DHX15

Summary

DHX15 (DEAH-box helicase 15, HGNC:2738) is a protein-coding gene on chromosome 4p15.2, encoding ATP-dependent RNA helicase DHX15 (O43143). RNA helicase involved in mRNA processing and antiviral innate immunity. It is a common-essential gene (DepMap: required in 99.8% of cancer cell lines).

The protein encoded by this gene is a putative ATP-dependent RNA helicase implicated in pre-mRNA splicing.

Source: NCBI Gene 1665 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 48 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_001358

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2738
Approved symbol	DHX15
Name	DEAH-box helicase 15
Location	4p15.2
Locus type	gene with protein product
Status	Approved
Aliases	HRH2, DBP1, Prp43, PrPp43p, PRPF43
Ensembl gene	ENSG00000109606
Ensembl biotype	protein_coding
OMIM	603403
Entrez	1665

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 13 protein_coding, 8 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000336812, ENST00000503562, ENST00000504279, ENST00000508032, ENST00000508368, ENST00000510645, ENST00000511553, ENST00000512903, ENST00000513036, ENST00000513092, ENST00000853183, ENST00000853184, ENST00000853185, ENST00000853186, ENST00000853187, ENST00000911558, ENST00000911559, ENST00000911560, ENST00000911561, ENST00000911562, ENST00000953075, ENST00000953076

RefSeq mRNA: 1 — MANE Select: NM_001358 NM_001358

CCDS: CCDS33966

Canonical transcript exons

ENST00000336812 — 14 exons

Exon	Start	End
ENSE00000707817	24542940	24543026
ENSE00000969434	24570654	24570847
ENSE00000969435	24556251	24556410
ENSE00000969436	24554725	24554943
ENSE00000969439	24537051	24537173
ENSE00001073852	24576243	24576678
ENSE00001123131	24540108	24540299
ENSE00001123144	24541873	24542022
ENSE00001123157	24548855	24549022
ENSE00001388331	24584323	24584554
ENSE00003531443	24532864	24533054
ENSE00003668089	24540840	24540948
ENSE00003686035	24529601	24529770
ENSE00003693578	24527475	24528041

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 64.4408 / max 655.4432, expressed in 1824 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51670	61.1649	1824
51669	1.6662	1024
51668	1.6097	792

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	99.22	gold quality
tibia	UBERON:0000979	99.12	gold quality
germinal epithelium of ovary	UBERON:0001304	99.07	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.02	gold quality
visceral pleura	UBERON:0002401	98.78	gold quality
colonic mucosa	UBERON:0000317	98.76	gold quality
skin of hip	UBERON:0001554	98.76	gold quality
parietal pleura	UBERON:0002400	98.76	gold quality
embryo	UBERON:0000922	98.68	gold quality
ventricular zone	UBERON:0003053	98.60	gold quality
pleura	UBERON:0000977	98.59	gold quality
upper leg skin	UBERON:0004262	98.58	gold quality
gingival epithelium	UBERON:0001949	98.49	gold quality
epithelium of nasopharynx	UBERON:0001951	98.47	gold quality
gingiva	UBERON:0001828	98.28	gold quality
ganglionic eminence	UBERON:0004023	98.28	gold quality
oral cavity	UBERON:0000167	98.25	gold quality
caput epididymis	UBERON:0004358	98.18	gold quality
esophagus squamous epithelium	UBERON:0006920	98.17	gold quality
rectum	UBERON:0001052	98.13	gold quality
squamous epithelium	UBERON:0006914	98.11	gold quality
cauda epididymis	UBERON:0004360	98.08	gold quality
mucosa of urinary bladder	UBERON:0001259	98.07	gold quality
skin of abdomen	UBERON:0001416	98.00	gold quality
trabecular bone tissue	UBERON:0002483	97.99	gold quality
corpus epididymis	UBERON:0004359	97.95	gold quality
endometrium	UBERON:0001295	97.92	gold quality
adrenal tissue	UBERON:0018303	97.91	gold quality
tibial nerve	UBERON:0001323	97.82	gold quality
pigmented layer of retina	UBERON:0001782	97.81	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10137	no	926.19
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

