DHX9

Summary

DHX9 (DExH-box helicase 9, HGNC:2750) is a protein-coding gene on chromosome 1q25.3, encoding ATP-dependent RNA helicase A (Q08211). Multifunctional ATP-dependent nucleic acid helicase that unwinds DNA and RNA in a 3’ to 5’ direction and that plays important roles in many processes, such as DNA replication, transcriptional activation, post-transcriptional RNA regulation, mRNA translation and RNA-mediated gene…. It is a common-essential gene (DepMap: required in 94.8% of cancer cell lines).

This gene encodes a member of the DEAH-containing family of RNA helicases. The encoded protein is an enzyme that catalyzes the ATP-dependent unwinding of double-stranded RNA and DNA-RNA complexes. This protein localizes to both the nucleus and the cytoplasm and functions as a transcriptional regulator. This protein may also be involved in the expression and nuclear export of retroviral RNAs. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 11 and 13.

Source: NCBI Gene 1660 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 195 total — 10 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 34
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Cancer dependency (DepMap): dependent in 94.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_001357

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2750
Approved symbol	DHX9
Name	DExH-box helicase 9
Location	1q25.3
Locus type	gene with protein product
Status	Approved
Aliases	RHA
Ensembl gene	ENSG00000135829
Ensembl biotype	protein_coding
OMIM	603115
Entrez	1660

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 11 protein_coding, 7 protein_coding_CDS_not_defined

ENST00000367549, ENST00000473076, ENST00000474446, ENST00000477802, ENST00000479271, ENST00000483416, ENST00000485081, ENST00000490519, ENST00000863481, ENST00000863482, ENST00000863483, ENST00000926361, ENST00000926362, ENST00000926363, ENST00000926364, ENST00000926365, ENST00000926366, ENST00000949150

RefSeq mRNA: 1 — MANE Select: NM_001357 NM_001357

CCDS: CCDS41444

Canonical transcript exons

ENST00000367549 — 28 exons

Exon	Start	End
ENSE00000790589	182854030	182854178
ENSE00000790590	182856532	182856578
ENSE00000790591	182858104	182858240
ENSE00000790592	182858551	182858640
ENSE00000790593	182858733	182858894
ENSE00000790595	182859993	182860184
ENSE00001176753	182876830	182876903
ENSE00001176761	182876447	182876541
ENSE00001176770	182876050	182876263
ENSE00001176794	182866444	182866585
ENSE00001176872	182839347	182839456
ENSE00001896425	182887083	182887982
ENSE00002211724	182872337	182872493
ENSE00002213926	182866961	182867043
ENSE00002219221	182874854	182874954
ENSE00003479021	182883520	182883635
ENSE00003480288	182852233	182852344
ENSE00003491211	182883139	182883368
ENSE00003492247	182880497	182880608
ENSE00003503935	182853306	182853418
ENSE00003509089	182878021	182878173
ENSE00003559534	182842545	182842677
ENSE00003576890	182843294	182843434
ENSE00003590758	182881520	182881647
ENSE00003610973	182879250	182879410
ENSE00003644344	182859040	182859117
ENSE00003652757	182884613	182884813
ENSE00003675053	182881264	182881425

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 87.1067 / max 1444.4397, expressed in 1822 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
7048	84.2841	1822
7049	1.5182	784
7050	1.3044	630

