DGKE

Summary

DGKE (diacylglycerol kinase epsilon, HGNC:2852) is a protein-coding gene on chromosome 17q22, encoding Diacylglycerol kinase epsilon (P52429). Membrane-bound diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids.

Diacylglycerol kinases are thought to be involved mainly in the regeneration of phosphatidylinositol (PI) from diacylglycerol in the PI-cycle during cell signal transduction. When expressed in mammalian cells, DGK-epsilon shows specificity for arachidonyl-containing diacylglycerol. DGK-epsilon is expressed predominantly in testis.

Source: NCBI Gene 8526 — RefSeq curated summary.

At a glance

• Gene–disease (curated): atypical hemolytic-uremic syndrome with DGKE deficiency (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 351 total — 25 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 17
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_003647

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2852
Approved symbol	DGKE
Name	diacylglycerol kinase epsilon
Location	17q22
Locus type	gene with protein product
Status	Approved
Aliases	DAGK6, DGK
Ensembl gene	ENSG00000153933
Ensembl biotype	protein_coding
OMIM	601440
Entrez	8526

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000284061, ENST00000570738, ENST00000571084, ENST00000572810, ENST00000572944, ENST00000576869, ENST00000878324, ENST00000878325, ENST00000951727

RefSeq mRNA: 1 — MANE Select: NM_003647 NM_003647

CCDS: CCDS11590

Canonical transcript exons

ENST00000284061 — 12 exons

Exon	Start	End
ENSE00001013200	56862612	56869567
ENSE00001101880	56848696	56848853
ENSE00001101884	56847922	56848065
ENSE00001101901	56862140	56862251
ENSE00001101903	56861791	56861918
ENSE00001101904	56849181	56849232
ENSE00001101907	56858594	56858665
ENSE00001101915	56856512	56856625
ENSE00001301686	56834151	56834260
ENSE00003484706	56834778	56835259
ENSE00003635024	56844019	56844178
ENSE00003682462	56845690	56845809

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 90.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.4003 / max 101.8605, expressed in 1597 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161810	7.4003	1597

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	90.18	gold quality
middle temporal gyrus	UBERON:0002771	89.78	gold quality
buccal mucosa cell	CL:0002336	89.33	gold quality
parietal lobe	UBERON:0001872	85.79	gold quality
postcentral gyrus	UBERON:0002581	85.48	gold quality
lateral globus pallidus	UBERON:0002476	85.08	gold quality
superior frontal gyrus	UBERON:0002661	84.96	gold quality
endothelial cell	CL:0000115	84.89	gold quality
lateral nuclear group of thalamus	UBERON:0002736	84.49	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.46	gold quality
entorhinal cortex	UBERON:0002728	84.43	gold quality
calcaneal tendon	UBERON:0003701	83.81	gold quality
primary visual cortex	UBERON:0002436	82.52	gold quality
medial globus pallidus	UBERON:0002477	82.38	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.30	gold quality
globus pallidus	UBERON:0001875	82.22	gold quality
occipital lobe	UBERON:0002021	82.12	gold quality
cardia of stomach	UBERON:0001162	81.83	gold quality
tendon	UBERON:0000043	81.40	gold quality
cerebellar cortex	UBERON:0002129	80.70	gold quality
cerebellar hemisphere	UBERON:0002245	80.69	gold quality
superior vestibular nucleus	UBERON:0007227	80.49	gold quality
tendon of biceps brachii	UBERON:0008188	80.48	gold quality
ventral tegmental area	UBERON:0002691	80.32	gold quality
pons	UBERON:0000988	79.90	gold quality
cerebellum	UBERON:0002037	79.85	gold quality
right hemisphere of cerebellum	UBERON:0014890	79.85	gold quality
dorsal root ganglion	UBERON:0000044	79.67	gold quality
colonic epithelium	UBERON:0000397	78.86	gold quality
prefrontal cortex	UBERON:0000451	78.51	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT2

miRNA regulators (miRDB)

224 targeting DGKE, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 24)

