DGKH

Summary

DGKH (diacylglycerol kinase eta, HGNC:2854) is a protein-coding gene on chromosome 13q14.11, encoding Diacylglycerol kinase eta (Q86XP1). Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids.

This gene encodes a member of the diacylglycerol kinase (DGK) enzyme family. Members of this family are involved in regulating intracellular concentrations of diacylglycerol and phosphatidic acid. Variation in this gene has been associated with bipolar disorder. Alternatively spliced transcript variants have been identified.

Source: NCBI Gene 160851 — RefSeq curated summary.

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 140 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_178009

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2854
Approved symbol	DGKH
Name	diacylglycerol kinase eta
Location	13q14.11
Locus type	gene with protein product
Status	Approved
Aliases	DGKeta
Ensembl gene	ENSG00000102780
Ensembl biotype	protein_coding
OMIM	604071
Entrez	160851

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 7 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000261491, ENST00000337343, ENST00000379274, ENST00000489851, ENST00000498255, ENST00000536612, ENST00000611224, ENST00000626247, ENST00000627777, ENST00000628433, ENST00000916518

RefSeq mRNA: 6 — MANE Select: NM_178009 NM_001204504, NM_001204505, NM_001204506, NM_001297429, NM_152910, NM_178009

CCDS: CCDS55898, CCDS55899, CCDS9381, CCDS9382

Canonical transcript exons

ENST00000337343 — 30 exons

Exon	Start	End
ENSE00000681370	42198478	42198595
ENSE00001277478	42221264	42221394
ENSE00001815998	42229099	42242896
ENSE00003484813	42187049	42187148
ENSE00003494672	42199566	42199676
ENSE00003504199	42189036	42189309
ENSE00003515438	42199813	42199909
ENSE00003516508	42165331	42165433
ENSE00003535897	42214507	42214612
ENSE00003540571	42219230	42219349
ENSE00003542301	42168440	42168548
ENSE00003543004	42159266	42159372
ENSE00003548304	42219686	42219794
ENSE00003565999	42190403	42190525
ENSE00003566192	42168679	42168818
ENSE00003600820	42155667	42155799
ENSE00003607732	42194885	42195016
ENSE00003612673	42209331	42209465
ENSE00003629727	42208959	42209072
ENSE00003639427	42174060	42174144
ENSE00003644474	42210602	42210765
ENSE00003644851	42166515	42166674
ENSE00003649913	42155291	42155395
ENSE00003661171	42215575	42215667
ENSE00003662138	42178135	42178220
ENSE00003674069	42206039	42206146
ENSE00003689743	42160011	42160136
ENSE00003731129	42129552	42129632
ENSE00003733888	42127463	42127573
ENSE00003899207	42048648	42048965

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 99.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.0148 / max 22.5949, expressed in 1506 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134863	2.9450	1484
134858	0.0660	13
134864	0.0038	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.00	gold quality
dorsal root ganglion	UBERON:0000044	99.00	gold quality
epithelial cell of pancreas	CL:0000083	96.87	gold quality
cartilage tissue	UBERON:0002418	95.06	gold quality
corpus epididymis	UBERON:0004359	94.22	gold quality
trigeminal ganglion	UBERON:0001675	93.77	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.54	gold quality
bronchial epithelial cell	CL:0002328	91.88	gold quality
oviduct epithelium	UBERON:0004804	91.82	gold quality
visceral pleura	UBERON:0002401	91.70	gold quality
bronchus	UBERON:0002185	91.24	gold quality
caput epididymis	UBERON:0004358	89.83	gold quality
mucosa of paranasal sinus	UBERON:0005030	89.76	gold quality
Brodmann (1909) area 23	UBERON:0013554	89.28	gold quality
cauda epididymis	UBERON:0004360	89.14	gold quality
cerebellar vermis	UBERON:0004720	88.50	gold quality
middle temporal gyrus	UBERON:0002771	88.42	gold quality
parietal pleura	UBERON:0002400	87.94	gold quality
pancreatic ductal cell	CL:0002079	86.44	silver quality
substantia nigra pars reticulata	UBERON:0001966	84.85	silver quality
tendon of biceps brachii	UBERON:0008188	84.76	silver quality
skin of hip	UBERON:0001554	84.43	gold quality
tibia	UBERON:0000979	84.35	gold quality
germinal epithelium of ovary	UBERON:0001304	82.49	gold quality
sperm	CL:0000019	82.44	silver quality
lateral globus pallidus	UBERON:0002476	82.29	silver quality
colonic epithelium	UBERON:0000397	82.27	gold quality
epithelium of nasopharynx	UBERON:0001951	82.16	gold quality
urinary bladder	UBERON:0001255	82.09	gold quality
upper leg skin	UBERON:0004262	82.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	1037.25
E-ANND-3	yes	10.86

