PRKRA

Summary

PRKRA (protein activator of interferon induced protein kinase EIF2AK2, HGNC:9438) is a protein-coding gene on chromosome 2q31.2, encoding Interferon-inducible double-stranded RNA-dependent protein kinase activator A (O75569). Activates EIF2AK2/PKR in the absence of double-stranded RNA (dsRNA), leading to phosphorylation of EIF2S1/EFI2-alpha and inhibition of translation and induction of apoptosis.

This gene encodes a protein kinase activated by double-stranded RNA which mediates the effects of interferon in response to viral infection. Mutations in this gene have been associated with dystonia. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 8575 — RefSeq curated summary.

At a glance

• Gene–disease (curated): isolated microphthalmia 3 (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 341 total — 7 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 39
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_003690

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9438
Approved symbol	PRKRA
Name	protein activator of interferon induced protein kinase EIF2AK2
Location	2q31.2
Locus type	gene with protein product
Status	Approved
Aliases	PACT, RAX, HSD14, DYT16
Ensembl gene	ENSG00000180228
Ensembl biotype	protein_coding
OMIM	603424
Entrez	8575

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 16 nonsense_mediated_decay, 11 retained_intron, 10 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000325748, ENST00000424699, ENST00000432031, ENST00000448279, ENST00000457633, ENST00000460433, ENST00000463882, ENST00000466165, ENST00000470200, ENST00000474793, ENST00000487082, ENST00000490501, ENST00000676505, ENST00000676586, ENST00000676752, ENST00000676832, ENST00000676922, ENST00000677136, ENST00000677206, ENST00000677253, ENST00000677386, ENST00000677460, ENST00000677584, ENST00000677689, ENST00000677806, ENST00000677859, ENST00000677981, ENST00000678053, ENST00000678058, ENST00000678167, ENST00000678379, ENST00000678775, ENST00000678813, ENST00000678845, ENST00000679037, ENST00000679202, ENST00000914392, ENST00000914393, ENST00000967043

RefSeq mRNA: 4 — MANE Select: NM_003690 NM_001139517, NM_001139518, NM_001316362, NM_003690

CCDS: CCDS2279, CCDS46460, CCDS46461, CCDS92908

Canonical transcript exons

ENST00000325748 — 8 exons

Exon	Start	End
ENSE00001248246	178431414	178432254
ENSE00001657361	178450966	178451175
ENSE00003538003	178447505	178447586
ENSE00003564337	178436145	178436319
ENSE00003603312	178444422	178444500
ENSE00003612478	178450242	178450411
ENSE00003640748	178443267	178443384
ENSE00003661256	178441610	178441704

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.5635 / max 120.6461, expressed in 1818 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
32014	19.9153	1816
32011	0.8787	539
32010	0.5710	339
32012	0.1839	56
32013	0.0147	4

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	98.45	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.77	gold quality
biceps brachii	UBERON:0001507	97.76	gold quality
male germ cell	CL:0000015	97.28	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.86	gold quality
heart right ventricle	UBERON:0002080	96.41	gold quality
gastrocnemius	UBERON:0001388	96.34	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.31	gold quality
muscle of leg	UBERON:0001383	95.98	gold quality
diaphragm	UBERON:0001103	95.89	gold quality
tibial artery	UBERON:0007610	95.49	gold quality
popliteal artery	UBERON:0002250	95.48	gold quality
descending thoracic aorta	UBERON:0002345	95.35	gold quality
aorta	UBERON:0000947	95.11	gold quality
muscle organ	UBERON:0001630	95.09	gold quality
ganglionic eminence	UBERON:0004023	94.98	gold quality
triceps brachii	UBERON:0001509	94.85	gold quality
right coronary artery	UBERON:0001625	94.78	gold quality
thoracic aorta	UBERON:0001515	94.66	gold quality
ascending aorta	UBERON:0001496	94.57	gold quality
ventricular zone	UBERON:0003053	94.56	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.47	gold quality
lower esophagus	UBERON:0013473	94.46	gold quality
gluteal muscle	UBERON:0002000	94.29	gold quality
embryo	UBERON:0000922	94.24	gold quality
left coronary artery	UBERON:0001626	94.21	gold quality
cauda epididymis	UBERON:0004360	94.21	gold quality
vastus lateralis	UBERON:0001379	94.16	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.14	gold quality
corpus epididymis	UBERON:0004359	94.09	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6108	no	200.33
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