• The hydrophobic domain of diacylglycerol kinase epsilon does not contribute to substrate specificity but plays a role in permanently sequestering the enzyme to a membrane. (PMID:17455907)
• The alpha and zeta isoforms of diacylglycerol kinase are inhibited by 2,3-dioleoylglycerol, but not the more substrate-selective epsilon isoform (PMID:18004883)
• Substrate specificity of diacylglycerol kinase epsilon is determined by selectivity of the sn-1 and sn-2 acyl chains phosphatidic acid or diacylglycerol. (PMID:19744926)
• Data show that Diacylglycerol that 2-arachidonoyl glycerol is a very poor substrate for either the epsilon or the zeta isoforms of diacylglycerol kinases. (PMID:21194521)
• DGK activity is reduced by oxidative stress in human mesangial cells cultured under high glucose conditions. (PMID:21725595)
• A role for diacylglycerol kinase (DGK) and its downstream product phosphatidic acid (PA) in ANCA-induced neutrophil exocytosis, is reported. (PMID:21833457)
• diacylglycerol kinase-epsilon (DGKepsilon) has less preference for the acyl chain at the sn-1 position of diacylglycerol (DAG) than the one at the sn-2 position (PMID:22108654)
• The region responsible for this arachidonoyl specificity is the lipoxygenase (LOX)-like motif found in the accessory domain, adjacent to DGKvarepsilon’s catalytic site. (PMID:22266092)
• Inhibition of lipid signaling enzyme diacylglycerol kinase epsilon attenuates mutant huntingtin toxicity. (PMID:22511757)
• Substrate specificity of DGKE is not a consequence of competition with hydrolysis of ATP. (PMID:23261795)
• performed homozygosity mapping and whole exome sequencing in a Turkish consanguineous family and identified DGKE gene variants as the cause of a membranoproliferative-like glomerular microangiopathy (PMID:23274426)
• Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. (PMID:23542698)
• Fully activating high-density transfected muscarinic receptors (M1Rs) by oxotremorine-M (Oxo-M) leads to similar calcium, DAG, and PKC signals, but PIP2 is depleted. (PMID:23630338)
• DGKzeta localizes to the nucleus and is considered to regulate nuclear diacylglycerol signaling.[review] (PMID:24119575)
• Our study expands the clinical phenotypes associated with mutations in DGKE and challenges the benefits of complement blockade treatment in such patients (PMID:24511134)
• Data suggest that complement dysregulation influences the onset and disease severity in carriers of diacylglycerol kinase-epsilon mutations (PMID:25135762)
• DGKE silencing in resting endothelial cells does not affect complement activation at their surface. (PMID:25498910)
• Report DGKE intronic mutations located beyond the exon-intron boundaries in familial hemolytic uremic syndrome. (PMID:25854283)
• Letter/Case Report: atypical haemolytic uraemic syndrome in a Japanese patient with DGKE genetic mutations. (PMID:26018111)
• mutations can lead to atypical hemolytic uremic syndrome or membranoproliferative glomerulonephritis (PMID:28526779)
• Various phenotypes of disease associated with mutated DGKE gene. (PMID:32413569)
• Loss of diacylglycerol kinase epsilon causes thrombotic microangiopathy by impairing endothelial VEGFA signaling. (PMID:33986189)
• An intact zinc finger motif of the C1B domain is critical for stability and activity of diacylglycerol kinase-epsilon. (PMID:36113832)
• Diacylglycerol kinase-epsilon is S-palmitoylated on cysteine in the cytoplasmic end of its N-terminal transmembrane fragment. (PMID:38008259)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	dgke	ENSDARG00000104793
mus_musculus	Dgke	ENSMUSG00000000276
rattus_norvegicus	Dgke	ENSRNOG00000002338
drosophila_melanogaster	CG34384	FBGN0085413
drosophila_melanogaster	rdgA	FBGN0261549
caenorhabditis_elegans		WBGENE00006483
caenorhabditis_elegans		WBGENE00019428

Paralogs (9): DGKG (ENSG00000058866), DGKA (ENSG00000065357), DGKD (ENSG00000077044), DGKH (ENSG00000102780), DGKB (ENSG00000136267), DGKQ (ENSG00000145214), DGKZ (ENSG00000149091), DGKI (ENSG00000157680), DGKK (ENSG00000274588)

Protein

Protein identifiers

Diacylglycerol kinase epsilon — P52429 (reviewed: P52429)

Alternative names: Diglyceride kinase epsilon

All UniProt accessions (4): P52429, A1L4Q0, I3L112, I3L2V2

UniProt curated annotations — full annotation on UniProt →

Function. Membrane-bound diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids. Thereby, acts as a central switch between the signaling pathways activated by these second messengers with different cellular targets and opposite effects in numerous biological processes. Also plays an important role in the biosynthesis of complex lipids. Displays specificity for diacylglycerol substrates with an arachidonoyl acyl chain at the sn-2 position, with the highest activity toward 1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycerol the main diacylglycerol intermediate within the phosphatidylinositol turnover cycle. Can also phosphorylate diacylglycerol substrates with a linoleoyl acyl chain at the sn-2 position but much less efficiently.

Subcellular location. Membrane. Cytoplasm.

Tissue specificity. Expressed predominantly in testis. Expressed in endothelium, platelets and podocytes (at protein level).