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

553 targeting DGKH, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-188-3P	100.00	68.76	1240
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3924	100.00	72.09	2394
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-4692	100.00	67.32	2066
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-9-5P	100.00	72.28	2361

Literature-anchored findings (GeneRIF, showing 20)

• alternative splicing of the human DGK eta gene generates at least two isoforms with distinct biochemical and cell biological properties responding to different cellular metabolic requirements (PMID:12810723)
• diacylglycerol kinase eta (DGKH) is association in the etiology of bipolar disorder. (PMID:17486107)
• No significant association after multiple-testing correction between any of the single nucleotide polymorphisms in DGKH and bipolar disorder, was found. (PMID:19478689)
• DGKeta acts as a novel critical regulatory component of the Ras/B-Raf/C-Raf/MEK/ERK signaling cascade via a previously unidentified mechanism. (PMID:19710016)
• While negative, our findings do not exclude an involvement of DGKH and NR1D1 in lithium prophylaxis. (PMID:19818381)
• Increased gene expression of diacylglycerol kinase eta is found in brain tissue from patients with bipolar disorder. (PMID:20519059)
• The results of tisd support DGKH as shared risk factor of bipolar disorder and schizophrenia in the Chinese Han population. (PMID:20733578)
• Although the association was not strong, the result of this study would support the association between DGKH and BD. (PMID:21507135)
• expressions of DGKeta and DGKzeta were increased and decreased, respectively, whereas those of DGKgamma and DGKepsilon remained unchanged. This is the first report that describes the differential regulation of DGK isoforms in normal and failing human hearts. (PMID:21548979)
• Four DGKH markers are linked to adult attention-hyperactivity disorder and seven to unipolar depression, making DGKH a risk factor gene for bipolar disorder, unipolar depression and adult attention-deficit hyperactivity disorder. (PMID:21654738)
• Differential effects of DGKH in healthy controls vs the bipolar high-risk group manifest as a failure to disengage default-mode regions in those at familial risk carrying the risk haplotype. (PMID:22048461)
• DGKK variants are associated with hypospadias (PMID:23177175)
• This study demonstrated that significant association of the DGKH risk haplotype with increased amygdala volume in Bipolar disorder, but not in schizophreia or healthy controls. (PMID:24958494)
• These findings implicate a link between nucleotide variant of DGKH and a cause for a complex-trait disease, calcium oxalate stone (PMID:25081328)
• DGKeta-Pleckstrin Homology Domain preferentially interacts with Phosphatidylinositol 4,5-Bisphosphate and has crucial roles in regulating the subcellular localization and physiological function of DGKeta. (PMID:26887948)
• DGKH is a replicated risk gene of bipolar disorder (BD). (PMID:27016658)
• This sstudy shown that the highest expression levels of DGKH in the human brain were found in the striatum. (PMID:27085324)
• several single variants and genes showed strong association with Panic Disorders, where DGKH was found to be the strongest Panic Disorder associated gene. Interestingly DGKH has previously demonstrated genome-wide significant association with bipolar disorder as well as evidence of association to other mental disorders. (PMID:27255576)
• The present study shows that a bipolar-risk allele of DGKH is associated with higher openness to experience, providing further evidence for the implication of this gene in the etiology of bipolar disorder. (PMID:29936393)
• Diacylglycerol Kinase Inhibition Reduces Airway Contraction by Negative Feedback Regulation of Gq-Signaling. (PMID:34293268)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	dgkh	ENSDARG00000018716
mus_musculus	Dgkh	ENSMUSG00000034731
rattus_norvegicus	Dgkh	ENSRNOG00000010065
drosophila_melanogaster	CG34384	FBGN0085413
drosophila_melanogaster	rdgA	FBGN0261549
caenorhabditis_elegans		WBGENE00006483
caenorhabditis_elegans		WBGENE00019428