59 targeting PRKRA, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-190A-5P	99.54	71.45	933
HSA-MIR-190B-5P	99.54	71.40	925
HSA-MIR-4452	99.50	68.45	1493
HSA-MIR-154-3P	99.50	70.05	831

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• The C-terminal, third conserved motif of the protein activator PACT plays an essential role in the activation of double-stranded-RNA-dependent protein kinase (PMID:11985496)
• Us11 protein of herpes simplex virus type 1 can block PKR activation by PACT both in vitro and in vivo (PMID:12368348)
• RAX, the cellular activator of PKR, has a novel role in synergistically stimulating SV40 large T antigen-dependent gene expression (PMID:12874289)
• RAX phosphorylation is required for PKR activation, full protein synthesis inhibition, and rapid apoptosis following stress. (PMID:15299031)
• The interaction with Dicer involves the third dsRNA-binding domain (dsRBD) of PACT and the N-terminal region of Dicer containing the helicase motif. Like TRBP, PACT is not required for the pre-microRNA (miRNA) cleavage reaction step. (PMID:16424907)
• RAX (PRKRA) may function as a negative regulator of growth that is required to activate PKR in response to a broad range of apoptosis-inducing stress. (PMID:16861340)
• The underlying biochemical mechanism of the activation of PKR via PACT phosphorylation at specific activation domain residues is reported as the major mode of transmission of cellular stress response to PKR. (PMID:16982605)
• Results show that PACT is expressed ubiquitously in different cell types at varying abundance, and Sp1 is the major transcription factor responsible for PACT promoter activity. (PMID:17125937)
• Results indicate that human TRBP and PACT directly interact with each other and associate with Dicer to stimulate the cleavage of double-stranded or short hairpin RNA to siRNA. (PMID:17452327)
• DYT16, a novel young-onset dystonia-parkinsonism disorder, identification of a segregating mutation in the stress-response protein PRKRA. (PMID:18243799)
• A heterozygous frameshift mutation in PRKRA (DYT16) associated with generalised dystonia in a German patient. (PMID:18420150)
• TRBP controls PACT activation of PKR, an activity that is reversed by stress. (PMID:18936160)
• writer’s cramp as presenting symptom is not associated with mutations in DYT11, DYT16, but it can be the sole manifestation of DYT1 GAG deletion mutation carriers. (PMID:19441135)
• Strong protein kinase R (PKR) binding is needed for PACT-mediated PKR activation and phosphorylation in vivo. (PMID:19580324)
• show that PACT physically binds to the C-terminal repression domain of RIG-I and potently stimulates RIG-I-induced type I interferon production (PMID:21501829)
• results demonstrate for the first time that stress-induced PACT phosphorylation functions to free PACT from the inhibitory interaction with TRBP and also to enhance its interaction with PKR (PMID:21526770)
• though mutation analysis demonstrated no mutation of PACT in the patients of microtia in the present study, suggest that PACT may play an essential role in mammalian ear development (PMID:21595004)
• The PACT-protein kinase PKR pathway represents a potential link between Abeta accumulation, PKR activation and tau phosphorylation. (PMID:21790829)
• NF-kappa-B is involved in the protein activator of PKR-RNA-dependent protein kinase interaction and the production of pro-inflammatory cytokines in periodontitis. (PMID:21882225)
• Altered PRKRA signalling and C / EBPbeta expression is associated with HLA-B27 expression in monocytic cells. (PMID:21988375)
• DGCR8, AGO1, AGO2, PACT, and TARBP1 expression levels were significantly higher in the epithelial skin cancer groups than the healthy controls (P > 0.05). (PMID:22025453)
• Data demonstrate that PACT-PACT interaction is essential for efficient PKR activation. (PMID:22473766)
• PACT may be associated with the plasma cell function and eosinophilic inflammation in CRSwNP. (PMID:22961479)
• RISC proteins PACT, TRBP, and Dicer, together with PKR, are steroid receptor RNA activator-binding nuclear receptor coregulators that are recruited to the promoters of hormone-regulated genes and regulate the expression of downstream target genes. (PMID:23550157)
• in vitro binding patterns of human TRBP and PACT to siRNA (PMID:23658827)
• The results show that PACT and TRBP have distinct effects on Dicer-mediated dsRNA processing. (PMID:23661684)
• Protein kinase R modulates c-Fos and c-Jun signaling to promote proliferation of hepatocellular carcinoma with hepatitis C virus infection. (PMID:23844083)
• Ebola virus VP35 inhibits PACT-induced RIG-I ATPase activity in a dose-dependent manner. (PMID:23870315)
• In contrast to its previously described activity, PACT contributes to PKR dephosphorylation during HIV-1 replication. (PMID:24020926)
• Herpes simplex virus 1 Us11 suppresses host interferon beta1 production through the inhibition of the PACT. (PMID:24067967)
• NS1 prevents PACT from interacting with an essential component of the virus. (PMID:24899174)
• PKR is activated in uninfected cells, specifically during mitosis, by binding to dsRNAs formed by inverted Alu repeats (IRAlus). (PMID:24939934)
• This stuidy provides the first independent replication of the DYT16 locus at 2q31.2 and strongly confirms the causal contribution of the PRKRA gene to DYT16. Our data suggest worldwide involvement of PRKRA in dystonia. (PMID:25142429)
• the affinity of PACT-PACT and PACT-PKR interactions is enhanced in dystonia patient lymphoblasts, thereby leading to intensified PKR activation and enhanced cellular death. (PMID:26231208)
• this study demonstrates for the first time that OV20.0 of Orf virus is also able to interact with the dsRNA binding domain of PACT and that the presence of dsRNA strengthened the interaction of these two molecules. (PMID:26355092)
• The interferon-induced protein kinase(PACT) partially rescued defects of interferon-beta1 and chemokine (C-C motif) ligand 5/RANTES (regulated on activation normal T cell expressed and secreted) induction in DDX3-knockdown HEK293 cells. (PMID:26454002)
• These findings support a model in which a measles virus defective interfering RNA is sensed by PACT and RIG-I to initiate an innate antiviral response via activation of interferon-beta production. (PMID:26608320)
• MicroRNA-122 Inhibits the Production of Inflammatory Cytokines by Targeting the PKR Activator PACT in Human Hepatic Stellate Cells. (PMID:26636761)
• phenotype of our patients overlaps that of previouslyreported DYT16 patients (PMID:26990861)
• High PRKRA mRNA expression is associated with colorectal cancer. (PMID:27859935)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	prkra	ENSDARG00000076718
mus_musculus	Prkra	ENSMUSG00000002731
rattus_norvegicus	Prkra	ENSRNOG00000011195
drosophila_melanogaster	loqs	FBGN0032515
drosophila_melanogaster	CG12493	FBGN0035571
drosophila_melanogaster	blanks	FBGN0035608
drosophila_melanogaster	Zn72D	FBGN0263603
caenorhabditis_elegans	zfr-1	WBGENE00022388