Disease relevance. Nephrotic syndrome 7 (NPHS7) [MIM:615008] A form of nephrotic syndrome, a renal disease clinically characterized by severe proteinuria, resulting in complications such as hypoalbuminemia, hyperlipidemia and edema. NPHS7 is an autosomal recessive form characterized by onset of proteinuria usually in the first decade of life. The disorder is progressive, and some patients develop end-stage renal disease within several years. Renal biopsy typically shows membranoproliferative glomerulonephritis. The disease is caused by variants affecting the gene represented in this entry. Hemolytic uremic syndrome, atypical, 7 (AHUS7) [MIM:615008] An atypical form of hemolytic uremic syndrome characterized by acute onset in the first year of life of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. After the acute episode, most patients develop chronic renal insufficiency. Unlike other genetic forms of aHUS, AHUS7 is not related to abnormal activation of the complement system. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. Undergoes competitive inhibition by its own product 1,2-diacyl-sn-glycero-3-phosphate/phosphatidic acid. The strongest inhibition being observed in vitro with 1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphate, a major intermediate in the phosphatidylinositol turnover cycle and more generally by diacylglycerols with an arachidonoyl acyl chain at the sn-2 position.

Pathway. Lipid metabolism; glycerolipid metabolism.

Similarity. Belongs to the eukaryotic diacylglycerol kinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P52429-1	1	yes
P52429-2	2

RefSeq proteins (1): NP_003638* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000756	Diacylglycerol_kin_accessory	Domain
IPR001206	Diacylglycerol_kinase_cat_dom	Domain
IPR002219	PKC_DAG/PE	Domain
IPR016064	NAD/diacylglycerol_kinase_sf	Homologous_superfamily
IPR017438	ATP-NAD_kinase_N	Homologous_superfamily
IPR037607	DGK	Family
IPR046349	C1-like_sf	Homologous_superfamily

Pfam: PF00130, PF00609, PF00781

Enzyme classification (BRENDA):

• EC 2.7.1.107 — diacylglycerol kinase (ATP) (BRENDA: 27 organisms, 171 substrates, 108 inhibitors, 81 Km, 16 kcat entries)

Substrate kinetics (BRENDA)

16 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.05–4.8	46
GTP	0.03–8.7	5
DIOLEIN	0.05–0.08	3
1,2-DIARACHIDONOYL-GLYCEROL	0.09–0.14	2
1-STEAROYL-2-ARACHIDONOYL-SN-GLYCEROL	0.07–0.09	2
SN-1,2-DIOLEOYLGLYCEROL	0.1–0.125	2
1,2-DIACYL-SN-GLYCEROL	0.25	1
1,2-DIOLEIN	0.45	1
1,2-DIOLEOYL-SN-GLYCEROL	0.125	1
2’-DEOXY-ATP	4.2	1
ADP	1	1
CERAMIDE	0.23	1
DIOLEOYLGLYCEROL	0.9	1
ITP	5.9	1
1-STEAROYL-2-LINOLEOYL-SN-GLYCEROL	—	0

Catalyzed reactions (Rhea), 8 shown:

• a 1,2-diacyl-sn-glycerol + ATP = a 1,2-diacyl-sn-glycero-3-phosphate + ADP + H(+) (RHEA:10272)
• 1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycerol + ATP = 1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphate + ADP + H(+) (RHEA:40323)
• 1,2-di-(9Z-octadecenoyl)-sn-glycerol + ATP = 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphate + ADP + H(+) (RHEA:40327)
• 1-eicosanoyl-2-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-sn-glycerol + ATP = 1-eicosanoyl-2-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-sn-glycero-3-phosphate + ADP + H(+) (RHEA:40331)
• 1-hexadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycerol + ATP = 1-hexadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphate + ADP + H(+) (RHEA:40335)
• 1-octadecanoyl-2-(9Z,12Z)-octadecadienoyl-sn-glycerol + ATP = 1-octadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphate + ADP + H(+) (RHEA:40339)
• 1,2-di-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-sn-glycerol + ATP = 1,2-di-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-sn-glycero-3-phosphate + ADP + H(+) (RHEA:40351)
• 1,2-di-(9Z,12Z-octadecadienoyl)-sn-glycerol + ATP = 1,2-di-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphate + ADP + H(+) (RHEA:40355)

UniProt features (16 total): mutagenesis site 6, sequence variant 3, zinc finger region 2, splice variant 2, chain 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P52429-F1	86.18	0.59

Functional residue map

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

Mutagenesis-validated functional residues (6):

Position	Phenotype
431	decreased diacylglycerol kinase activity toward 1-octadecanoyl-2-(5z,8z,11z,14z-eicosatetraenoyl)-sn-glycerol.
431	loss of diacylglycerol kinase activity toward 1-octadecanoyl-2-(5z,8z,11z,14z-eicosatetraenoyl)-sn-glycerol.
438	decreased diacylglycerol kinase activity toward 1-octadecanoyl-2-(5z,8z,11z,14z-eicosatetraenoyl)-sn-glycerol.
438	decreased protein abundance and diacylglycerol kinase activity toward 1-octadecanoyl-2-(5z,8z,11z,14z-eicosatetraenoyl)-
438	loss of diacylglycerol kinase activity toward 1-octadecanoyl-2-(5z,8z,11z,14z-eicosatetraenoyl)-sn-glycerol.
439	decreased diacylglycerol kinase activity toward 1-octadecanoyl-2-(5z,8z,11z,14z-eicosatetraenoyl)-sn-glycerol.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-114508	Effects of PIP2 hydrolysis