87 targeting DHX15, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4799-5P	99.82	70.60	2663

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 21)

• Data suggest that G-patch domain of RBM5 is indispensable for its ability to interact with DHX15; RBM5 stimulates helicase activity of DHX15 in a G-patch domain-dependent manner. (PMID:22569250)
• Data indicate that DEAH-box RNA helicase DHX15/PRP43 stimulates the NF-kappaB and MAPK pathways downstream of virus-induced signaling adapter protein MAVS and contributes to MAVS-mediated cytokine production and apoptosis. (PMID:24782566)
• The results suggest that activation of Prp43p by Gno1p/PINX1 within early pre-ribosomal particles is crucial for their subsequent maturation. (PMID:24823796)
• Mutation in DHX15 is associated with core-binding factor acute myeloid leukemia. (PMID:27798625)
• depletion of NKRF, XRN2 or DHX15 impairs an early pre-rRNA cleavage step. (PMID:28115624)
• The crystal structure of human DHX15 reveals a domain organization of the mammalian DEAH/RHA family. (PMID:28580923)
• Loss of DHX15 expression is associated with glioma. (PMID:28829764)
• DHX15 regulates androgen receptor (AR) activity by modulating E3 ligase Siah2-mediated AR ubiquitination independent of its ATPase activity promoting prostate cancer progression. (PMID:28991234)
• ETS1 and SP1 regulated DHX15 expression in acute lymphoblastic leukaemia. (PMID:29512921)
• these findings demonstrate, for the first time, that DHX15 is significantly upregulated in hepatocellular carcinoma and its high expression was correlated with poor prognosis, suggesting its pivotal role in the progression of hepatocellular carcinoma (PMID:30339968)
• CMTr1 binds ATP-dependent RNA DHX15 helicase and that this interaction, mediated by the G-patch domain of CMTr1, has an advantageous effect on CMTr1 activity towards highly structured RNA substrates. (PMID:30397098)
• The DHX15 selectively binds PAMP RNA to promote RIG-I ATP hydrolysis and signaling activation in response to viral RNA. The results define DHX15 as a coreceptor required for RLR innate immune responses to control RNA virus infection. (PMID:31090472)
• RNA affinity, helicase, and ATPase activity of DHX15 are increased when the G-patch motif of NKRF binds in an extended conformation across the helicase surface (PMID:32179686)
• Dhx15 regulates zebrafish definitive hematopoiesis through the unfolded protein response pathway. (PMID:34077586)
• DHX15 is required to control RNA virus-induced intestinal inflammation. (PMID:34161762)
• Prp43/DHX15 exemplify RNA helicase multifunctionality in the gene expression network. (PMID:35993807)
• Relationship between DHX15 expression and survival in colorectal cancer. (PMID:36177832)
• DHX15 is involved in SUGP1-mediated RNA missplicing by mutant SF3B1 in cancer. (PMID:36459648)
• Splicing quality control mediated by DHX15 and its G-patch activator SUGP1. (PMID:37805921)
• GPATCH4 regulates rRNA and snRNA 2’-O-methylation in both DHX15-dependent and DHX15-independent manners. (PMID:38113271)
• Unveiling the DHX15-G-patch interplay in retroviral RNA packaging. (PMID:39320912)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dhx15	ENSDARG00000015392
mus_musculus	Dhx15	ENSMUSG00000029169
rattus_norvegicus	Dhx15	ENSRNOG00000003844
drosophila_melanogaster	Dhx15	FBGN0033160
caenorhabditis_elegans		WBGENE00018967

Paralogs (18): DHX33 (ENSG00000005100), YTHDC2 (ENSG00000047188), DHX29 (ENSG00000067248), DHX8 (ENSG00000067596), DHX32 (ENSG00000089876), DHX35 (ENSG00000101452), DHX40 (ENSG00000108406), HELB (ENSG00000127311), DHX30 (ENSG00000132153), DHX34 (ENSG00000134815), DHX9 (ENSG00000135829), DHX38 (ENSG00000140829), DQX1 (ENSG00000144045), DHX37 (ENSG00000150990), TDRD9 (ENSG00000156414), DHX57 (ENSG00000163214), DHX36 (ENSG00000174953), DHX16 (ENSG00000204560)