Paralogs (14): STAU2 (ENSG00000040341), ZFR (ENSG00000056097), ADAT1 (ENSG00000065457), ZFR2 (ENSG00000105278), STAU1 (ENSG00000124214), ILF3 (ENSG00000129351), TARBP2 (ENSG00000139546), ADAD2 (ENSG00000140955), ILF2 (ENSG00000143621), ADAR (ENSG00000160710), ADAD1 (ENSG00000164113), STRBP (ENSG00000165209), ADARB2 (ENSG00000185736), ADARB1 (ENSG00000197381)

Protein

Protein identifiers

Interferon-inducible double-stranded RNA-dependent protein kinase activator A — O75569 (reviewed: O75569)

Alternative names: PKR-associated protein X, PKR-associating protein X, Protein activator of the interferon-induced protein kinase, Protein kinase, interferon-inducible double-stranded RNA-dependent activator

All UniProt accessions (16): O75569, A0A7I2V2I8, A0A7I2V2P4, A0A7I2V315, A0A7I2V332, A0A7I2V3J2, A0A7I2V3L6, A0A7I2V593, A0A7I2V5C2, A0A7I2V5H3, A0A7I2YQ87, A0A7I2YQP2, B4DJC7, C9JMM3, F8WEG8, G5E9Q4

UniProt curated annotations — full annotation on UniProt →

Function. Activates EIF2AK2/PKR in the absence of double-stranded RNA (dsRNA), leading to phosphorylation of EIF2S1/EFI2-alpha and inhibition of translation and induction of apoptosis. Required for siRNA production by DICER1 and for subsequent siRNA-mediated post-transcriptional gene silencing. Does not seem to be required for processing of pre-miRNA to miRNA by DICER1. Promotes UBC9-p53/TP53 association and sumoylation and phosphorylation of p53/TP53 at ‘Lys-386’ at ‘Ser-392’ respectively and enhances its activity in a EIF2AK2/PKR-dependent manner. May function as regulator of gastric epithelial differentiation.