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.28	gold quality
ganglionic eminence	UBERON:0004023	99.17	gold quality
cortical plate	UBERON:0005343	98.70	gold quality
embryo	UBERON:0000922	98.09	gold quality
sperm	CL:0000019	97.70	gold quality
calcaneal tendon	UBERON:0003701	97.66	gold quality
male germ cell	CL:0000015	97.65	gold quality
adrenal tissue	UBERON:0018303	97.39	gold quality
right ovary	UBERON:0002118	97.18	gold quality
left ovary	UBERON:0002119	97.13	gold quality
right testis	UBERON:0004534	97.12	gold quality
endocervix	UBERON:0000458	97.04	gold quality
body of uterus	UBERON:0009853	96.97	gold quality
left testis	UBERON:0004533	96.85	gold quality
ectocervix	UBERON:0012249	96.82	gold quality
cerebellar hemisphere	UBERON:0002245	96.78	gold quality
right uterine tube	UBERON:0001302	96.77	gold quality
cerebellar cortex	UBERON:0002129	96.77	gold quality
lymph node	UBERON:0000029	96.76	gold quality
left lobe of thyroid gland	UBERON:0001120	96.71	gold quality
right lobe of thyroid gland	UBERON:0001119	96.69	gold quality
tibial nerve	UBERON:0001323	96.63	gold quality
metanephros cortex	UBERON:0010533	96.58	gold quality
adenohypophysis	UBERON:0002196	96.57	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.56	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	96.54	gold quality
islet of Langerhans	UBERON:0000006	96.54	gold quality
tendon	UBERON:0000043	96.54	gold quality
ovary	UBERON:0000992	96.40	gold quality
upper lobe of left lung	UBERON:0008952	96.38	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.68

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, FLI1, HESX1, HOPX, JUN, MYOD1, NFAT5, NKX2-5, SOX4