Paralogs (9): DGKG (ENSG00000058866), DGKA (ENSG00000065357), DGKD (ENSG00000077044), DGKB (ENSG00000136267), DGKQ (ENSG00000145214), DGKZ (ENSG00000149091), DGKE (ENSG00000153933), DGKI (ENSG00000157680), DGKK (ENSG00000274588)

Protein

Protein identifiers

Diacylglycerol kinase eta — Q86XP1 (reviewed: Q86XP1)

Alternative names: Diglyceride kinase eta

All UniProt accessions (4): Q86XP1, A0A087WZ02, A0A0D9SF65, A0A0D9SFR6

UniProt curated annotations — full annotation on UniProt →

Function. 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. Plays a key role in promoting cell growth. Activates the Ras/B-Raf/C-Raf/MEK/ERK signaling pathway induced by EGF. Regulates the recruitment of RAF1 and BRAF from cytoplasm to membranes and their heterodimerization.

Subunit / interactions. Interacts with RAF1 and BRAF. Homooligomers. Heterooligomers. Oligomerization through the SAM domain inhibits the diacylglycerol kinase activity. Heterooligomerizes with SAM domain-containing isoforms of DGKD. Does not form homooligomers.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Expressed only in testis, kidney and colon. Ubiquitously expressed.

Post-translational modifications. Phosphorylated. Phosphorylation does not inhibit catalytic activity.

Domain organisation. The SAM domain mediates homooligomerization.

Induction. Down-regulated by glucocorticoid. Up-regulated by glucocorticoid.

Pathway. Lipid metabolism; glycerolipid metabolism.

Similarity. Belongs to the eukaryotic diacylglycerol kinase family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q86XP1-1	1, DAG kinase eta-2, DGKH-2	yes
Q86XP1-2	2, DAG kinase eta-1, DGKH-1
Q86XP1-3	3
Q86XP1-5	4

RefSeq proteins (6): NP_001191433, NP_001191434, NP_001191435, NP_001284358, NP_690874, NP_821077* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000756	Diacylglycerol_kin_accessory	Domain
IPR001206	Diacylglycerol_kinase_cat_dom	Domain
IPR001660	SAM	Domain
IPR001849	PH_domain	Domain
IPR002219	PKC_DAG/PE	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR016064	NAD/diacylglycerol_kinase_sf	Homologous_superfamily
IPR017438	ATP-NAD_kinase_N	Homologous_superfamily
IPR037607	DGK	Family
IPR046349	C1-like_sf	Homologous_superfamily
IPR047480	C1_DGKeta_rpt2	Domain
IPR054474	DGKD_4H	Domain

Pfam: PF00130, PF00169, PF00609, PF00781, PF07647, PF22944

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), 2 shown:

• a 1,2-diacyl-sn-glycerol + ATP = a 1,2-diacyl-sn-glycero-3-phosphate + ADP + H(+) (RHEA:10272)
• 1,2-di-(9Z-octadecenoyl)-sn-glycerol + ATP = 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphate + ADP + H(+) (RHEA:40327)

UniProt features (19 total): domain 3, compositionally biased region 3, splice variant 3, region of interest 3, zinc finger region 2, chain 1, sequence variant 1, mutagenesis site 1, sequence conflict 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86XP1-F1	71.33	0.28

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 (1):

Position	Phenotype
1151	loss of homoligomerization and heterooligomerization but not diacylglycerol kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-114508	Effects of PIP2 hydrolysis

MSigDB gene sets: 333 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_LIPID_MODIFICATION, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GOBP_PLATELET_ACTIVATION, AAGCCAT_MIR135A_MIR135B, AMIT_SERUM_RESPONSE_20_MCF10A, IVANOVA_HEMATOPOIESIS_MATURE_CELL, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_WOUND_HEALING, REACTOME_EFFECTS_OF_PIP2_HYDROLYSIS

GO Biological Process (11): phosphatidic acid biosynthetic process (GO:0006654), 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), phosphatidic acid metabolic process (GO:0046473), lipid phosphorylation (GO:0046834), phospholipase C/protein kinase C signal transduction (GO:0141212), lipid metabolic process (GO:0006629), signal transduction (GO:0007165), glycerolipid metabolic process (GO:0046486)