Protein

Protein identifiers

ATP-dependent RNA helicase DHX15 — O43143 (reviewed: O43143)

Alternative names: ATP-dependent RNA helicase #46, DEAH box protein 15, Splicing factor Prp43

All UniProt accessions (1): O43143

UniProt curated annotations — full annotation on UniProt →

Function. RNA helicase involved in mRNA processing and antiviral innate immunity. Pre-mRNA processing factor involved in disassembly of spliceosomes after the release of mature mRNA. In cooperation with TFIP11 seem to be involved in the transition of the U2, U5 and U6 snRNP-containing IL complex to the snRNP-free IS complex leading to efficient debranching and turnover of excised introns. Plays a key role in antiviral innate immunity by promoting both MAVS-dependent signaling and NLRP6 inflammasome. Acts as an RNA virus sensor: recognizes and binds viral double stranded RNA (dsRNA) and activates the MAVS-dependent signaling to produce interferon-beta and interferon lambda-3 (IFNL3). Involved in intestinal antiviral innate immunity together with NLRP6: recognizes and binds viral dsRNA and promotes activation of the NLRP6 inflammasome in intestinal epithelial cells to restrict infection by enteric viruses. The NLRP6 inflammasome acts by promoting maturation and secretion of IL18 in the extracellular milieu. Also involved in antibacterial innate immunity by promoting Wnt-induced antimicrobial protein expression in Paneth cells.

Subunit / interactions. Component of the U11/U12 snRNPs that are part of the U12-type spliceosome. Identified in the Intron Large spliceosome complex (IL, also named intron lariat spliceosome), a post-mRNA release spliceosomal complex containing the excised intron, U2, U5 and U6 snRNPs, and splicing factors; the association may be transient. The IL complex exists in two distinct conformations, one with the DHX15 (ILS2) and one without (ILS1). Interacts with TFIP11 (via G-patch domain); indicative for a recruitment to the IL complex. Interacts with SSB/La. Interacts with GPATCH2 (via G-patch domain); promoting the RNA helicase activity. Interacts with NKRF (via G-patch domain); promoting the RNA helicase activity. Interacts with NLRP6.

Subcellular location. Nucleus. Nucleolus.

Tissue specificity. Ubiquitous.

Activity regulation. ATPase activity is enhanced upon binding to G-patch domain-containing proteins. G-patch domain-containing proteins act like a brace that tethers mobile sections of DHX15 together, stabilizing a functional conformation with high RNA affinity, thereby promoting the ATPase activity.

Similarity. Belongs to the DEAD box helicase family. DEAH subfamily. DDX15/PRP43 sub-subfamily.

RefSeq proteins (1): NP_001349* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001650	Helicase_C-like	Domain
IPR002464	DNA/RNA_helicase_DEAH_CS	Conserved_site
IPR007502	Helicase-assoc_dom	Domain
IPR011545	DEAD/DEAH_box_helicase_dom	Domain
IPR011709	DEAD-box_helicase_OB_fold	Domain
IPR014001	Helicase_ATP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR044756	DHX15_DEXHc	Domain
IPR048333	HA2_WH	Domain

Pfam: PF00270, PF00271, PF04408, PF07717, PF21010

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (95 total): helix 33, strand 27, mutagenesis site 12, turn 8, sequence conflict 4, domain 2, compositionally biased region 2, modified residue 2, chain 1, cross-link 1, region of interest 1, short sequence motif 1, binding site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
8EJM	X-RAY DIFFRACTION	1.8
6SH6	X-RAY DIFFRACTION	1.85
5XDR	X-RAY DIFFRACTION	2
6SH7	X-RAY DIFFRACTION	2.21
6ID1	ELECTRON MICROSCOPY	2.86
9ZE0	ELECTRON MICROSCOPY	3.43
8RO2	ELECTRON MICROSCOPY	3.5
9ZE3	ELECTRON MICROSCOPY	3.93
9R8V	ELECTRON MICROSCOPY	8.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43143-F1	86.17	0.66