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 94.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• Nuclear DNA helicase II recruitment to PML nuclear bodies(NBs) is connected with transcriptional regulation of interferon-alpha-inducible genes attached to PML NBs. (PMID:12163469)
• propose that NDH II operates in both nucleoplasmic and nucleolar mode, and that its redistribution reflects accumulations indicating a possible cycling of NDH II between nucleoplasm and the nucleolus (PMID:12243751)
• Overexpression of a truncated RHA peptide that binds to the BRCA1 carboxy-terminus prevents normal BRCA1 function & association with nuclear foci following DNA damage. It induces pleomorphic nuclei, aberrant mitoses with extra centrosomes, & tetraploidy. (PMID:12592385)
• DNA-PK phosphorylated recombinant NDH II in the presence of RNA (PMID:14704337)
• RNA helicase A in the MEF1 transcription factor complex up-regulates the MDR1 gene in multidrug-resistant cancer cells (PMID:14769796)
• RHA interacts with NF-kappa B p65 and functions as a transcriptional coactivator. (PMID:15355351)
• Results suggest that nuclear DNA helicase II plays a role in promoting the DNA processing function of Werner syndrome helicase, which in turn might be necessary for maintaining genomic stability. (PMID:15995249)
• Our results indicate that the nuclear import of RHA is mediated by the importin-alpha3/importin-beta-dependent pathway and suggest that the specificity for importin may regulate the functions of cargo proteins. (PMID:16375861)
• RHA represents the first example of cellular RNA helicases that participate in HIV-1 particle production and promote viral reverse transcription (PMID:16527808)
• Phosphorylated Zic2 protein makes a stable complex with RNA helicase A. (PMID:17251188)
• RNA interference is a conserved pathway of sequence-specific gene silencing that depends on small guide RNAs and the action of proteins assembled in the RNA-induced silencing complex (RISC). (PMID:17531811)
• In vitro dephosphorylation of HeLa cellular HDH II/Ku caused a significant decrease in the DNA helicase activity of this enzyme. (PMID:18053790)
• These results establish a link between the p53 tumor suppressor and RNA processing via hnRNPA2/B1 and RNA Helicase A. (PMID:18519039)
• knockdown of DHX-9 by siRNA did not inhibit the rRNA synthesis or cause the nucleolar disruption (PMID:18600529)
• A 21-day follow-up of the response of HCV replication to the presence and absence of RNAi indicated that RHA is a cellular factor involved in the HCV replication process. (PMID:18782589)
• Four genes encoding BRCA1-interacting proteins were analyzed in a cohort of 96 breast cancer individuals from high-risk non-BRCA1/BRCA2 French Canadian families. (PMID:19197335)
• protein kinase R (PKR) is shown to interact with RNA helicase A; RHA is identified as a substrate for PKR, with phosphorylation perturbing the association of the helicase with double-stranded RNA (PMID:19229320)
• Results show overexpression or depletion of RHA could influence the interaction of Pol II with beta-actin and beta-actin-involved gene transcription regulation. (PMID:19309309)
• the preferential unwinding of RNA-containing substrates by WRN helicase is stimulated by DHX9 in vitro, both on Okazaki fragment-like hybrids and on RNA-containing ‘chicken-foot’ structures. (PMID:20385589)
• Proteomic analysis indicates that cellular proteins interacted with Kaposi’s sarcoma-associated herpesvirus viral protein kinase (ORF36), and co-immunoprecipitation reactions further reveal interactions with human RNA helicase A. (PMID:20437153)
• DHX9 lacks base-selective contacts, forms an unspecific but important stacking interaction with the base of the bound nucleotide and the protein can hydrolyze ATP, guanosine 5’-triphosphate, cytidine 5’-triphosphate, and uridine 5’-triphosphate. (PMID:20510246)
• DHX9 displaced the third strand from a specific triplex DNA structure and catalyzed the unwinding with a 3’ –> 5’ polarity with respect to the displaced third strand. (PMID:20669935)
• DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of plasmacytoid dendritic cells and suggest a much broader role for DHX helicases in viral sensing (PMID:20696886)
• observed a positive correlation of the nuclear expression of EGF receptor, RHA, and cyclin D1 in human breast cancer samples (PMID:20802156)
• the molecular basis for the activation of translation by RHA is recognition of target mRNA by the N-terminal domain that tethers the ATP-dependent helicase for rearrangement of the complex 5’-UTR. (PMID:21123178)
• DHX9 also unwound RNA-based G-quadruplexes that have been reported to occur in human transcripts (PMID:21561811)
• DHX9 is an important RNA sensor that is dependent on interferon-beta promoter stimulator (IPS)-1 to sense pathogenic RNA. (PMID:21957149)
• L1TD1 is part of the L1TD1-RHA-LIN28 complex that could influence levels of OCT4, suggesting that L1TD1 has an important role in the regulation of stemness. (PMID:22162396)
• RNA helicase A as a cellular factor that interacts with influenza A virus NS1 protein and its role in the virus life cycle. (PMID:22171255)
• RNA helicase A (RHA) is tethered to the 5’ SL of collagen mRNAs by interaction with the C-terminal domain of LARP6. (PMID:22190748)
• The crystal structure of huma DHX9 RNA binding domains in complex with double stranded RNA. (PMID:23361462)
• Data suggest that M029 (an RNA-binding protein) plays pivotal role in determining cellular tropism of Myxoma virus in all mammalian cells tested; human RNA helicase A/DHX9 and protein kinase R/EIF2AK2 are two binding partners of M029. (PMID:23853588)
• The data implicate DHX9 in processing intra-molecular triplex H-DNA structures in vivo and support its role in the overall maintenance of genomic stability at sites of alternatively structured DNA. (PMID:24049074)
• RNA helicase A participates in HIV-1 RNA metabolism by multiple distinct mechanisms. (PMID:24223160)
• Results show RNA helicase DHX9 as an interacting partner of KIF1Bbeta and found that DHX9 is necessary for KIF1Bbeta to induce apoptosis. (PMID:24469107)
• The conserved lysine residues of dsRBDs play critical roles in the promotion of HIV-1 production by RNA helicase A. (PMID:24726449)
• results demonstrate an essential role of DHX9 in DNA replication and normal cell cycle progression. (PMID:24990949)
• OB-fold is involved in modulating HIV-1 RNA splicing in the context of some HIV-1 strains while it is dispensable for the activation of HIV-1 transcription. (PMID:25149208)
• Genotoxic stress inhibits Ewing sarcoma cell growth by modulating alternative pre-mRNA processing of the RNA helicase DHX9. (PMID:26450900)
• RNA helicase A was shown to cooperate with both tumor suppressors and oncoproteins in different tumours, indicating that its specific role in cancer is strongly influenced by the cellular context. (PMID:26885691)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dhx9	ENSDARG00000079725
mus_musculus	Dhx9	ENSMUSG00000042699
rattus_norvegicus	Dhx9	ENSRNOG00000002735
drosophila_melanogaster	mle	FBGN0002774
caenorhabditis_elegans		WBGENE00004355

