene assays revealed direct p53 binding to these sites, with activation of the PKR promoter. Binding and activation of PKR by p53 was independent of interferon binding. In response to genotoxic stress, cytoplasmic PKR was largely phosphorylated and was associated with the phosphorylation and activation of EIF2-alpha. Knockdown of either p53 or PKR abrogated all cellular effects of genotoxic stress. PKR also played a role in p53-mediated inhibition of translation, G2 arrest, and apoptosis following DNA damage. Furthermore, knockdown of PKR in HCT116 cells and derived tumors provided resistance to anticancer agents. Yoon et al. (2009) concluded that PKR has a role in p53-mediated cellular responses to genotoxic stress.
By studying HMGB1 (163905) release mechanisms, Lu et al. (2012) identified a role for PKR in inflammasome activation. Exposure of macrophages to inflammasome agonists induced PKR autophosphorylation. PKR inactivation by genetic deletion or pharmacologic inhibition severely impaired inflammasome activation in response to double-stranded RNA, ATP, monosodium urate, adjuvant aluminum, rotenone, live E. coli, anthrax lethal toxin, DNA transfection, and S. typhimurium infection. PKR deficiency significantly inhibited the secretion of IL1-beta (147720), IL18 (600953), and HMGB1 in E. coli-induced peritonitis. PKR physically interacts with several inflammasome components, including NLRP3 (606416), NLRP1 (606636), NLRC4 (606831), and AIM2 (604578), and broadly regulates inflammasome activation. PKR autophosphorylation in a cell-free system with recombinant NLRP3, ASC (PYCARD; 606838), and pro-caspase-1 (147678) reconstituted inflammasome activity. Lu et al. (2012) concluded that their results showed a crucial role for PKR in inflammasome activation, and indicated that it should be possible to pharmacologically target this molecule to treat inflammation.
Lee et al. (2011) found that the long noncoding RNA VTRNA2-1 (614938), which they called pre-MIR886, directly bound to PKR in human cell lines and inhibited its autoactivation. VTRNA2-1 was downregulated and PKR was activated in a significant number of diverse cancer cell lines. Knockdown of VTRNA2-1 resulted in PKR activation and PKR-dependent phosphorylation of EIF2-alpha. PKR activation also independently induced the NF-kappa-B pathway.
Kunkeaw et al. (2013) confirmed that VTRNA2-1, which they called NC886, was a direct inhibitor of PKR. Knockdown of NC886 in nontransformed cholangiocyte cells consistently activated the canonical PKR-EIF2-alpha cell death pathway. However, in cholangiocarcinoma cells that either lacked endogenous NC886 expression or in which NC886 expression was knocked down, PKR activation frequently induced the NF-kappa-B cell survival pathway. Kunkeaw et al. (2013) concluded that the effects of NC886 downregulation or PKR activation depend on cellular context.
Jeon et al. (2012) found that a central region of NC886 stably interacted with the 2 N-terminal dsRNA-binding motifs of PKR, with much weaker binding to each motif individually. PKR bound preferentially to NC886 in its slow-migrating conformation when the PKR-binding sequence was single-stranded and sensitive to RNase digestion, but not when it assumed a 4-nucleotide duplex structure. NC886 reciprocally competed with double-stranded poly(I:C) for PKR binding. Because NC886 does not show an extensive duplex region, Jeon et al. (2012) predicted that NC886 and dsRNAs bind PKR via different mechanisms. They hypothesized that NC886 provides a threshold for PKR activation so that it occurs during genuine viral infection and not in response to basal levels of cellular dsRNA.