MSigDB gene sets: 243 (showing top): GOBP_LIPID_MODIFICATION, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GOBP_PLATELET_ACTIVATION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CELL_CELL_SIGNALING, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_WOUND_HEALING, REACTOME_EFFECTS_OF_PIP2_HYDROLYSIS, MODULE_99, GOBP_GLYCEROLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROPHOSPHOLIPID_METABOLIC_PROCESS

GO Biological Process (12): phosphatidic acid biosynthetic process (GO:0006654), phosphatidylinositol biosynthetic process (GO:0006661), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), platelet activation (GO:0030168), intracellular signal transduction (GO:0035556), diacylglycerol metabolic process (GO:0046339), glycerolipid metabolic process (GO:0046486), lipid phosphorylation (GO:0046834), modulation of chemical synaptic transmission (GO:0050804), lipid metabolic process (GO:0006629), signal transduction (GO:0007165), glycerophospholipid biosynthetic process (GO:0046474)

GO Molecular Function (7): ATP-dependent diacylglycerol kinase activity (GO:0004143), ATP binding (GO:0005524), zinc ion binding (GO:0008270), kinase activity (GO:0016301), nucleotide binding (GO:0000166), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
G alpha (q) signalling events	1
Platelet activation, signaling and aggregation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular anatomical structure	2
phosphatidic acid metabolic process	1
glycerophospholipid biosynthetic process	1
biosynthetic process	1
phosphatidylinositol metabolic process	1
G protein-coupled receptor signaling pathway	1
phospholipase C activator activity	1
cell activation	1
blood coagulation	1
signal transduction	1
acylglycerol metabolic process	1
lipid metabolic process	1
phosphorylation	1
lipid modification	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
primary metabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
glycerophospholipid metabolic process	1
phospholipid biosynthetic process	1
glycerolipid biosynthetic process	1
lipid kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
transferase activity, transferring phosphorus-containing groups	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
cation binding	1
nuclear lumen	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

874 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DGKE	THBD	P07204	809
DGKE	CFHR5	Q9BXR6	797
DGKE	CFB	P00751	797
DGKE	CFHR1	Q03591	792
DGKE	MMACHC	Q9Y4U1	780
DGKE	CFH	P08603	773
DGKE	CFHR3	Q02985	772
DGKE	ADAMTS13	Q76LX8	768
DGKE	CD46	P15529	764
DGKE	LMOD1	P29536	764
DGKE	CFI	P05156	698
DGKE	CFHR4	Q92496	669
DGKE	CFHR2	P36980	633
DGKE	INF2	Q27J81	554
DGKE	C17orf67	Q0P5P2	538

IntAct

68 interactions, top by confidence:

A	B	Type	Score
IFT70A	IFT56	psi-mi:“MI:0914”(association)	0.790
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
IFT46	IFT56	psi-mi:“MI:0914”(association)	0.640
TSPAN17	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
HEATR3	SLC27A2	psi-mi:“MI:0914”(association)	0.530
UNC93B1	GPR89A	psi-mi:“MI:0914”(association)	0.530
DGKE	MRPL44	psi-mi:“MI:0915”(physical association)	0.370
ARRB1		psi-mi:“MI:0914”(association)	0.350
ARRB2		psi-mi:“MI:0914”(association)	0.350
CD74		psi-mi:“MI:0914”(association)	0.350
P2RY6	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC15A3		psi-mi:“MI:0914”(association)	0.350
UNC93B1		psi-mi:“MI:0914”(association)	0.350
P2RY6		psi-mi:“MI:0914”(association)	0.350
P2RY6	RAVER1	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
SLC16A11	ESYT2	psi-mi:“MI:0914”(association)	0.350
RAF1	MYO9A	psi-mi:“MI:0914”(association)	0.350
GRK4	TCERG1	psi-mi:“MI:0914”(association)	0.350
JAK3	PIK3R2	psi-mi:“MI:0914”(association)	0.350
STYK1	XPO1	psi-mi:“MI:0914”(association)	0.350
ADCK2	ILVBL	psi-mi:“MI:0914”(association)	0.350
PSKH2	AIP	psi-mi:“MI:0914”(association)	0.350
PRKAG3	CNOT1	psi-mi:“MI:0914”(association)	0.350
POMK	ESYT2	psi-mi:“MI:0914”(association)	0.350
NTRK1	ILVBL	psi-mi:“MI:0914”(association)	0.350