Paralogs (18): DHX33 (ENSG00000005100), YTHDC2 (ENSG00000047188), DHX29 (ENSG00000067248), DHX8 (ENSG00000067596), DHX32 (ENSG00000089876), DHX35 (ENSG00000101452), DHX40 (ENSG00000108406), DHX15 (ENSG00000109606), HELB (ENSG00000127311), DHX30 (ENSG00000132153), DHX34 (ENSG00000134815), DHX38 (ENSG00000140829), DQX1 (ENSG00000144045), DHX37 (ENSG00000150990), TDRD9 (ENSG00000156414), DHX57 (ENSG00000163214), DHX36 (ENSG00000174953), DHX16 (ENSG00000204560)

Protein

Protein identifiers

ATP-dependent RNA helicase A — Q08211 (reviewed: Q08211)

Alternative names: DEAH box protein 9, DExH-box helicase 9, Leukophysin, Nuclear DNA helicase II, RNA helicase A

All UniProt accessions (1): Q08211

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional ATP-dependent nucleic acid helicase that unwinds DNA and RNA in a 3’ to 5’ direction and that plays important roles in many processes, such as DNA replication, transcriptional activation, post-transcriptional RNA regulation, mRNA translation and RNA-mediated gene silencing. Requires a 3’-single-stranded tail as entry site for acid nuclei unwinding activities as well as the binding and hydrolyzing of any of the four ribo- or deoxyribo-nucleotide triphosphates (NTPs). Unwinds numerous nucleic acid substrates such as double-stranded (ds) DNA and RNA, DNA:RNA hybrids, DNA and RNA forks composed of either partially complementary DNA duplexes or DNA:RNA hybrids, respectively, and also DNA and RNA displacement loops (D- and R-loops), triplex-helical DNA (H-DNA) structure and DNA and RNA-based G-quadruplexes. Binds dsDNA, single-stranded DNA (ssDNA), dsRNA, ssRNA and poly(A)-containing RNA. Also binds to circular dsDNA or dsRNA of either linear and/or circular forms and stimulates the relaxation of supercoiled DNAs catalyzed by topoisomerase TOP2A. Plays a role in DNA replication at origins of replication and cell cycle progression. Plays a role as a transcriptional coactivator acting as a bridging factor between polymerase II holoenzyme and transcription factors or cofactors, such as BRCA1, CREBBP, RELA and SMN1. Binds to the CDKN2A promoter. Plays several roles in post-transcriptional regulation of gene expression. In cooperation with NUP98, promotes pre-mRNA alternative splicing activities of a subset of genes. As component of a large PER complex, is involved in the negative regulation of 3’ transcriptional termination of circadian target genes such as PER1 and NR1D1 and the control of the circadian rhythms. Also acts as a nuclear resolvase that is able to bind and neutralize harmful massive secondary double-stranded RNA structures formed by inverted-repeat Alu retrotransposon elements that are inserted and transcribed as parts of genes during the process of gene transposition. Involved in the positive regulation of nuclear export of constitutive transport element (CTE)-containing unspliced mRNA. Component of the coding region determinant (CRD)-mediated complex that promotes cytoplasmic MYC mRNA stability. Plays a role in mRNA translation. Positively regulates translation of selected mRNAs through its binding to post-transcriptional control element (PCE) in the 5’-untranslated region (UTR). Involved with LARP6 in the translation stimulation of type I collagen mRNAs for CO1A1 and CO1A2 through binding of a specific stem-loop structure in their 5’-UTRs. Stimulates LIN28A-dependent mRNA translation probably by facilitating ribonucleoprotein remodeling during the process of translation. Plays also a role as a small interfering (siRNA)-loading factor involved in the RNA-induced silencing complex (RISC) loading complex (RLC) assembly, and hence functions in the RISC-mediated gene silencing process. Binds preferentially to short double-stranded RNA, such as those produced during rotavirus intestinal infection. This interaction may mediate NLRP9 inflammasome activation and trigger inflammatory response, including IL18 release and pyroptosis. Finally, mediates the attachment of heterogeneous nuclear ribonucleoproteins (hnRNPs) to actin filaments in the nucleus. (Microbial infection) Plays a role in HIV-1 replication and virion infectivity. Enhances HIV-1 transcription by facilitating the binding of RNA polymerase II holoenzyme to the proviral DNA. Binds (via DRBM domain 2) to the HIV-1 TAR RNA and stimulates HIV-1 transcription of transactivation response element (TAR)-containing mRNAs. Involved also in HIV-1 mRNA splicing and transport. Positively regulates HIV-1 gag mRNA translation, through its binding to post-transcriptional control element (PCE) in the 5’-untranslated region (UTR). Binds (via DRBM domains) to a HIV-1 double-stranded RNA region of the primer binding site (PBS)-segment of the 5’-UTR, and hence stimulates DHX9 incorporation into virions and virion infectivity. Also plays a role as a cytosolic viral MyD88-dependent DNA and RNA sensors in plasmacytoid dendritic cells (pDCs), and hence induce antiviral innate immune responses. Binds (via the OB-fold region) to viral single-stranded DNA unmethylated C-phosphate-G (CpG) oligonucleotide.