Functional residue map

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

Ligand- & substrate-binding residues (1): 160–167

Post-translational modifications (3): 786, 15, 488

Mutagenesis-validated functional residues (12):

Position	Phenotype
166	abolished atpase activity without affecting ability to activate the mavs-dependent signaling to produce interferon-beta.
167	abolished atpase activity without affecting ability to activate the mavs-dependent signaling to produce interferon-beta.
260	abolished atpase activity without affecting ability to activate the mavs-dependent signaling to produce interferon-beta.
261	abolished atpase activity without affecting ability to activate the mavs-dependent signaling to produce interferon-beta.
327	abolished interaction with nkrf.
429	abolished atpase activity.
485	abolished interaction with nkrf.
489	decreased, but not abolished interaction, with nkrf.
523	abolished interaction with nkrf.
533	abolished interaction with nkrf.
536	abolished interaction with nkrf.
540	abolished interaction with nkrf.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-9770562	mRNA Polyadenylation
R-HSA-9918481	Dengue Virus-Host Interactions
R-HSA-9943411	CHD1 and CHD2 subfamily

MSigDB gene sets: 367 (showing top): GOBP_DIGESTION, MODULE_97, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_ACID_SECRETION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, MORF_UBE2N, MODULE_182, GNF2_MCM5, GGGTGGRR_PAX4_03, GOBP_CELL_CELL_SIGNALING, AGGCACT_MIR5153P, PUJANA_CHEK2_PCC_NETWORK, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE

GO Biological Process (11): mRNA splicing, via spliceosome (GO:0000398), mRNA processing (GO:0006397), RNA splicing (GO:0008380), response to toxic substance (GO:0009636), defense response to bacterium (GO:0042742), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), response to alkaloid (GO:0043279), defense response to virus (GO:0051607), antiviral innate immune response (GO:0140374), immune system process (GO:0002376), innate immune response (GO:0045087)

GO Molecular Function (11): RNA binding (GO:0003723), RNA helicase activity (GO:0003724), double-stranded RNA binding (GO:0003725), helicase activity (GO:0004386), ATP binding (GO:0005524), ATP-dependent activity, acting on RNA (GO:0008186), ATP hydrolysis activity (GO:0016887), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), spliceosomal complex (GO:0005681), U12-type spliceosomal complex (GO:0005689), nucleolus (GO:0005730), nuclear speck (GO:0016607), U2-type post-mRNA release spliceosomal complex (GO:0071008)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
mRNA Splicing	1
mRNA 3’-end processing	1
Dengue Virus Infection	1
CHD chromatin remodelers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ATP-dependent activity	3
RNA processing	2
defense response	2
binding	2
nuclear lumen	2
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
mRNA metabolic process	1
response to chemical	1
response to bacterium	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
response to nitrogen compound	1
response to virus	1
innate immune response	1
defense response to virus	1
biological_process	1
immune response	1
defense response to symbiont	1
nucleic acid binding	1
helicase activity	1
ATP-dependent activity, acting on RNA	1
catalytic activity, acting on RNA	1
RNA binding	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1
spliceosomal complex	1
intracellular membraneless organelle	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

4474 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DHX15	NTSR2	O95665	995
DHX15	TFIP11	Q9UBB9	994
DHX15	GPATCH2	Q9NW75	948
DHX15	RBM5	P52756	839
DHX15	SRSF2	Q01130	825
DHX15	MAVS	Q7Z434	812
DHX15	NLRP6	P59044	805
DHX15	CWC25	Q9NXE8	804
DHX15	SNRNP200	O75643	798
DHX15	SLU7	O95391	791
DHX15	DDX1	Q92499	787
DHX15	NTSR1	P30989	777
DHX15	BYSL	Q13895	775
DHX15	XAB2	Q9HCS7	772
DHX15	DDX23	Q9BUQ8	768

IntAct

250 interactions, top by confidence:

A	B	Type	Score
KIFAP3	KIF3B	psi-mi:“MI:0914”(association)	0.900
DHX15	RBM17	psi-mi:“MI:0915”(physical association)	0.880
RBM17	DHX15	psi-mi:“MI:0915”(physical association)	0.880
ZGPAT	DHX15	psi-mi:“MI:0915”(physical association)	0.850
DHX15	ZGPAT	psi-mi:“MI:0915”(physical association)	0.850
ZGPAT	DHX15	psi-mi:“MI:0914”(association)	0.850
COMMD1	VPS26C	psi-mi:“MI:0914”(association)	0.730
COMMD4	VPS26C	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
DHX15	ZGPAT	psi-mi:“MI:0915”(physical association)	0.670
ZGPAT	DHX15	psi-mi:“MI:0915”(physical association)	0.670
NKRF	DHX15	psi-mi:“MI:0915”(physical association)	0.670
POLR2C	SUPT5H	psi-mi:“MI:0914”(association)	0.640
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640

BioGRID (652): DHX15 (Affinity Capture-MS), ZGPAT (Two-hybrid), RBM17 (Two-hybrid), DHX15 (Affinity Capture-RNA), DHX15 (Affinity Capture-RNA), DHX15 (Affinity Capture-RNA), DHX15 (Affinity Capture-MS), DHX15 (Affinity Capture-MS), DHX15 (Affinity Capture-MS), DHX15 (Affinity Capture-MS), PINX1 (Affinity Capture-Western), DHX15 (Affinity Capture-Western), DHX15 (Affinity Capture-MS), DHX15 (Affinity Capture-RNA), DHX15 (Affinity Capture-MS)

ESM2 similar proteins: A0A0L0P6P7, A4I2L4, A5PKR8, A8D8P8, A9U328, A9VB27, A9ZSZ2, D3TQJ5, F4IE66, F4ISQ7, O22899, O43143, O54747, O60126, O61660, O70157, O76922, O95985, O96651, P13099, P54358, P90829, P97283, Q07803, Q08BB1, Q0J0S6, Q13472, Q20875, Q22307, Q23223, Q4P1V1, Q5R9V1, Q5RAZ4, Q5RBD4, Q5XQC7, Q7K3M5, Q80VY9, Q8K0D5, Q8T2T7, Q96RP9

Diamond homologs: A1Z9L3, A2A4P0, B4GEU5, B4JT42, B4K5R2, B4RC48, D4A2Z8, F4HYJ7, F4IE66, F4IJV4, F4ILR7, F4IM84, F4JMJ3, F4JRJ6, F4K2E9, F4KGU4, O17438, O22243, O22899, O35286, O42643, O42945, O43143, O45244, O46072, O51767, O60114, O60231, O70133, O94536, P0C7L7, P0CE10, P15938, P20095, P24384, P34305, P34498, P36009, P37024, P43329

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 167 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
mRNA Splicing	14	13.8×	3e-10
mRNA Splicing - Minor Pathway	6	12.1×	6e-04
mRNA Polyadenylation	15	11.9×	3e-10
Processing of Capped Intron-Containing Pre-mRNA	16	11.8×	1e-10
mRNA Splicing - Major Pathway	21	10.3×	5e-13
snRNP Assembly	5	9.5×	8e-03
CHD1 and CHD2 subfamily	9	8.8×	8e-05
Dengue Virus-Host Interactions	15	6.2×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
mRNA cis splicing, via spliceosome	5	36.4×	5e-05
spliceosomal complex assembly	6	26.6×	3e-05
U2-type prespliceosome assembly	5	22.9×	4e-04
intrinsic apoptotic signaling pathway	6	15.8×	4e-04
G1/S transition of mitotic cell cycle	7	10.3×	7e-04
mRNA splicing, via spliceosome	15	10.1×	3e-08
negative regulation of translation	7	10.1×	8e-04
RNA splicing	13	8.4×	3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	37
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2835 predictions. Top by Δscore:

Variant	Effect	Δscore
4:24529595:ACTT:A	donor_loss	1.0000
4:24529596:CTTA:C	donor_loss	1.0000
4:24529597:TTACC:T	donor_loss	1.0000
4:24529598:TAC:T	donor_loss	1.0000
4:24529599:A:T	donor_loss	1.0000
4:24529599:AC:A	donor_gain	1.0000
4:24529600:CC:C	donor_gain	1.0000
4:24529600:CCA:C	donor_gain	1.0000
4:24529600:CCATT:C	donor_gain	1.0000
4:24529767:CCAC:C	acceptor_gain	1.0000
4:24529768:CAC:C	acceptor_gain	1.0000
4:24529768:CACC:C	acceptor_gain	1.0000
4:24529769:ACC:A	acceptor_loss	1.0000
4:24529771:C:CC	acceptor_gain	1.0000
4:24532914:C:A	donor_gain	1.0000
4:24532936:T:TA	donor_gain	1.0000
4:24532936:TCG:T	donor_gain	1.0000
4:24537148:C:CT	acceptor_gain	1.0000
4:24540154:G:C	donor_gain	1.0000
4:24540159:A:AT	donor_gain	1.0000
4:24540295:AGGAG:A	acceptor_gain	1.0000
4:24540296:GGAG:G	acceptor_gain	1.0000
4:24540297:GAG:G	acceptor_gain	1.0000
4:24540298:AG:A	acceptor_gain	1.0000
4:24540299:GC:G	acceptor_loss	1.0000
4:24540300:C:CA	acceptor_loss	1.0000
4:24540300:C:CC	acceptor_gain	1.0000
4:24540301:T:A	acceptor_loss	1.0000
4:24541867:CCATA:C	donor_loss	1.0000
4:24541869:ATAC:A	donor_loss	1.0000

AlphaMissense

5203 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:24527973:A:G	L780S	1.000
4:24528000:A:G	F771S	1.000
4:24528019:A:G	Y765H	1.000
4:24529602:A:G	W757R	1.000
4:24529602:A:T	W757R	1.000
4:24529628:C:G	R748P	1.000
4:24529631:A:T	I747N	1.000
4:24529635:A:C	Y746D	1.000
4:24529646:G:A	T742I	1.000
4:24529649:A:G	L741P	1.000
4:24529652:A:T	V740D	1.000
4:24529674:A:G	W733R	1.000
4:24529674:A:T	W733R	1.000
4:24529705:A:C	H722Q	1.000
4:24529705:A:T	H722Q	1.000
4:24529706:T:C	H722R	1.000
4:24529707:G:C	H722D	1.000
4:24529715:A:T	V719D	1.000
4:24529721:T:G	Q717P	1.000
4:24529727:T:A	D715V	1.000
4:24529727:T:G	D715A	1.000
4:24529728:C:A	D715Y	1.000
4:24529728:C:G	D715H	1.000
4:24529729:T:A	K714N	1.000
4:24529729:T:G	K714N	1.000
4:24529731:T:C	K714E	1.000
4:24529743:A:C	Y710D	1.000
4:24529764:G:C	H703D	1.000
4:24529766:G:T	A702E	1.000
4:24529767:C:G	A702P	1.000

dbSNP variants (sampled 300 via entrez): RS1000060729 (4:24542731 A>G), RS1000075360 (4:24569499 G>A), RS1000098598 (4:24529040 C>T), RS1000104447 (4:24557218 C>T), RS1000173526 (4:24528907 A>C), RS1000177650 (4:24569067 G>A), RS1000183383 (4:24548292 G>A), RS1000207658 (4:24570284 C>T), RS1000229232 (4:24574922 A>G), RS1000266333 (4:24557876 A>C), RS1000352872 (4:24553898 A>G), RS1000359760 (4:24576565 C>A,T), RS1000371503 (4:24541163 C>T), RS1000428883 (4:24560759 C>G,T), RS1000433254 (4:24542490 C>T)

Disease associations

OMIM: gene MIM:603403 | disease phenotypes: MIM:607411

GenCC curated gene-disease

Mondo (1): patent ductus arteriosus (MONDO:0011827)