BioGRID (103): DGKE (Affinity Capture-MS), DGKE (Proximity Label-MS), DGKE (Proximity Label-MS), DGKE (Affinity Capture-MS), DGKE (Affinity Capture-MS), IFT46 (Affinity Capture-MS), NUDC (Affinity Capture-MS), SET (Affinity Capture-MS), PAICS (Affinity Capture-MS), NUF2 (Affinity Capture-MS), PDHA1 (Affinity Capture-MS), DGKE (Affinity Capture-MS), DGKE (Synthetic Lethality), DGKE (Reconstituted Complex), DGKE (Affinity Capture-MS)

ESM2 similar proteins: A0JPF9, C0LT23, D3YXJ0, E9PUQ8, F4JKI3, F4JQ95, O82387, P52429, Q0V9N0, Q10HL3, Q149N8, Q16760, Q1PDI2, Q3U3W5, Q49MI3, Q4R3W5, Q53NI2, Q56YN3, Q58CU3, Q5JK52, Q5SNL7, Q5T8I9, Q5W9E7, Q5XH30, Q60E60, Q64398, Q68EP9, Q6E7H0, Q6P2P2, Q6USK2, Q7TPQ3, Q7XD96, Q7XQT2, Q7ZU91, Q7ZW00, Q80VJ4, Q811C2, Q8BZT9, Q8C0L9, Q8L5Z4

Diamond homologs: A0JN54, A8JQ65, B3LXF2, B3NYS4, B4I4Y1, B4JHJ7, B4K6T8, B4PRE2, B4R0A5, D3YWQ0, D3ZEY4, F1MAB7, O08560, O75912, O88673, P0CM54, P0CM55, P20192, P23743, P25296, P34057, P34125, P35243, P49619, P49620, P49621, P51556, P52429, P52824, P87072, Q01583, Q03603, Q09103, Q10024, Q13574, Q39017, Q6BWS8, Q6CGE6, Q6DT37, Q6FLU4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 78 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
R-HSA-425393	5	12.2×	9e-03
SLC-mediated transmembrane transport	8	8.9×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	25
Likely pathogenic	9
Uncertain significance	142
Likely benign	100
Benign	31

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1179079	NM_003647.3(DGKE):c.62_65dup (p.Ile23fs)	Pathogenic
135639	NM_003647.3(DGKE):c.486dup (p.Val163fs)	Pathogenic
135640	NM_003647.3(DGKE):c.889-1G>A	Pathogenic
135641	NM_003647.3(DGKE):c.966G>A (p.Trp322Ter)	Pathogenic
1409113	NM_003647.3(DGKE):c.328G>T (p.Glu110Ter)	Pathogenic
1455376	NM_003647.3(DGKE):c.888+1G>C	Pathogenic
1986461	NM_003647.3(DGKE):c.562_583del (p.Pro188fs)	Pathogenic
2027497	NM_003647.3(DGKE):c.943_944insT (p.Asp315fs)	Pathogenic
2076260	NM_003647.3(DGKE):c.219C>G (p.Tyr73Ter)	Pathogenic
3674177	NM_003647.3(DGKE):c.541G>T (p.Glu181Ter)	Pathogenic
39578	NM_003647.3(DGKE):c.127C>T (p.Gln43Ter)	Pathogenic
39579	NM_003647.3(DGKE):c.610del (p.Thr204fs)	Pathogenic
39580	NM_003647.3(DGKE):c.889-2A>G	Pathogenic
397599	NM_003647.3(DGKE):c.1376G>A (p.Trp459Ter)	Pathogenic
4278125	NM_003647.3(DGKE):c.389G>A (p.Gly130Asp)	Pathogenic
4280346	NM_003647.3(DGKE):c.171del (p.Ser58fs)	Pathogenic
4280382	NM_003647.3(DGKE):c.1524+2T>C	Pathogenic
4292482	NM_003647.3(DGKE):c.142_143del (p.Gln48fs)	Pathogenic
4293294	NM_003647.3(DGKE):c.433_443del (p.Cys145fs)	Pathogenic
446215	NM_003647.3(DGKE):c.301A>T (p.Lys101Ter)	Pathogenic
4722049	NM_003647.3(DGKE):c.1113del (p.Asn371fs)	Pathogenic
548648	NM_003647.3(DGKE):c.888+40A>G	Pathogenic
635454	NM_003647.3(DGKE):c.610dup (p.Thr204fs)	Pathogenic
812509	NM_003647.3(DGKE):c.447del (p.Lys150fs)	Pathogenic
829884	NM_003647.3(DGKE):c.1099-2A>T	Pathogenic
1329494	NM_003647.3(DGKE):c.842G>A (p.Gly281Glu)	Likely pathogenic
2683681	NM_003647.3(DGKE):c.1057del (p.Gln353fs)	Likely pathogenic
3256952	NM_003647.3(DGKE):c.1247del (p.Cys415_Leu416insTer)	Likely pathogenic
397600	NM_003647.3(DGKE):c.1169G>A (p.Arg390His)	Likely pathogenic
4280381	NM_003647.3(DGKE):c.1493C>G (p.Pro498Arg)	Likely pathogenic