GO Molecular Function (11): ATP-dependent diacylglycerol kinase activity (GO:0004143), ATP binding (GO:0005524), zinc ion binding (GO:0008270), kinase binding (GO:0019900), SAM domain binding (GO:0032093), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): cytoplasm (GO:0005737), endosome (GO:0005768), plasma membrane (GO:0005886), actin cytoskeleton (GO:0015629), protein-containing complex (GO:0032991), membrane (GO:0016020)

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
intracellular anatomical structure	2
cellular anatomical structure	2
phosphatidic acid metabolic process	1
glycerophospholipid biosynthetic 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
glycerophospholipid metabolic process	1
phosphorylation	1
lipid modification	1
intracellular signaling cassette	1
primary metabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
lipid metabolic 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
enzyme binding	1
protein domain specific binding	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cation binding	1
endomembrane system	1
cytoplasmic vesicle	1
membrane	1
cell periphery	1
cytoskeleton	1

Protein interactions and networks

STRING

960 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DGKH	ANK3	Q12955	659
DGKH	EDNRA	P25101	582
DGKH	PLEK2	Q9NYT0	563
DGKH	PLEK	P08567	557
DGKH	DGKQ	P52824	516
DGKH	DGKA	P23743	476
DGKH	DGKB	Q9Y6T7	467
DGKH	CACNA1C	Q13936	453
DGKH	TENM4	Q6N022	447
DGKH	MINDY4	Q4G0A6	434
DGKH	PLCE1	Q9P212	429
DGKH	DGKK	Q5KSL6	419
DGKH	RGS4	P49798	413
DGKH	PDE4B	Q07343	402
DGKH	ZNF804A	Q7Z570	400

IntAct

131 interactions, top by confidence:

A	B	Type	Score
DEUP1	HIP1	psi-mi:“MI:0914”(association)	0.530
DGKH	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
RHPN1	DGKH	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	ARHGEF12	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	GRID2IP	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	LNX1	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	SNTG1	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	APBA3	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	MAGI1	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	MPP2	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	LIN7B	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	TIAM2	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	SIPA1L2	psi-mi:“MI:0407”(direct interaction)	0.440
DGKH	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (46): DGKH (Affinity Capture-MS), DGKH (Affinity Capture-MS), DGKH (Affinity Capture-MS), DGKH (Affinity Capture-MS), DGKH (Affinity Capture-MS), DGKH (Affinity Capture-MS), DGKH (Affinity Capture-MS), DGKH (Affinity Capture-RNA), DGKH (Affinity Capture-MS), DGKH (Affinity Capture-RNA), DGKH (Affinity Capture-Western), DGKH (Reconstituted Complex), DGKD (Affinity Capture-Western), DGKH (Affinity Capture-MS), DGKH (Synthetic Lethality)

ESM2 similar proteins: A0A0R4IXF6, A1A5R8, A9ZLX4, D3YXJ0, E9PUQ8, G3UZ78, O00750, O15164, O54828, P30052, P40818, P48984, P52963, P59997, P97496, Q02225, Q08AX9, Q08BR4, Q08D35, Q16760, Q1LUC3, Q2I6J1, Q3UWM4, Q498F0, Q5JSH3, Q5JTW2, Q5RHD1, Q60665, Q64398, Q68FF0, Q6INA9, Q6NSI8, Q6NVE8, Q6PDG5, Q6ZMT4, Q7ZVP1, Q80U87, Q86XP1, Q8C5W4, Q8N7X0

Diamond homologs: A0JN54, A8JQ65, B3LXF2, B3NYS4, B4I4Y1, B4JHJ7, B4K6T8, B4PRE2, B4R0A5, D3YWQ0, D3YXJ0, D3YZU1, D3ZEY4, E9PUQ8, F1MAB7, F4JKI3, F4JQ95, G9CGD6, O08560, O75912, O88673, P09216, P10830, P16054, P20192, P23298, P23743, P34885, P49619, P49620, P49621, P51556, P52429, P52824, P90980, Q01583, Q02156, Q03603, Q05655, Q09103