Leukoencephalopathy, Developmental Delay, And Episodic Neurologic Regression Syndrome
In 8 unrelated children with leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (LEUDEN; 618877), Mao et al. (2020) identified de novo heterozygous missense mutations in the EIF2AK2 gene (see, e.g., 176871.0001-176871.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. The mutations were spread throughout the gene, but most occurred in the kinase or double-stranded RNA-binding motif (DSRM) domains. Studies of fibroblasts derived from 3 patients showed that the mutant proteins were stably expressed, but had decreased kinase activity toward EIF2S1 (603907) compared to wildtype. Patient cells also showed decreased levels of the downstream regulator ATF4 (604064), and 2 of the cell lines showed impaired response to stress induced by poly(I:C) treatment. Mao et al. (2020) concluded that reduced EIF2S1 phosphorylation would interfere with downstream molecular pathways critical for responding to cellular stressors, which may lead to neurologic decompensation and damage. These downstream effects may also impact the EIF2B protein complex, which activates the stress response: biallelic mutations in related EIF2B genes, including EIF2B1 (606686) and EIF2B2 (606454), are associated with an overlapping phenotype (see VWM, 603896). Given that EIF2AK2 requires dimerization for the kinase to function, the authors postulated a dominant-negative effect as the pathogenetic mechanism, rather than haploinsufficiency or a gain-of-function effect.
Dystonia 33
In 9 patients from 3 unrelated families with dystonia-33 (DYT33; 619687), Kuipers et al. (2021) identified a heterozygous G130R mutation in the EIF2AK2 gene (c.388G-A; 176871.0006). The mutation, which was found by a combination of linkage analysis (in 1 family) and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families, although there was evidence of incomplete penetrance. It was not present in public databases, including gnomAD. The mutation was inherited in an autosomal dominant pattern in 1 family, was inherited from an unaffected parent in a second family, and occurred de novo in the third family. Analysis of other patient cohorts identified a different heterozygous missense variant (G138A) in a mother and son with the disorder. Functional studies of this variant were not performed. The authors also identified a homozygous missense variant (N32T; 176871.0007) in a patient with DYT33 who had additional neurologic abnormalities. Fibroblasts derived from patients with the G130R and N32T variants stimulated with poly(I:C) showed sustained and significantly increased levels of phosphorylated EIF2AK2 and EIF2A (609234) compared to controls, consistent with persistent activation of this pathway and prolonged activation of the integrated stress response (ISR). The findings indicated variable inheritance patterns and variable expressivity of the disorder, which may be due to environmental factors. The G130R and N32T substitutions occurred at residues in the dsRNA-binding domain that are not well conserved, and the authors emphasized that in silico analysis did not predict the variants to be functionally damaging. The authors concluded that this gene lacks evolutionary conservation, suggesting that it has acquired special functions in the recent evolution of primates. The accelerated evolution and species specificity may be related to the involvement of this protein in the cellular response to viral infections and its coevolution with infecting viruses.
In 3 members of a 3-generation German family with autosomal dominant inheritance of DYT33, Musacchio et al. (2021) identified a heterozygous G130R mutation in the EIF2AK2 gene using exome sequencing. The authors stated that it was the same mutation identified by Kuipers et al. (2021) in several of their families. Functional studies and studies of patient cells were not performed by Musacchio et al. (2021), but the authors noted that Kuipers et al. (2021) demonstrated a gain-of-function effect for the variant.
In a 28-year-old Algerian man with adolescent-onset DYT33, Magrinelli et al. (2021) identified a de novo heterozygous c.388G-C transversion in the EIF2AK2 gene, resulting in a G130R substitution (176871.0008). The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the same amino acid substitution (G130R) resulting from a different nucleotide change (c.388G-A) had been reported in other DYT33 patients (176871.0006).
In a 10-year-old boy (patient 2) with leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (LEUDEN; 618877), Mao et al. (2020) identified a de novo heterozygous c.31A-C transversion (c.31A-C, NM_002759.3) in the EIF2AK2 gene, resulting in a met11-to-leu (M11L) substitution before the first DSRM domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Studies of patient-derived fibroblasts showed that the mutant protein was stably expressed, but had decreased kinase activity toward EIF2S1 (603907) compared to wildtype.
In a 13-year-old Chinese boy (patient 3) with leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (LEUDEN; 618877), Mao et al. (2020) identified a de novo heterozygous c.398A-T transversion (c.398A-T, NM_002759.3) in the EIF2AK2 gene, resulting in a tyr133-to-phe (Y133F) substitution in the second DSRM domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Studies of patient-derived fibroblasts showed that the mutant protein was stably expressed, but had decreased kinase activity toward EIF2S1 (603907) compared to wildtype.