Orphanet (2): Familial patent arterial duct (Orphanet:466729), NON RARE IN EUROPE: Patent arterial duct (Orphanet:706)

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001712_24	Myopia (pathological)	3.000000e-26
GCST002326_2	Pulmonary emphysema	2.000000e-10
GCST003174_22	Sense of smell	9.000000e-06
GCST010241_357	Apolipoprotein A1 levels	4.000000e-11
GCST010242_235	HDL cholesterol levels	1.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004207	pathological myopia
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D004374	Ductus Arteriosus, Patent	C14.240.400.340; C14.280.400.340; C16.131.240.400.340

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295661 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2067474	HRH2		0.00	0

ChEMBL bioactivities

5 potent at pChembl≥5 of 7 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.05	Kd	89	nM	MOLIBRESIB
6.72	IC50	190	nM	MOLIBRESIB
6.43	Kd	372.1	nM	CHEMBL3752910
6.43	ED50	372.1	nM	CHEMBL3752910
5.20	IC50	6300	nM	CHEMBL5438085

PubChem BioAssay actives

4 with measured affinity, of 13 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179119: Binding affinity against DHX15 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0890	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148236: Binding affinity to human DHX15 incubated for 45 mins by Kinobead based pull down assay	kd	0.3721	uM
1-(3-cyano-5-methylthiophen-2-yl)-N-(6-methoxy-1H-benzimidazol-2-yl)-2,5-dimethylpyrrole-3-carboxamide	2036891: Inhibition of N-terminal thioredoxin-tagged human recombinant DHX15 transformed in Escherichia coli BL21(DE3)pLysS cells	ic50	6.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	2
sodium arsenite	affects binding, increases reaction, decreases expression, increases activity	2
Valproic Acid	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	affects expression	1
arsenite	affects binding, decreases reaction	1
methylparaben	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
mercuric bromide	decreases expression	1
pinosylvin	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
yessotoxin	decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
deguelin	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1
nutlin 3	increases secretion, affects cotreatment	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	decreases expression	1
PP242	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	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
CHEMBL4119022	Binding	Binding affinity to DHX15 in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00217191	PHASE4	COMPLETED	Ibuprofen and Renal Function in Premature Infants
NCT00642330	PHASE4	COMPLETED	Comparative Study of Efficacy and Safety of Oral Ibuprofen and Intravenous Ibuprofen in Closure of Patent Ductus Arteriosus in Very Low Birth Weight Infants
NCT00767039	PHASE4	TERMINATED	Curosurf and Survanta Treatment(CAST)of RDS in Very Premature Infants
NCT00961753	PHASE4	TERMINATED	Safety/Efficacy Study of Optimizing Ibuprofen Dosing to Achieve Higher PDA Closure Rates
NCT01536158	PHASE4	COMPLETED	Oral Paracetamol Versus Oral Ibuprofen in Management of Patent Ductus Arteriosus in Preterm Infants: A Randomised Controlled Trial
NCT01544972	PHASE4	UNKNOWN	Serum Level Measurement of Oral Paracetamol and Oral Ibuprofen for Patent Ductus Arteriosus Treatment in Preterm Infants
NCT03265782	PHASE4	UNKNOWN	Paracetamol Versus Ibuprofen for PDA Closure
NCT00440804	PHASE3	COMPLETED	Safety and Efficacy Study of Ibuprofen l-Lysine Solution in Premature Infants for Treatment of PDA