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 96 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
Ras activation upon Ca2+ influx through NMDA receptor	5	47.6×	3e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	45.3×	3e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	45.3×	3e-06
Assembly and cell surface presentation of NMDA receptors	10	42.3×	3e-12
Dopamine Neurotransmitter Release Cycle	5	41.4×	4e-06
Long-term potentiation	5	39.6×	4e-06
Neurexins and neuroligins	11	36.1×	2e-12
Protein-protein interactions at synapses	7	31.0×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	70.2×	1e-15
protein localization to synapse	6	50.5×	3e-07
receptor clustering	7	48.0×	2e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	6	32.7×	2e-06
cell-cell adhesion	10	11.2×	2e-06
protein-containing complex assembly	8	10.0×	8e-05
regulation of small GTPase mediated signal transduction	6	9.5×	1e-03
chemical synaptic transmission	7	6.0×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	99
Likely benign	13
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4070959	NM_178009.5(DGKH):c.1032_1033insTTTTTTT (p.Gln345fs)	Pathogenic

SpliceAI

5177 predictions. Top by Δscore:

Variant	Effect	Δscore
13:42127461:A:AG	acceptor_gain	1.0000
13:42127462:G:GA	acceptor_gain	1.0000
13:42127462:GACCA:G	acceptor_gain	1.0000
13:42129545:T:G	acceptor_gain	1.0000
13:42129550:A:AG	acceptor_gain	1.0000
13:42129551:G:GT	acceptor_gain	1.0000
13:42129551:GT:G	acceptor_gain	1.0000
13:42129551:GTCT:G	acceptor_gain	1.0000
13:42129551:GTCTC:G	acceptor_gain	1.0000
13:42155391:ACGAG:A	donor_loss	1.0000
13:42155392:CGAG:C	donor_loss	1.0000
13:42155394:AGG:A	donor_loss	1.0000
13:42155395:GGT:G	donor_loss	1.0000
13:42155396:G:T	donor_loss	1.0000
13:42155397:T:G	donor_loss	1.0000
13:42159264:A:AG	acceptor_gain	1.0000
13:42159265:G:GG	acceptor_gain	1.0000
13:42159265:GT:G	acceptor_gain	1.0000
13:42159369:TGGC:T	donor_gain	1.0000
13:42159370:GGC:G	donor_gain	1.0000
13:42159370:GGCG:G	donor_gain	1.0000
13:42159371:GC:G	donor_gain	1.0000
13:42159371:GCG:G	donor_gain	1.0000
13:42159373:G:GG	donor_gain	1.0000
13:42159449:A:G	donor_gain	1.0000
13:42160124:GT:G	donor_gain	1.0000
13:42165444:GTAGT:G	donor_gain	1.0000
13:42165447:GT:G	donor_gain	1.0000
13:42166592:G:GT	donor_gain	1.0000
13:42166659:G:GT	donor_gain	1.0000

AlphaMissense

8011 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:42127485:T:A	L72Q	1.000
13:42127485:T:C	L72P	1.000
13:42127492:G:C	K74N	1.000
13:42127492:G:T	K74N	1.000
13:42127505:T:C	F79L	1.000
13:42127507:C:A	F79L	1.000
13:42127507:C:G	F79L	1.000
13:42127512:G:T	R81M	1.000
13:42127513:G:C	R81S	1.000
13:42127513:G:T	R81S	1.000
13:42127524:G:C	R85P	1.000
13:42127529:T:C	F87L	1.000
13:42127530:T:C	F87S	1.000
13:42127531:C:A	F87L	1.000
13:42127531:C:G	F87L	1.000
13:42127536:T:C	L89P	1.000
13:42127551:T:A	L94H	1.000
13:42127551:T:C	L94P	1.000
13:42127553:T:G	Y95D	1.000
13:42127556:T:G	Y96D	1.000
13:42129559:T:A	I104K	1.000
13:42129577:T:A	L110H	1.000
13:42129577:T:C	L110P	1.000
13:42129628:T:C	F127S	1.000
13:42155319:T:A	L138Q	1.000
13:42155319:T:C	L138P	1.000
13:42155351:T:A	W149R	1.000
13:42155351:T:C	W149R	1.000
13:42155353:G:C	W149C	1.000
13:42155353:G:T	W149C	1.000

dbSNP variants (sampled 300 via entrez): RS1000016288 (13:42076143 T>A,C), RS1000033561 (13:42218042 C>T), RS1000054051 (13:42047594 T>C), RS1000079835 (13:42163160 A>G), RS1000085702 (13:42217665 A>G), RS1000141511 (13:42176807 C>T), RS1000162247 (13:42124450 A>G), RS1000165076 (13:42246040 G>A), RS1000177151 (13:42158566 A>G), RS1000181808 (13:42249387 G>A), RS1000190828 (13:42062352 A>G), RS1000193771 (13:42106474 A>G), RS1000251243 (13:42112887 C>T), RS1000264963 (13:42138657 T>G), RS1000343579 (13:42204097 C>T)