SpliceAI

1659 predictions. Top by Δscore:

Variant	Effect	Δscore
17:56844145:GATGC:G	donor_gain	1.0000
17:56844146:A:G	donor_gain	1.0000
17:56844176:GTG:G	donor_gain	1.0000
17:56848849:GATCG:G	donor_gain	1.0000
17:56848851:TCGG:T	donor_loss	1.0000
17:56848852:CGG:C	donor_loss	1.0000
17:56848853:GGT:G	donor_loss	1.0000
17:56848854:G:C	donor_loss	1.0000
17:56848854:G:GG	donor_gain	1.0000
17:56848855:T:G	donor_loss	1.0000
17:56858592:AGGC:A	acceptor_gain	1.0000
17:56858593:GGCG:G	acceptor_gain	1.0000
17:56858665:GGTAA:G	donor_loss	1.0000
17:56858666:GTAAG:G	donor_loss	1.0000
17:56858667:T:TC	donor_loss	1.0000
17:56861789:A:AG	acceptor_gain	1.0000
17:56861790:G:GG	acceptor_gain	1.0000
17:56861790:GCTA:G	acceptor_gain	1.0000
17:56862132:A:AG	acceptor_gain	1.0000
17:56862134:TTTTA:T	acceptor_loss	1.0000
17:56862135:TTTA:T	acceptor_loss	1.0000
17:56862136:TTAGG:T	acceptor_loss	1.0000
17:56862137:TAGG:T	acceptor_loss	1.0000
17:56862139:GGC:G	acceptor_gain	1.0000
17:56862250:GG:G	donor_gain	1.0000
17:56862251:GG:G	donor_gain	1.0000
17:56862801:G:GT	donor_gain	1.0000
17:56834257:CGAG:C	donor_loss	0.9900
17:56834259:AG:A	donor_loss	0.9900
17:56834260:GGTA:G	donor_loss	0.9900

AlphaMissense

3735 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:56848751:A:C	D315A	1.000
17:56848751:A:G	D315G	1.000
17:56848751:A:T	D315V	1.000
17:56848853:G:C	R349P	1.000
17:56849182:T:A	W350R	1.000
17:56849182:T:C	W350R	1.000
17:56856543:G:A	G377E	1.000
17:56835017:C:G	C74W	0.999
17:56844020:T:C	C156R	0.999
17:56845800:T:A	N245K	0.999
17:56845800:T:G	N245K	0.999
17:56847959:T:C	L261P	0.999
17:56848004:T:A	V276D	0.999
17:56848010:G:A	G278E	0.999
17:56848015:G:C	D280H	0.999
17:56848016:A:C	D280A	0.999
17:56848016:A:T	D280V	0.999
17:56848037:T:C	L287P	0.999
17:56848738:G:A	G311R	0.999
17:56848738:G:C	G311R	0.999
17:56848739:G:A	G311E	0.999
17:56848745:G:A	G313D	0.999
17:56848745:G:T	G313V	0.999
17:56848748:A:T	N314I	0.999
17:56848749:C:A	N314K	0.999
17:56848749:C:G	N314K	0.999
17:56848750:G:C	D315H	0.999
17:56848752:T:A	D315E	0.999
17:56848752:T:G	D315E	0.999
17:56848754:T:C	L316P	0.999

dbSNP variants (sampled 300 via entrez): RS1000073733 (17:56833662 TC>T,TCC), RS1000293956 (17:56868074 A>C,T), RS1000510378 (17:56833497 G>A), RS1000540243 (17:56848898 A>G), RS1000667162 (17:56868383 G>T), RS1000694326 (17:56858614 A>G), RS1000764556 (17:56860181 C>T), RS1000876969 (17:56867507 G>A), RS1000891456 (17:56841955 A>G), RS1001113438 (17:56832395 G>A), RS1001179069 (17:56848198 C>A,T), RS1001238740 (17:56841745 G>A), RS1001286328 (17:56842049 C>G), RS1001287233 (17:56855254 T>G), RS1001338936 (17:56842253 A>G)

Disease associations

OMIM: gene MIM:601440 | disease phenotypes: MIM:615008, MIM:235400

GenCC curated gene-disease

Disease	Classification	Inheritance
immunoglobulin-mediated membranoproliferative glomerulonephritis	Strong	Autosomal recessive
atypical hemolytic-uremic syndrome with DGKE deficiency	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
atypical hemolytic-uremic syndrome with DGKE deficiency	Definitive	AR
membranoproliferative glomerulonephritis	Definitive	AR