In an 18-month-old boy (patient 5) with leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (LEUDEN; 618877), Mao et al. (2020) identified a de novo heterozygous c.1382C-G transversion (c.1382C-G, NM_002759.3) in the EIF2AK2 gene, resulting in a ser461-to-cys (S461C) substitution in the kinase domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Studies of patient-derived fibroblasts showed that the mutant protein was stably expressed, but had decreased kinase activity toward EIF2S1 (603907) compared to wildtype.
In a 3-year-old boy (patient 7) with leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (LEUDEN; 618877), Mao et al. (2020) identified a de novo heterozygous c.325G-T transversion (c.325G-T, NM_0027759.3) in the EIF2AK2 gene, resulting in an ala109-to-ser (A109S) substitution in the second DSRM domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In a 12-year-old boy (patient 8) with leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (LEUDEN; 618877), Mao et al. (2020) identified a de novo heterozygous c.95A-G transition (c.95A-G, NM_002759.3) in the EIF2AK2 gene, resulting in an asn32-to-ser (N32S) substitution in the first DSRM domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed.
In 7 members of a multigenerational consanguineous Taiwanese family (family A) with dystonia-33 (DYT33; 619687), Kuipers et al. (2021) identified a heterozygous c.388G-A transition (c.388G-A, NM_002759) in the EIF2AK2 gene, resulting in a gly130-to-arg (G130R) substitution in the second dsRNA-binding domain. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in public databases, including gnomAD. A de novo heterozygous G130R mutation was identified in a 6-year-old Canadian boy (family C) who had onset of DYT33 with additional neurologic symptoms at age 3. Finally, a heterozygous G130R mutation was also found in a 14-year-old German boy (family B) who had onset of DYT33 at age 7. His unaffected father was a carrier of the mutation, indicating incomplete penetrance. The G130R substitution occurs at a residue that is not well conserved, and the authors emphasized that in silico analysis did not predict the variant to be functionally damaging. However, patient-derived fibroblasts stimulated with poly(I:C) showed sustained and significantly increased levels of phosphorylated EIF2AK2 and EIF2A (609234) compared to controls, consistent with persistent activation of this pathway and prolonged activation of the integrated stress response (ISR).
In 3 members of a 3-generation German family with DYT33, Musacchio et al. (2021) identified a heterozygous G130R mutation in the EIF2AK2 gene using exome sequencing. The authors stated that it was the same mutation identified by Kuipers et al. (2021) in several of their families. Functional studies and studies of patient cells were not performed by Musacchio et al. (2021), but the authors noted that Kuipers et al. (2021) demonstrated a gain-of-function effect for the variant.
In a 42-year-old Italian man, born of consanguineous parents (family E), with dystonia-33 (DYT33; 619687), Kuipers et al. (2021) identified a homozygous c.95A-C transversion (c.95A-C, NM_002759) in the EIF2AK2 gene, resulting in an asn32-to-thr (N32T) substitution in the first dsRNA-binding domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Heterozygous mutation carriers were clinically unaffected; the transmission pattern was consistent with autosomal recessive inheritance. The variant was not present in the gnomAD database. The N32T substitution occurs at a residue that is not well conserved, and the authors emphasized that in silico analysis did not predict the variant to be functionally damaging. However, patient-derived fibroblasts stimulated with poly(I:C) showed sustained and significantly increased levels of phosphorylated EIF2AK2 and EIF2A (609234) compared to controls, consistent with persistent activation of this pathway and prolonged activation of the integrated stress response (ISR). Kuipers et al. (2021) noted that this EIF2AK2 mutation causing DYT33 affects the same residue as that identified in the heterozygous state in a patient with LEUDEN (618877): N32S (176871.0005).
In a 28-year-old Algerian man with adolescent-onset dystonia-33 (DYT33; 619687), Magrinelli et al. (2021) identified a de novo heterozygous c.388G-C transversion (c.388G-C, NM_001135651) in the EIF2AK2 gene, resulting in a gly130-to-arg (G130R) substitution. The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the same amino acid substitution resulting from a different nucleotide change (c.388G-A) had been reported in other DYT33 patients (G130R; 176871.0006).
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