Disease associations

OMIM: gene MIM:604071 | disease phenotypes: MIM:143890

GenCC curated gene-disease

Mondo (1): hypercholesterolemia, familial, 1 (MONDO:0007750)

Orphanet (1): Homozygous familial hypercholesterolemia (Orphanet:391665)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST000033_1	Bipolar disorder	2.000000e-08
GCST000611_13	Height	7.000000e-06
GCST001432_3	Nephrolithiasis	5.000000e-09
GCST002119_11	Metabolite levels (X-11787)	3.000000e-06
GCST002201_6	Calcium levels	9.000000e-10
GCST002608_1	Pulmonary function in asthmatics	1.000000e-06
GCST004780_4	Cortisol levels (saliva)	4.000000e-07
GCST005984_62	Glomerular filtration rate	3.000000e-11
GCST005985_40	Creatinine levels	1.000000e-11
GCST005986_17	Blood urea nitrogen levels	9.000000e-09
GCST006624_20	Systolic blood pressure	2.000000e-10
GCST007344_49	Estimated glomerular filtration rate	3.000000e-08
GCST007833_9	Urolithiasis	4.000000e-22
GCST007876_33	Estimated glomerular filtration rate	5.000000e-12
GCST008058_299	Estimated glomerular filtration rate	3.000000e-11
GCST008369_23	Plasma anti-thyroglobulin levels	5.000000e-06
GCST009598_11	Kidney stones	1.000000e-24
GCST009599_10	Kidney stones	5.000000e-11
GCST010989_56	Body size at age 10	6.000000e-09
GCST90000025_1042	Appendicular lean mass	1.000000e-12

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0005276	hydroxy-leucine measurement
EFO:0004838	calcium measurement
EFO:0003892	pulmonary function measurement
EFO:0004314	forced expiratory volume
EFO:0005843	cortisol measurement
EFO:0006335	systolic blood pressure
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105940 (SINGLE PROTEIN)