Mondo (10): immunoglobulin-mediated membranoproliferative glomerulonephritis (MONDO:0014005), atypical hemolytic-uremic syndrome with DGKE deficiency (MONDO:0018159), kidney disorder (MONDO:0005240), membranoproliferative glomerulonephritis (MONDO:0002461), atypical hemolytic-uremic syndrome (MONDO:0016244), hemolytic uremic syndrome, atypical, susceptibility to, 7 (MONDO:0100590), focal segmental glomerulosclerosis (MONDO:0100313), nephrotic syndrome (MONDO:0005377), hemolytic-uremic syndrome (MONDO:0001549), hemolytic uremic syndrome, atypical, susceptibility to, 1 (MONDO:0009335)

Orphanet (5): Immunoglobulin-mediated membranoproliferative glomerulonephritis (Orphanet:329903), Hemolytic uremic syndrome with DGKE deficiency (Orphanet:357008), Atypical hemolytic uremic syndrome (Orphanet:2134), Hemolytic uremic syndrome (Orphanet:544458), Shiga toxin-associated hemolytic uremic syndrome (Orphanet:90038)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000100	Nephrotic syndrome
HP:0000793	Membranoproliferative glomerulonephritis
HP:0001873	Thrombocytopenia
HP:0001878	Hemolytic anemia
HP:0001919	Acute kidney injury
HP:0003073	Hypoalbuminemia
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003676	Progressive
HP:0003774	Stage 5 chronic kidney disease
HP:0004722	Thickened glomerular basement membrane
HP:0005575	Hemolytic-uremic syndrome
HP:0011463	Childhood onset
HP:0025708	Early young adult onset
HP:0031266	Podocyte foot process effacement

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000175_3	Height	1.000000e-07
GCST004132_96	Crohn’s disease	4.000000e-06
GCST008178_13	Early spontaneous preterm birth	8.000000e-06
GCST009959_15	Retinal detachment or retinal break	4.000000e-06
GCST010002_126	Refractive error	7.000000e-42

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006917	spontaneous preterm birth
EFO:0010698	retinal break

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D065766	Atypical Hemolytic Uremic Syndrome	C12.050.351.968.419.936.463.500; C12.200.777.419.936.463.500; C12.950.419.936.463.500; C15.378.050.141.610.500; C15.378.140.855.925.500.500; C15.378.243.937.925.500.500
D015432	Glomerulonephritis, Membranoproliferative	C12.050.351.968.419.570.363.615; C12.200.777.419.570.363.615; C12.950.419.570.363.615; C20.425
D005923	Glomerulosclerosis, Focal Segmental	C12.050.351.968.419.570.363.640; C12.200.777.419.570.363.660; C12.950.419.570.363.640
D006463	Hemolytic-Uremic Syndrome	C12.050.351.968.419.936.463; C12.200.777.419.936.463; C12.950.419.936.463; C15.378.050.141.610; C15.378.140.855.925.500; C15.378.243.937.925.500
D007674	Kidney Diseases	C12.050.351.968.419; C12.200.777.419; C12.950.419
D009404	Nephrotic Syndrome	C12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1075187 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, increases expression	3
sodium arsenite	affects expression, increases abundance, increases expression	2
Benzo(a)pyrene	decreases expression, increases expression	2
Estradiol	increases expression	2
Tobacco Smoke Pollution	increases expression	2
Genistein	affects expression, increases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
trichostatin A	increases expression	1
methylparaben	increases expression	1
di-n-butylphosphoric acid	affects expression	1
1-stearoyl-2-arachidonoylglycerol	increases phosphorylation	1
perfluorooctane sulfonic acid	increases expression	1
entinostat	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
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Bortezomib	decreases expression	1
Resveratrol	increases expression, affects cotreatment	1
Sunitinib	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	increases abundance, increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Diazinon	increases methylation	1
Ethinyl Estradiol	affects expression	1
Methyl Methanesulfonate	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Smoke	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1111692	Binding	Inhibition of DAGepsilon up to 100 uM	Discovery, biological evaluation, and structure-activity relationship of amidine based sphingosine kinase inhibitors. — J Med Chem