Subunit / interactions. Homodimer. Interacts with EIF2AK2/PKR through its DRBM domains. Interacts with DICER1, AGO2 and TARBP2. Also able to interact with dsRNA. Interacts with UBC9. Forms a complex with UBC9 and p53/TP53. Interacts with DUS2L (via DRBM domain). Interacts with RIGI. (Microbial infection) Interacts with ebolavirus protein VP35; this interaction inhibits the interaction between RIGI and PRKRA. In addition, this interaction disrupts the interaction between VP35 and the viral polymerase L. So the VP35-PRKRA interaction plays a critical role in determining the outcome of ebolavirus infection. The interaction PRKRA-VP35 also prevents PRKRA binding to DICER1 and thus allows the virus to counteract host RNA silencing. (Microbial infection) Interacts with human herpesvirus 8 protein MTA/ORF57; this interaction inhibits stress granule formation.

Subcellular location. Cytoplasm. Perinuclear region.

Post-translational modifications. Phosphorylated at Ser-246 in unstressed cells and at Ser-287 in stressed cells. Phosphorylation at Ser-246 appears to be a prerequisite for subsequent phosphorylation at Ser-287. Phosphorylation at Ser-246 and Ser-287 are necessary for activation of EIF2AK2/PKR under conditions of stress.

Disease relevance. Dystonia 16 (DYT16) [MIM:612067] An early-onset dystonia-parkinsonism disorder. Dystonia is defined by the presence of sustained involuntary muscle contraction, often leading to abnormal postures. DYT16 patients have progressive, generalized dystonia with axial muscle involvement, oro-mandibular (sardonic smile) and laryngeal dystonia and, in some cases, parkinsonian features. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Self-association may occur via interactions between DRBM domains as follows: DRBM 1/DRBM 1, DRBM 1/DRBM 2, DRBM 2/DRBM 2 or DRBM 3/DRBM3.

Similarity. Belongs to the PRKRA family.

Isoforms (3)

UniProt ID	Names	Canonical?
O75569-1	1	yes
O75569-2	2
O75569-3	3

RefSeq proteins (4): NP_001132989, NP_001132990, NP_001303291, NP_003681* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR014720	dsRBD_dom	Domain
IPR044465	PRKRA_DSRM_1	Domain
IPR044466	PRKRA_DSRM_2	Domain
IPR044467	PRKRA_DSRM_3	Domain
IPR051247	RLC_Component	Family

Pfam: PF00035

UniProt features (38 total): mutagenesis site 15, modified residue 4, strand 4, region of interest 4, domain 3, splice variant 2, helix 2, chain 1, sequence variant 1, sequence conflict 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2DIX	SOLUTION NMR
8ZU6	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75569-F1	75.55	0.33

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (4): 167, 246, 287, 18

Mutagenesis-validated functional residues (15):

Position	Phenotype
18	no effect on apoptosis induction under conditions of stress.
18	does not induce apoptosis.
243	abrogates apoptosis induction under conditions of stress.
246	abrogates apoptosis induction under conditions of stress and binding to eif2ak2. prevents activation of eif2ak2 in stres
246	induces activation of eif2ak2 and apoptosis in unstressed cells; when associated with d-287.
260	abrogates apoptosis induction under conditions of stress.
262	abrogates apoptosis induction under conditions of stress.
265	abrogates apoptosis induction under conditions of stress.
271	abrogates apoptosis induction under conditions of stress.
279	abrogates apoptosis induction under conditions of stress.
287	abrogates apoptosis induction under conditions of stress. prevents activation of eif2ak2 in stressed cells; when associa
287	induces activation of eif2ak2 and apoptosis in unstressed cells; when associated with d-246.
288	abrogates apoptosis induction under conditions of stress.
291	abrogates apoptosis induction under conditions of stress.
298–299	abrogates interaction with dicer1 but does not affect interaction with ago2.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-203927	MicroRNA (miRNA) biogenesis
R-HSA-426486	Small interfering RNA (siRNA) biogenesis
R-HSA-9833482	PKR-mediated signaling

MSigDB gene sets: 375 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, BENPORATH_ES_WITH_H3K27ME3, GCM_GSPT1, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GCM_ZNF198, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, LHX3_01, BOYLAN_MULTIPLE_MYELOMA_D_DN