NCT00485160	PHASE3	COMPLETED	Ibuprofen vs. Continuous Indomethacin in the Treatment of PDA
NCT01593163	PHASE3	COMPLETED	Echocardiographically Guided Versus Standard Ibuprofen Treatment for Patent Ductus Arteriosus
NCT01630278	PHASE3	COMPLETED	Early Ibuprofen Treatment of Patent Ductus Arteriosus (PDA) in Premature Infants (TRIOCAPI)
NCT01755728	PHASE3	COMPLETED	Paracetamol (Acetaminophen) for Closure of PDA in Preterm Infants
NCT03022253	PHASE3	COMPLETED	Platelet Transfusion for Treatment of Patent Ductus Arteriosus in Thrombocytopenic Preterm Neonates
NCT03456336	PHASE3	ACTIVE_NOT_RECRUITING	Management of the PDA Trial
NCT03537144	PHASE3	TERMINATED	Acetaminophen vs Indomethacin in Treating hsPDA
NCT00187447	PHASE2	COMPLETED	Comparison of 2 Different Indomethacin Dosing Protocols to Treat Infants Delivered at <28 Weeks Gestation With a Persistent Patent Ductus Arteriosus
NCT00616382	PHASE2	UNKNOWN	Treating the Resistant Patent Ductus Arteriosus (PDA)
NCT01070745	PHASE2	WITHDRAWN	Second Course of Therapy for Resistant Patent Ductus Arteriosus (PDA)
NCT01291654	PHASE2	UNKNOWN	Paracetamol and Patent Ductus Arteriosus (PDA)
NCT01958320	PHASE2	COMPLETED	Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus
NCT02819414	PHASE2	UNKNOWN	Paracetamol Treatment of the Borderline Significant PDA
NCT03701074	PHASE2	TERMINATED	Randomized Controlled Trial to Evaluate the Safety and Efficacy of Acetaminophen in Preterm Infants Used in Combination With Ibuprofen for Closure of the Ductus Arteriosus
NCT04026464	PHASE2	WITHDRAWN	Addition of Acetaminophen in Standard PDA Management
NCT06152796	PHASE2	UNKNOWN	Comparision Between Paracetamol and Ibuprofen in Closure of Patent Ductus Arteriosus
NCT07143201	PHASE2	RECRUITING	Precision Dosing of Oral Ibuprofen for PDA, A Pilot RCT
NCT03103022	PHASE1	COMPLETED	Combination of Acetaminophen and Ibuprofen in the Management of Patent Ductus Arteriosus
NCT03648437	PHASE1	TERMINATED	Paracetamol And Ibuprofen/Indomethacin in Closing Patent Ductus Arteriosus
NCT00750581	PHASE2/PHASE3	TERMINATED	An Escalating Dose Indomethacin for the Treatment of Persistent Patent Ductus Arteriosus (PDA) In Preterm Infants
NCT02620761	PHASE2/PHASE3	TERMINATED	Fenoldopam to Prevent Renal Dysfunction in Indomethacin Treated Preterm Infants
NCT04459117	PHASE2/PHASE3	COMPLETED	Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen
NCT04986839	PHASE2/PHASE3	UNKNOWN	PAIR (Paracetamol and Ibuprofen Research) Pilot Trial
NCT07067177	PHASE2/PHASE3	COMPLETED	Prophylactic IV Paracetamol in Extremely Premature Infants
NCT01149564	PHASE1/PHASE2	UNKNOWN	Comparison of Oral and Intravenous Ibuprofen for PDA Treatment in Premature Infants
NCT06256211	PHASE1/PHASE2	UNKNOWN	Assessment of Therapeutic Effect of Rectal Vs. Intravenous Paracetamol in The Treatment of Patent Ductus Arteriosus (PDA) in Neonates
NCT06298344	EARLY_PHASE1	COMPLETED	The Role of Thiamine After Transcatheter Closure in Children With Left-to-Right Shunt Congenital Heart Disease
NCT00162903	Not specified	COMPLETED	Nitric Oxide, Endothelin-1, and the Patency of Ductus Arteriosus in Preterm Infants
NCT00500305	Not specified	COMPLETED	The Use of B-type Natriuretic Peptide (BNP) to Predict Closure of a Patent Ductus Arteriosus (PDA) in Premature Infants
NCT00554307	Not specified	WITHDRAWN	Brain, Gut and Kidney Blood Flow During Medical Closure of PDA
NCT00583596	Not specified	COMPLETED	Closure Of Patent Ductus Arteriosus With the AMPLATZER Duct Occluder the AMPLATZER® Duct Occluder
NCT00713700	Not specified	COMPLETED	AMPLATZER Duct Occluder II Clinical Study