EIF2AK1 eukaryotic translation initiation factor 2 alpha kinase 1 [Homo sapiens (human)] - Gene

Summary

Official Symbol: EIF2AK1provided by HGNC
Official Full Name: eukaryotic translation initiation factor 2 alpha kinase 1provided by HGNC
Primary source: HGNC:HGNC:24921
See related: Ensembl:ENSG00000086232 MIM:613635; AllianceGenome:HGNC:24921
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: HCR; HRI; hHRI; LEMSPAD
Summary: The protein encoded by this gene acts at the level of translation initiation to downregulate protein synthesis in response to stress. The encoded protein is a kinase that can be inactivated by hemin. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]
Expression: Ubiquitous expression in bone marrow (RPKM 37.9), placenta (RPKM 32.2) and 25 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 7p22.1

Exon count:: 16

Annotation release	Status	Assembly	Chr	Location
RS_2023_10	current	GRCh38.p14 (GCF_000001405.40)	7	NC_000007.14 (6022247..6059175, complement)
RS_2023_10	current	T2T-CHM13v2.0 (GCF_009914755.1)	7	NC_060931.1 (6140020..6176976, complement)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	7	NC_000007.13 (6061878..6098806, complement)

Chromosome 7 - NC_000007.14 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Targeting the EIF2AK1 Signaling Pathway Rescues Red Blood Cell Production in SF3B1-Mutant Myelodysplastic Syndromes With Ringed Sideroblasts.
Title: Targeting the EIF2AK1 Signaling Pathway Rescues Red Blood Cell Production in SF3B1-Mutant Myelodysplastic Syndromes With Ringed Sideroblasts.
The eIF2alpha kinase HRI triggers the autophagic clearance of cytosolic protein aggregates.
Title: The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates.
The eIF2alpha kinase HRI in innate immunity, proteostasis, and mitochondrial stress.
Title: The eIF2α kinase HRI in innate immunity, proteostasis, and mitochondrial stress.
The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression.
Title: The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression.
mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway; the OMA1-DELE1-HRI pathway represents a potential therapeutic target that could enable fine-tuning of the integrated stress response for beneficial outcomes in diseases that involve mitochondrial dysfunction
Title: Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.
Human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported.
Title: De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation.
Recently, HRI has been implicated in the regulation of human fetal hemoglobin production. Therefore, HRI-integrated stress response has emerged as a potential therapeutic target for hemoglobinopathies. especially under iron/heme deficiency and beta-thalassemia. [review]
Title: Heme-regulated eIF2α kinase in erythropoiesis and hemoglobinopathies.
Activation of HRI is mediated by Hsp90 during stress through modulation of the HRI-Hsp90 complex
Title: Activation of HRI is mediated by Hsp90 during stress through modulation of the HRI-Hsp90 complex.
Taken together, these results suggest HRI as a potential therapeutic target for hemoglobinopathies.
Title: Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells.
data suggests that glutamatergic stimulation induces HRI activation by NO to trigger GluN2B expression and this process would be relevant to maintain postsynaptic activity in cortical neurons
Title: Glutamatergic stimulation induces GluN2B translation by the nitric oxide-Heme-Regulated eIF2α kinase in cortical neurons.

Submit: New GeneRIF Correction See all GeneRIFs (18)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome MedGen: C5394371 OMIM: 618878 GeneReviews: Not available	Compare labs

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

G60390 (e-PCR)
- UniSTS:137496

GDB:4585095 (e-PCR)
- UniSTS:43824

G54017 (e-PCR)
- UniSTS:109399

SHGC-37403 (e-PCR)
- UniSTS:1951

RH12212 (e-PCR)
- UniSTS:52950

D7S2761 (e-PCR)
- UniSTS:25571

SHGC-30897 (e-PCR)
- UniSTS:56575

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables ATP binding	IEA Inferred from Electronic Annotation more info
enables eukaryotic translation initiation factor 2alpha kinase activity	IBA Inferred from Biological aspect of Ancestor more info
enables eukaryotic translation initiation factor 2alpha kinase activity	IDA Inferred from Direct Assay more info	PubMed
enables heme binding	ISS Inferred from Sequence or Structural Similarity more info
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein homodimerization activity	ISS Inferred from Sequence or Structural Similarity more info
enables protein serine kinase activity	IEA Inferred from Electronic Annotation more info