Subunit / interactions. Component of the coding region determinant (CRD)-mediated complex, composed of DHX9, HNRNPU, IGF2BP1, SYNCRIP and YBX1. Identified in a mRNP complex, at least composed of DHX9, DDX3X, ELAVL1, HNRNPU, IGF2BP1, ILF3, PABPC1, PCBP2, PTBP2, STAU1, STAU2, SYNCRIP and YBX1. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1 and POLR2A (active). Associates (via DRBM domains) with the RISC complex; this association occurs in a small interfering (siRNA)-dependent manner. Associates with the SMN complex; this association induces recruitment of DHX9 to the RNA polymerase II (ref.8). Associates with polysomes in a LIN28A-dependent manner. Interacts (via C-terminus) with ACTB; this interaction is direct and mediates the attachment to nuclear ribonucleoprotein complexes. Interacts with ADAR isoform 1; this interaction occurs in a RNA-independent manner. Interacts (via DRBM domains) with AGO2 (via middle region); this interaction promotes active RISC assembly by promoting the association of siRNA with AGO2. Interacts (via RGG region) with AKAP8L (via N-terminus). Interacts with BRCA1 (via C-terminus); this interaction is direct and links BRCA1 to the RNA polymerase II holoenzyme. Interacts (via N-terminus) with CREBBP; this interaction mediates association with RNA polymerase II holoenzyme and stimulates CREB-dependent transcriptional activation. Interacts (via N-terminus) with EIF2AK2/PKR; this interaction is dependent upon the activation of the kinase. Interacts (via DRBM domains) with DICER1. Interacts with H2AX; this interaction is direct, requires phosphorylation of histone H2AX on ‘Ser-140’ by PRKDC and promotes binding of DHX9 to transcriptionally stalled sites on chromosomal DNA in response to genotoxic stress. Interacts with HNRNPC; this interaction is direct, enhanced probably by their concomitant binding to RNA and mediates the attachment to actin filaments. Interacts (via RGG region) with PRMT1. Interacts with IGF2BP1. Interacts with IGF2BP2, IGF2BP3. Interacts (via DRBM domains) with ILF3; this interaction occurs in a RNA-independent manner. Interacts with Importin alpha/Importin beta receptor. Interacts with LARP6 (via C-terminus); this interaction occurs in a mRNA-independent manner. Interacts (via N- and C-terminus) with LIN28A (via C-terminus); this interaction occurs in a RNA-independent manner. Interacts with LMX1B. Interacts (via helicase C-terminal domain, HA2 and OB-fold regions) with MAVS (via CARD domain); this interaction occurs in both resting and double-stranded RNA poly(I:C)-induced cells. Interacts with MBD2; this interaction stimulates transcriptional activation in a CREB-dependent manner. Interacts (via H2A and OB-fold regions) with MYD88 (via TIR domain); this interaction is direct. Interacts with NLRP9 upon rotavirus infection; this interaction may trigger NLRP9 inflammasome activation and inflammatory response. Interacts (via DRBM, OB-fold and RGG regions) with NUP98 (via N-terminus); this interaction occurs in a RNA-dependent manner and stimulates DHX9-mediated ATPase activity and regulates transcription and splicing of a subset of genes. Interacts (via N-terminus) with NXF1 (via N-terminus); this interaction is direct and negatively regulates NXF1-mediated nuclear export of constitutive transport element (CTE)-containing cellular mRNAs. Interacts with RELA; this interaction is direct and activates NF-kappa-B-mediated transcription. Interacts (via MTAD region) with RNA polymerase II holoenzyme; this interaction stimulates transcription activation in a CREB-dependent manner. Interacts (via RGG region) with SMN1; this interaction links SMN1 to the RNA polymerase II holoenzyme. Interacts with SP7. Interacts (via DRBM domains) with TARBP2 (via DRBM first and second domains); this interaction occurs in a small interfering (siRNA)-dependent manner. Interacts with TOP2A; this interaction occurs in a E2 enzyme UBE2I- and RNA-dependent manner, negatively regulates DHX9-mediated double-stranded DNA and RNA duplex helicase activity and stimulates TOP2A-mediated supercoiled DNA relaxation activity. Interacts (via DRBM domains and C-terminus) with WRN (via 3’-5’ exonuclease domain); this interaction inhibits the DNA-dependent NTPase and DNA helicase activities of DHX9 and stimulates the 3’-5’ exonuclease activity of WRN. Interacts with XRCC5; this interaction occurs in a RNA-dependent manner. Interacts with ZIC2 (via C2H2-type domain 3). Interacts with MCM3AP isoform GANP. (Microbial infection) Interacts with Chikungunya virus non-structural protein 3 (via C-terminus); this interaction allows the recruitment of DHX9 to the plasma membrane, where it associates with viral replication complexes and may play a role in the translation-to-replication switch. (Microbial infection) Interacts with Epstein-Barr virus (EBV) mRNA export factor ICP27 homolog/SM protein; this interaction may have an inhibitory effect on virion production.