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7NK	Ubigene A-549 DGKE KO	Cancer cell line	Male
CVCL_D8K0	Ubigene HCT 116 DGKE KO	Cancer cell line	Male
CVCL_D9D9	Ubigene HEK293 DGKE KO	Transformed cell line	Female
CVCL_E0BP	Ubigene HeLa DGKE KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00067990	PHASE4	COMPLETED	Angiotensin II Blockade for Chronic Allograft Nephropathy
NCT00117078	PHASE4	COMPLETED	Aranesp® Monthly Preference Study - 2
NCT00117130	PHASE4	COMPLETED	Study to Evaluate Effectiveness of Aranesp®
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00140985	PHASE4	COMPLETED	Antiproteinuric Efficacy of Losartan Potassium in Patients With Non-Diabetic Proteinuric Renal Diseases (0954-213)
NCT00246129	PHASE4	COMPLETED	CamTac Trial:Campath-Tacrolimus vs IL2R MoAb/Tacrolimus/MMF in Renal Transplantation
NCT00275535	PHASE4	COMPLETED	The Comparison of Tacrolimus and Sirolimus Immunosuppression Based Drug Regimens in Kidney Transplant Recipients
NCT00282217	PHASE4	COMPLETED	Study Evaluating Sirolimus in the Treatment of Kidney Transplant
NCT00289614	PHASE4	COMPLETED	Patients With Renal Impairment and Diabetes Undergoing Computed Tomography (CT)
NCT00290069	PHASE4	UNKNOWN	Renal Function Optimization With Mycophenolate Mofetil (MMF) Immunosuppressor Regimes (ALHAMBRA)
NCT00338468	PHASE4	TERMINATED	A Study to Assess Disability in Anemic Elderly Patients With Kidney Disease Receiving PROCRIT (Epoetin Alfa)
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	PHASE4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00443508	PHASE4	UNKNOWN	Reduction or Discontinuation of CNI’s With Conversion to Everolimus-Based Immunosuppresion
NCT00452478	PHASE4	TERMINATED	Conversion From Standard Phosphate Binder Therapy to Fosrenol® (Lanthanum Carbonate) in Chronic Kidney Disease Stage 5
NCT00492518	PHASE4	COMPLETED	Acetylcysteine, Theophylline, and a Combination of Both in the Prophylaxis of Contrast-Induced Nephropathy
NCT00505102	PHASE4	UNKNOWN	Safe Renal Function In Long Term Heart Transplanted Patients
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00688480	PHASE4	COMPLETED	Do Xanthine Oxidase Inhibitors Reduce Both Left Ventricular Hypertrophy and Endothelial Dysfunction in Cardiovascular Patients With Renal Dysfunction?
NCT00863707	PHASE4	COMPLETED	A Study of the Safety and Tolerance of Regadenoson in Subjects With Renal Impairment
NCT01101698	PHASE4	UNKNOWN	Vitamin K2 and Vessel Calcification in Chronic Kidney Disease Patients
NCT01150201	PHASE4	COMPLETED	Aliskiren Combined With Losartan in Proteinuric, Non-diabetic Chronic Kidney Disease
NCT01155141	PHASE4	COMPLETED	Idiopathic Focal Segmental Glomerulosclerosis (FSGS) and Treatment With ACTH
NCT01228279	PHASE4	COMPLETED	Sympathetic Activity in Patients With End-stage Renal Disease on Peritoneal Dialysis
NCT01334333	PHASE4	COMPLETED	Comparison of Medication Adherence Between Once and Twice Daily Tacrolimus in Stable Renal Transplant Recipients
NCT01437943	PHASE4	TERMINATED	Effect of Short Term Aliskiren Treatment in Kidney Transplant Patients
NCT01545479	PHASE4	COMPLETED	Increased Renal Oxygenation and Angiotensin Converting Enzyme Inhibition
NCT01614431	PHASE4	COMPLETED	N Acetyl Cysteine for Cystinosis Patients
NCT01631149	PHASE4	COMPLETED	Effect of Deep BLock on Intraoperative Surgical Conditions
NCT01722513	PHASE4	UNKNOWN	Efficacy and Safety of Alprostadil Prevent Contrast Induced Nephropathy
NCT01985360	PHASE4	COMPLETED	ISCHEMIA-Chronic Kidney Disease Trial
NCT02311010	PHASE4	UNKNOWN	Practical Use of Advagraf de Novo After Kidney Transplantation According to Recipient Genetic Polymorphism
NCT02413073	PHASE4	COMPLETED	Whole Body Vibration in Kidney Disease
NCT02444013	PHASE4	UNKNOWN	Folic Acid for Prevention of Contrast Induced Nephropathy
NCT02663713	PHASE4	COMPLETED	A Randomized, Pharmacodynamic Comparison of Low Dose Ticagrelor to Clopidogrel in Patients With Prior Myocardial Infarction
NCT02707809	PHASE4	COMPLETED	Effects of Dexmedetomidine on Microcirculation of Kidney Transplant Recipient
NCT02761577	PHASE4	COMPLETED	A Prospective Study on Incidence and Prevention of Contrast-induced Nephropathy in Croatia
NCT03029351	PHASE4	TERMINATED	GLP-1 Receptor Agonist Therapy and Albuminuria in Patients With Type 2 Diabetes