GO Biological Process (17): immune response (GO:0006955), negative regulation of cell population proliferation (GO:0008285), response to virus (GO:0009615), siRNA processing (GO:0030422), pre-miRNA processing (GO:0031054), cellular response to oxidative stress (GO:0034599), miRNA processing (GO:0035196), outer ear morphogenesis (GO:0042473), middle ear morphogenesis (GO:0042474), skeletal system morphogenesis (GO:0048705), protein stabilization (GO:0050821), regulation of regulatory ncRNA processing (GO:0070920), RISC complex assembly (GO:0070922), antiviral innate immune response (GO:0140374), positive regulation of intrinsic apoptotic signaling pathway (GO:2001244), regulatory ncRNA-mediated gene silencing (GO:0031047), ear development (GO:0043583)

GO Molecular Function (11): RNA binding (GO:0003723), double-stranded RNA binding (GO:0003725), enzyme activator activity (GO:0008047), enzyme binding (GO:0019899), siRNA binding (GO:0035197), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), pre-miRNA binding (GO:0070883), protein binding (GO:0005515), kinase activity (GO:0016301), protein kinase activator activity (GO:0030295)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), RISC complex (GO:0016442), perinuclear region of cytoplasm (GO:0048471), RISC-loading complex (GO:0070578)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Gene Silencing by RNA	2
Antimicrobial mechanism of IFN-stimulated genes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
regulatory ncRNA processing	3
ear morphogenesis	2
embryonic morphogenesis	2
RNA binding	2
protein binding	2
cytoplasm	2
immune system process	1
response to stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
response to other organism	1
miRNA processing	1
response to oxidative stress	1
cellular response to chemical stress	1
skeletal system development	1
animal organ morphogenesis	1
regulation of protein stability	1
regulation of gene silencing by regulatory ncRNA	1
regulation of primary metabolic process	1
protein-RNA complex assembly	1
regulatory ncRNA-mediated gene silencing	1
innate immune response	1
defense response to virus	1
intrinsic apoptotic signaling pathway	1
positive regulation of intracellular signal transduction	1
positive regulation of apoptotic signaling pathway	1
regulation of intrinsic apoptotic signaling pathway	1
negative regulation of gene expression	1
sensory organ development	1
nucleic acid binding	1
catalytic activity	1
enzyme regulator activity	1
molecular function activator activity	1
regulatory RNA binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
transferase activity, transferring phosphorus-containing groups	1

Protein interactions and networks

STRING

1560 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRKRA	DICER1	Q9UPY3	994
PRKRA	EIF2AK2	P19525	925
PRKRA	TARBP2	Q15633	875
PRKRA	AGO1	Q9UL18	719
PRKRA	AGO2	Q9UKV8	702
PRKRA	THAP1	Q9NVV9	664
PRKRA	FMR1	Q06787	660
PRKRA	XPO5	Q9HAV4	644
PRKRA	DROSHA	Q9NRR4	638
PRKRA	RIGI	O95786	623
PRKRA	DNAJC3	Q13217	616
PRKRA	DGCR8	Q8WYQ5	610
PRKRA	IFIH1	Q9BYX4	610
PRKRA	SGCE	O43556	597
PRKRA	TOR1A	O14656	571

IntAct

300 interactions, top by confidence:

A	B	Type	Score
TARBP2	PRKRA	psi-mi:“MI:0915”(physical association)	0.920
PRKRA	TARBP2	psi-mi:“MI:0915”(physical association)	0.920
LYAR	PRKRA	psi-mi:“MI:0915”(physical association)	0.800
PRKRA	PRKRA	psi-mi:“MI:0915”(physical association)	0.800
PRKRA	LYAR	psi-mi:“MI:0915”(physical association)	0.800
DICER1	PRKRA	psi-mi:“MI:0407”(direct interaction)	0.800
DICER1	PRKRA	psi-mi:“MI:0914”(association)	0.800
PRKRA	EIF2AK2	psi-mi:“MI:0915”(physical association)	0.800
N	PRKRA	psi-mi:“MI:0915”(physical association)	0.780
PRKRA	N	psi-mi:“MI:0915”(physical association)	0.780
PRKRA	N	psi-mi:“MI:0403”(colocalization)	0.780
N	PRKRA	psi-mi:“MI:0403”(colocalization)	0.780
NKRF	PRKRA	psi-mi:“MI:0915”(physical association)	0.740
PRKRA	RIGI	psi-mi:“MI:0914”(association)	0.690
PRKRA	RIGI	psi-mi:“MI:0915”(physical association)	0.690