Subcellular location. Nucleus. Nucleoplasm. Nucleolus. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome.

Post-translational modifications. Methylated. PRMT1-mediated methylation of undefined Arg residues in the RGG region is required for nuclear import of DHX9. Phosphorylated by PRKDC; phosphorylation occurs in a RNA-dependent manner. Phosphorylated by EIF2AK2/PKR; this phosphorylation reduces its association with double-stranded RNA.

Disease relevance. Intellectual developmental disorder, autosomal dominant 75 (MRD75) [MIM:620988] An autosomal dominant neurodevelopmental disorder characterized by developmental delay, mild to severe impaired intellectual development, and neuropsychiatric manifestations including autism spectrum disorder, anxiety, and obsessive compulsive disorder. Disease features are highly variable and may include hypotonia, seizures, non-specific dysmorphism, poor overall growth with small head circumference, abnormal brain imaging, and heart disease. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. DRBM domains cooperate for the binding to nucleic acid but not for unwinding helicase activity. The helicase-associated domain-2 (HA2) region is essential for the duplex RNA unwinding helicase activity. The minimal transactivation region (MTAD) mediates interaction with the RNA polymerase II holoenzyme and stimulates transcriptional activation in a CREB-dependent manner. The oligonucleotide- or oligosaccharide-binding (OB-fold) and the repeated arginine and glycine-glycine (RGG) regions are dispensable for both RNA-binding and unwinding helicase activities. The RGG region contains both nuclear localization signal (NLS) and nuclear export signal (NES) and is necessary and sufficient for nucleocytoplasmic shuttling in a RNA-independent manner.