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1012053	DGKH		0.00	0
rs1170191	DGKH		0.00	0
rs9315885	DGKH		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
potassium chromate(VI)	affects cotreatment, decreases expression	2
Air Pollutants	decreases expression, increases abundance, affects expression, affects cotreatment	2
Estradiol	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases expression	1
arsenite	decreases reaction, affects binding	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	increases expression	1
nickel sulfate	decreases expression	1
methacrylaldehyde	decreases expression, increases abundance, affects cotreatment	1
epigallocatechin gallate	decreases expression, increases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
perfluoro-n-nonanoic acid	increases expression	1
entinostat	increases expression	1
abrine	decreases expression	1
NSC 689534	increases expression, affects binding	1
Resveratrol	affects cotreatment, increases expression	1
Microplastics	decreases expression, increases abundance	1
Acetaminophen	increases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	increases expression	1
Calcitriol	decreases expression, affects cotreatment	1
Copper	affects binding, increases expression	1
Methotrexate	decreases expression	1
Ozone	affects cotreatment, decreases expression, increases abundance	1
Phthalic Acids	increases methylation	1
Plant Extracts	increases expression, affects cotreatment	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4034310	Binding	Inhibition of DGKH ATP binding site (unknown origin) at 10 uM	Developing DYRK inhibitors derived from the meridianins as a means of increasing levels of NFAT in the nucleus. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7NM	Ubigene A-549 DGKH KO	Cancer cell line	Male
CVCL_D8K1	Ubigene HCT 116 DGKH KO	Cancer cell line	Male
CVCL_D9DA	Ubigene HEK293 DGKH KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06231459	PHASE4	COMPLETED	Expression of Pro- and Anti-inflammatory Cytokines During Anti-PCSK9 in Familial Hypercholesterolemia
NCT00000594	PHASE3	COMPLETED	NHLBI Type II Coronary Intervention Study
NCT00092833	PHASE3	TERMINATED	Investigational Drug in Patients With Hypercholesterolemia or in Patients With Sitosterolemia (0653-026)(COMPLETED)
NCT00134485	PHASE3	COMPLETED	Study To Evaluate The Safety And Efficacy Of Torcetrapib/Atorvastatin In Subjects With Familial Hypercholerolemia
NCT00134511	PHASE3	COMPLETED	Study To Evaluate The Effect Of Torcetrapib/Atorvastatin In Patients With Genetic High Cholesterol Disorder
NCT00136981	PHASE3	COMPLETED	Carotid B-Mode Ultrasound Study to Compare Anti-Atherosclerotic Effect of Torcetrpib/Atorvastatin to Atorvastatin Alone.
NCT00384293	PHASE3	TERMINATED	Carotid IMT (Intima Media Thickening) Study (0524A-041)(TERMINATED)
NCT01524289	PHASE3	COMPLETED	Study to Assess the Tolerability and Efficacy of Anacetrapib (MK-0859) Co-Administered With Statin in Participants With Heterozygous Familial Hypercholesterolemia (MK-0859-020)
NCT00280995	PHASE2	COMPLETED	Dose-escalating Safety Study of ISIS 301012 in Homozygous Familial Hypercholesterolemia Subjects on Lipid Lowering Therapy
NCT00281008	PHASE2	COMPLETED	Study of ISIS 301012 (Mipomersen) in Heterozygous Familial Hypercholesterolemia Subjects on Lipid Lowering Therapy
NCT01375751	PHASE2	COMPLETED	Reduction of Low-Density Lipoprotein Cholesterol (LDL-C) With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Study
NCT00515307	PHASE1	COMPLETED	Bone Marrow Stem Cells as a Source of Allogenic Hepatocyte Transplantation in Homozygous Familial Hypercholesterolemia
NCT01583647	PHASE1	TERMINATED	A Study of Extended-release (ER) Niacin/Laropiprant in Adolescents With Heterozygous Familial Hypercholesterolemia (MK-0524A-158)
NCT00005168	Not specified	COMPLETED	Hyperapo B and Coronary Heart Disease
NCT01753232	Not specified	COMPLETED	Safety and Efficacy of the DALI LDL-adsorber and MONET Lipoprotein Filter
NCT03018678	Not specified	COMPLETED	Screening Protocol for a Gene Therapy Trial in Subjects With Homozygous Familial Hypercholesterolemia
NCT03110432	Not specified	COMPLETED	Prospective German Very High Cardiovascular Risk Patients Dyslipidemia Treatment Indication Registry
NCT03795038	Not specified	COMPLETED	Comparison of the Plasma Lipoprotein Apheresis Systems DIAMED and MONET vs. the Whole Blood Apheresis System DALI
NCT03989167	Not specified	RECRUITING	Clinical Decision Support for Familial Hypercholesterolemia
NCT04073797	Not specified	RECRUITING	PET Imaging of Inflammation and Lipid Lowering Study
NCT04118348	Not specified	COMPLETED	Evaluating the Efficacy of Pediatric Lipid Screening Alerts
NCT04313270	Not specified	UNKNOWN	Subclinical Atherosclerosis in Patients With Familial Hypercholesterolemia Treated With Evolocumab®
NCT04526457	Not specified	COMPLETED	Is Family Screening Improved by Genetic Testing of Familial Hypercholesterolemia
NCT04656028	Not specified	ACTIVE_NOT_RECRUITING	Genetic Testing and Motivational Counseling for FH
NCT04722068	Not specified	COMPLETED	Regeneron 1331 Kinetics Sub-Study HoFH
NCT04837638	Not specified	UNKNOWN	Diet Quality and Coronary Artery Calcification in Adults With Heterozygous Familial Hypercholesterolemia
NCT06555120	Not specified	RECRUITING	Screening for Familial Hypercholesterolemia in Children
NCT07543731	Not specified	NOT_YET_RECRUITING	A Real-World Study of Long-Term Adherence and Persistence to Inclisiran, Evolocumab, and Alirocumab