BioGRID (550): PRKRA (Two-hybrid), PRKRA (Two-hybrid), LYAR (Two-hybrid), ZMAT3 (Two-hybrid), PRKRA (Affinity Capture-MS), PRKRA (Affinity Capture-MS), PRKRA (Affinity Capture-MS), PRKRA (Affinity Capture-MS), PRKRA (Co-fractionation), PRKRA (Affinity Capture-MS), PRKRA (Proximity Label-MS), PRKRA (Two-hybrid), PRKRA (Affinity Capture-MS), TARBP2 (Two-hybrid), BTRC (Affinity Capture-Western)

ESM2 similar proteins: B0V3F8, D2GVP7, E1BVR9, E9PYK3, O75569, O82387, O95793, P51400, P55265, P55266, P78563, P86049, Q08BH5, Q0P4R6, Q10HL3, Q175F8, Q2HJ92, Q32PY6, Q3EBC8, Q3U3W5, Q4R2Z0, Q4R3W5, Q4V8C7, Q5M7M7, Q5N870, Q5N8Z0, Q5T8I9, Q5W9E7, Q68SB1, Q6DCB7, Q6P2P2, Q7XD96, Q7ZW47, Q7ZYA5, Q8BGG7, Q8CAE2, Q8CJ67, Q8K4M9, Q8NHP6, Q8TBY0

Diamond homologs: A1AE97, A1JKK3, A3MZQ9, A4TKX8, A5F5H8, A6TCI1, A7FFT9, A7ZQ11, A8A377, A8F397, A8GI25, A8GM79, A8GYE2, A9R402, A9WJ69, B0BUA6, B0V3F8, B1IVR0, B1LP80, B1XB41, B2TXY0, B2VI46, B4F047, B5BAT0, B5QTU8, B5RD49, B5XNH0, B5Z141, B6I5E1, B7LDG0, B7LUZ7, B7M8I0, B7MIQ2, B7MYJ8, B7N6F5, B7NRM0, B7UH07, B8GAM6, B9KGT5, B9LB70

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PRKRA	“form complex”	DICER1/hAgo2/PRKRA	binding
EIF2AK2	“up-regulates activity”	PRKRA	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 136 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
MicroRNA (miRNA) biogenesis	5	27.2×	3e-05
Peptide chain elongation	14	21.1×	3e-13
Viral mRNA Translation	14	21.1×	3e-13
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	14	20.9×	3e-13
Selenocysteine synthesis	14	20.0×	4e-13
Eukaryotic Translation Termination	14	20.0×	4e-13
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	14	19.6×	4e-13
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	14	19.6×	4e-13

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	16	26.5×	7e-16
translation	17	15.6×	3e-13
ribosomal small subunit biogenesis	7	14.2×	1e-04
negative regulation of translation	7	12.2×	2e-04
protein import into nucleus	6	7.7×	7e-03
rRNA processing	6	7.6×	7e-03
defense response to virus	8	5.0×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

341 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	7
Uncertain significance	175
Likely benign	84
Benign	29

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1723189	NM_013435.3(RAX):c.560G>A (p.Arg187Gln)	Pathogenic
1723190	NM_013435.3(RAX):c.266del (p.Pro89fs)	Pathogenic
1879402	NM_013435.3(RAX):c.499G>T (p.Glu167Ter)	Pathogenic
6347	NM_003690.5(PRKRA):c.267_268del (p.His89fs)	Pathogenic
7635	NM_013435.3(RAX):c.439C>T (p.Gln147Ter)	Pathogenic
7636	NM_013435.3(RAX):c.575G>A (p.Arg192Gln)	Pathogenic
7638	NM_013435.3(RAX):c.909C>G (p.Tyr303Ter)	Pathogenic
1049461	NM_003690.5(PRKRA):c.610-1_610insGAATGCTGCTGAGAAATTTCTTGCCAAATTTAGTAATATTTCTCCAGAGAACCACATTTCTTTA	Likely pathogenic
1723188	NM_013435.3(RAX):c.543+3A>G	Likely pathogenic
3247289	NC_000002.11:g.(?179296824)(179502166_?)dup	Likely pathogenic
3583379	NM_013435.3(RAX):c.50_53dup (p.Gly19fs)	Likely pathogenic
3772677	NM_003690.5(PRKRA):c.74A>G (p.Lys25Arg)	Likely pathogenic
504029	NM_013435.3(RAX):c.262_263delinsA (p.Ala88fs)	Likely pathogenic
932556	NM_013435.3(RAX):c.106G>T (p.Glu36Ter)	Likely pathogenic