Process	Evidence Code	Pubs
involved_in HRI-mediated signaling	IDA Inferred from Direct Assay more info	PubMed
involved_in acute inflammatory response	IEA Inferred from Electronic Annotation more info
involved_in establishment of localization in cell	IEA Inferred from Electronic Annotation more info
involved_in integrated stress response signaling	IDA Inferred from Direct Assay more info	PubMed
involved_in macrophage differentiation	IEA Inferred from Electronic Annotation more info
involved_in multicellular organismal-level iron ion homeostasis	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of cell population proliferation	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of hemoglobin biosynthetic process	ISS Inferred from Sequence or Structural Similarity more info
involved_in negative regulation of translational initiation by iron	NAS Non-traceable Author Statement more info	PubMed
involved_in phagocytosis	IEA Inferred from Electronic Annotation more info
involved_in protein autophosphorylation	ISS Inferred from Sequence or Structural Similarity more info
involved_in protoporphyrinogen IX metabolic process	IEA Inferred from Electronic Annotation more info
involved_in regulation of eIF2 alpha phosphorylation by heme	IEA Inferred from Electronic Annotation more info
involved_in regulation of translational initiation by eIF2 alpha phosphorylation	IBA Inferred from Biological aspect of Ancestor more info
involved_in response to iron ion starvation	IDA Inferred from Direct Assay more info	PubMed

Component	Evidence Code	Pubs
is_active_in cytoplasm	IBA Inferred from Biological aspect of Ancestor more info
is_active_in cytosol	IDA Inferred from Direct Assay more info	PubMed
located_in cytosol	TAS Traceable Author Statement more info
is_active_in nucleus	IBA Inferred from Biological aspect of Ancestor more info

General protein information

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Preferred Names: eukaryotic translation initiation factor 2-alpha kinase 1

Names: heme regulated initiation factor 2 alpha kinase; heme sensitive initiation factor 2a kinase; heme-controlled repressor; heme-regulated eukaryotic initiation factor eIF-2-alpha kinase; heme-regulated inhibitor; heme-regulated repressor; hemin-controlled repressor; hemin-sensitive initiation factor 2-alpha kinase

NP_001127807.1

EC 2.7.11.1

NP_055228.2

EC 2.7.11.1

XP_047276156.1

EC 2.7.11.1

XP_054213880.1

EC 2.7.11.1

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

mRNA and Protein(s)

NM_001134335.2 → NP_001127807.1 eukaryotic translation initiation factor 2-alpha kinase 1 isoform b

See identical proteins and their annotated locations for NP_001127807.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) uses an alternate in-frame splice site at the end of an exon compared to variant 1. The resulting isoform (b) has the same N- and C-termini but is 1 aa shorter compared to isoform a.

Source sequence(s)

AC005995, AL136563, DC341983

UniProtKB/Swiss-Prot

Q9BQI3

Conserved Domains (2) summary

smart00220
Location:167 → 582

S_TKc; Serine/Threonine protein kinases, catalytic domain

cd14049
Location:160 → 580

STKc_EIF2AK1_HRI; Catalytic domain of the Serine/Threonine kinase, eukaryotic translation Initiation Factor 2-Alpha Kinase 2 or Heme-Regulated Inhibitor kinase
NM_014413.4 → NP_055228.2 eukaryotic translation initiation factor 2-alpha kinase 1 isoform a

See identical proteins and their annotated locations for NP_055228.2

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (a).

Source sequence(s)

AC005995, BC006524, DC341983

Consensus CDS

CCDS5345.1

UniProtKB/Swiss-Prot

A8K2R2, Q549K6, Q8NBW3, Q9BQI3, Q9HC02, Q9NYE0, Q9P0V6, Q9P1J5, Q9P2H8, Q9UHG4

Related

ENSP00000199389.6, ENST00000199389.11

Conserved Domains (2) summary

smart00220
Location:167 → 583

S_TKc; Serine/Threonine protein kinases, catalytic domain

cd14049
Location:160 → 581

STKc_EIF2AK1_HRI; Catalytic domain of the Serine/Threonine kinase, eukaryotic translation Initiation Factor 2-Alpha Kinase 2 or Heme-Regulated Inhibitor kinase