SpliceAI

1413 predictions. Top by Δscore:

Variant	Effect	Δscore
2:178436147:ATAT:A	donor_gain	1.0000
2:178436177:T:TA	donor_gain	1.0000
2:178436315:TTTGT:T	acceptor_gain	1.0000
2:178436320:C:CC	acceptor_gain	1.0000
2:178441608:A:AC	donor_gain	1.0000
2:178441609:C:CC	donor_gain	1.0000
2:178443287:AG:A	donor_gain	1.0000
2:178444499:AG:A	acceptor_gain	1.0000
2:178449373:T:TA	donor_gain	1.0000
2:178436138:ATCAT:A	donor_loss	0.9900
2:178436139:TCATA:T	donor_loss	0.9900
2:178436140:CATAC:C	donor_loss	0.9900
2:178436141:ATAC:A	donor_loss	0.9900
2:178436142:TA:T	donor_loss	0.9900
2:178436143:A:AG	donor_loss	0.9900
2:178436144:CC:C	donor_loss	0.9900
2:178436316:TTGT:T	acceptor_gain	0.9900
2:178436317:TGT:T	acceptor_gain	0.9900
2:178436318:GT:G	acceptor_gain	0.9900
2:178436318:GTC:G	acceptor_loss	0.9900
2:178436320:CTGAA:C	acceptor_loss	0.9900
2:178436321:TGAAA:T	acceptor_loss	0.9900
2:178436322:GAAAA:G	acceptor_loss	0.9900
2:178436323:AAAAA:A	acceptor_loss	0.9900
2:178441637:A:AC	donor_gain	0.9900
2:178443288:G:A	donor_gain	0.9900
2:178444498:AAG:A	acceptor_gain	0.9900
2:178444501:C:CC	acceptor_gain	0.9900
2:178444501:CTA:C	acceptor_loss	0.9900
2:178444502:T:C	acceptor_loss	0.9900

AlphaMissense

2068 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:178447538:G:T	A95D	1.000
2:178447548:C:G	A92P	1.000
2:178447558:T:A	K88N	1.000
2:178447558:T:G	K88N	1.000
2:178432135:C:G	A302P	0.999
2:178432147:C:G	A298P	0.999
2:178432221:A:G	L273P	0.999
2:178441665:G:T	A185D	0.999
2:178441666:C:G	A185P	0.999
2:178441668:G:T	A184D	0.999
2:178441669:C:G	A184P	0.999
2:178441676:T:A	K181N	0.999
2:178441676:T:G	K181N	0.999
2:178441681:C:G	A180P	0.999
2:178441688:T:A	K177N	0.999
2:178441688:T:G	K177N	0.999
2:178443292:G:C	C163W	0.999
2:178443294:A:G	C163R	0.999
2:178443348:A:G	Y145H	0.999
2:178443353:G:T	P143H	0.999
2:178443377:G:T	A135D	0.999
2:178444426:A:G	L131S	0.999
2:178447539:C:G	A95P	0.999
2:178447547:G:T	A92E	0.999
2:178447550:G:T	A91D	0.999
2:178447551:C:G	A91P	0.999
2:178447570:C:A	K84N	0.999
2:178447570:C:G	K84N	0.999
2:178447581:C:G	G81R	0.999
2:178450268:A:T	V70E	0.999

dbSNP variants (sampled 300 via entrez): RS1000176496 (2:178448826 GTAGT>G), RS1000208344 (2:178452579 AT>A,ATT), RS1000239298 (2:178452769 G>A), RS1000277615 (2:178449465 T>A), RS1000574880 (2:178439839 G>A), RS1000594473 (2:178440432 A>G), RS1000924250 (2:178437330 A>C), RS1001008706 (2:178450821 G>A,C), RS1001060221 (2:178445008 T>G), RS1001114014 (2:178444720 G>A), RS1001210574 (2:178447187 T>A,C), RS1001236031 (2:178434476 G>A), RS1001359814 (2:178440991 C>T), RS1001376575 (2:178436883 C>A), RS1001417028 (2:178441198 A>G)

Disease associations

OMIM: gene MIM:603424 | disease phenotypes: MIM:612067, MIM:611038, MIM:604145, MIM:608807

GenCC curated gene-disease

Disease	Classification	Inheritance
isolated microphthalmia 3	Definitive	Autosomal recessive
dystonia 16	Strong	Autosomal recessive
isolated anophthalmia-microphthalmia syndrome	Supportive	Autosomal dominant
coloboma	Limited	Autosomal recessive

Mondo (6): dystonia 16 (MONDO:0012789), isolated microphthalmia 3 (MONDO:0012604), dilated cardiomyopathy 1G (MONDO:0011400), autosomal recessive limb-girdle muscular dystrophy type 2J (MONDO:0012127), isolated anophthalmia-microphthalmia syndrome (MONDO:0016764), coloboma (MONDO:0001476)

Orphanet (4): Dystonia 16 (Orphanet:210571), Isolated microphthalmia-anophthalmia-coloboma (Orphanet:2542), Titin-related limb-girdle muscular dystrophy R10 (Orphanet:140922), Familial isolated dilated cardiomyopathy (Orphanet:154)

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000473	Torticollis
HP:0000486	Strabismus
HP:0000501	Glaucoma
HP:0000528	Anophthalmia
HP:0000568	Microphthalmia
HP:0000610	Abnormal choroid morphology
HP:0000647	Sclerocornea
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001260	Dysarthria
HP:0001270	Motor delay
HP:0001288	Gait disturbance
HP:0001300	Parkinsonism
HP:0001347	Hyperreflexia
HP:0001618	Dysphonia
HP:0002015	Dysphagia
HP:0002062	Abnormal pyramidal tract morphology
HP:0002067	Bradykinesia
HP:0002174	Postural tremor
HP:0002310	Orofacial dyskinesia
HP:0002317	Unsteady gait
HP:0002451	Limb dystonia
HP:0002544	Retrocollis
HP:0003621	Juvenile onset
HP:0003676	Progressive
HP:0004305	Involuntary movements
HP:0007256	Abnormal pyramidal sign
HP:0007325	Generalized dystonia
HP:0007703	Abnormal retinal pigmentation

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001892_2	Multiple sclerosis (OCB status)	3.000000e-07
GCST002740_13	Inflammatory skin disease	1.000000e-34
GCST003332_1	Rapid functional decline in sporadic amyotrophic lateral sclerosis	2.000000e-08
GCST003837_8	Chronotype	7.000000e-10
GCST003838_8	Morning vs. evening chronotype	1.000000e-06
GCST006976_20	Macular thickness	7.000000e-24
GCST009612_2	Triglyceride levels x thiazide or thiazide-like diuretics use interaction	5.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005206	oligoclonal band measurement
EFO:0007784	functional decline measurement
EFO:0004530	triglyceride measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003103	Coloboma	C11.250.110; C11.270.147; C16.131.384.282
C565824	Cardiomyopathy, Dilated, 1g (supp.)
C567430	Dystonia 16 (supp.)
C567025	Microphthalmia, Isolated 3 (supp.)
C563854	Muscular Dystrophy, Limb-Girdle, Type 2J (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

37 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	4
bisphenol A	increases expression, affects expression	2
sodium arsenite	affects cotreatment, decreases expression	2
Doxorubicin	decreases expression, affects phosphorylation, affects response to substance	2
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
2,4,6-tribromophenol	decreases expression	1
lead acetate	affects cotreatment, decreases expression	1
beta-lapachone	decreases expression	1
coumarin	increases phosphorylation	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases expression, increases abundance	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	increases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	increases expression	1
Hydrogen Peroxide	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Ribonucleotides	affects binding	1

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 1 transformed cell line, 1 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3EZ	Abcam HEK293T PRKRA KO	Transformed cell line	Female
CVCL_TH05	HAP1 PRKRA (-) 1	Cancer cell line	Male
CVCL_TH06	HAP1 PRKRA (-) 2	Cancer cell line	Male
CVCL_TH07	HAP1 PRKRA (-) 3	Cancer cell line	Male
CVCL_YP36	NH50198	Finite cell line	Male

Clinical trials (associated diseases)

5 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00368004	Not specified	TERMINATED	Family Studies of Uveal Coloboma
NCT01778543	Not specified	RECRUITING	Pathogenesis and Genetics of Microphthalmia, Anophthalmia and Uveal Coloboma (MAC)
NCT04833361	Not specified	COMPLETED	Potential Environmental Causes of Uveal Coloboma
NCT06293560	Not specified	RECRUITING	Microphthalmia, Anophthalmia, and Coloboma Genetic Epidemiology in Children
NCT05989620	Not specified	RECRUITING	Long-Term Development of Muscular Dystrophy Outcome Assessments