Similarity. Belongs to the DEAD box helicase family. DEAH subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q08211-1	1	yes
Q08211-2	2, Leukophysin, LKP

RefSeq proteins (1): NP_001348* (*=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
IPR014720	dsRBD_dom	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR044445	DHX9_DSRM_1	Domain
IPR044446	DHX9_DSRM_2	Domain
IPR044447	DHX9_DEXHc	Domain
IPR048333	HA2_WH	Domain

Pfam: PF00035, PF00270, PF00271, PF04408, PF07717, PF21010

Enzyme classification (BRENDA):

• EC 3.6.4.13 — RNA helicase (BRENDA: 3 organisms, 3 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (203 total): helix 50, strand 36, mutagenesis site 29, sequence conflict 19, modified residue 17, sequence variant 17, region of interest 16, turn 6, domain 4, short sequence motif 3, binding site 3, chain 1, cross-link 1, splice variant 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
3VYX	X-RAY DIFFRACTION	2.29
8SZP	X-RAY DIFFRACTION	2.62
9MFT	X-RAY DIFFRACTION	2.75
3LLM	X-RAY DIFFRACTION	2.8
3VYY	X-RAY DIFFRACTION	2.9
9MFO	X-RAY DIFFRACTION	3.26

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q08211-F1	81.84	0.55

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 (3): 411–419; 418; 512

Post-translational modifications (18): 87, 125, 146, 146, 191, 199, 321, 449, 506, 1024, 1166, 1175, 1219, 1235, 1242, 1249, 1265, 697

Mutagenesis-validated functional residues (29):

Position	Phenotype
5	reduces sirna-binding and interaction with ago2; when associated with a-6.
6	reduces sirna-binding; when associated with a-5.
9	inhibits sirna-binding and interaction with ago2.
30	does not reduce sirna-binding and interaction with ago2.
53	inhibits sirna-binding and decreases interaction with ago2; when associated with a-54 and a-55.
54	inhibits sirna-binding and decreases interaction with ago2; when associated with a-53 and a-55.
55	inhibits sirna-binding and decreases interaction with ago2; when associated with a-53 and a-54.
182	reduces sirna-binding and interaction with ago2.
186	reduces sirna-binding and interaction with ago2; when associated with a-187.
187	reduces sirna-binding and interaction with ago2; when associated with a-186.
207	reduces sirna-binding and interaction with ago2.
234	inhibits sirna-binding and interaction with ago2; when associated with a-235 and a-236.
235	inhibits sirna-binding and interaction with ago2; when associated with a-234 and a-236.
236	inhibits sirna-binding and interaction with ago2; when associated with a-234 and a-235.
332	abrogates transcriptional activation by the mtad region. no change in rna polymerase ii holoenzyme binding.
339	abrogates transcriptional activation and rna polymerase ii binding by the mtad region. no change in atp binding and atpa
342	abrogates transcriptional activation by the mtad region. no change in rna polymerase ii holoenzyme binding.
347	reduces nup98-induced mrna transcription and alternative splicing activities.
417	inhibits interaction with ago2, dicer1 and tarbp2. abrogates helicase activity and transcriptional activation. does not
417	reduces nup98-induced mrna transcription and alternative splicing activities.
511	does not inhibit binding to origins of dna replication; when associated with a-512.
512	does not inhibit binding to origins of dna replication; when associated with a-511.
543	does not inhibit binding to origins of dna replication.
1160	localizes in the nucleus and interacts with the importin complex.
1163	localizes in the cytoplasm and does not interact with the importin complex.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1810476	RIP-mediated NFkB activation via ZBP1
R-HSA-3134963	DEx/H-box helicases activate type I IFN and inflammatory cytokines production
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-9770562	mRNA Polyadenylation
R-HSA-9833482	PKR-mediated signaling
R-HSA-9918481	Dengue Virus-Host Interactions

MSigDB gene sets: 430 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_POSITIVE_REGULATION_OF_DNA_REPLICATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_INNATE_IMMUNE_SYSTEM, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_DNA_TEMPLATED_TRANSCRIPTION_TERMINATION, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, GOBP_RESPONSE_TO_PEPTIDE, GCM_MSN, GOBP_ALTERNATIVE_MRNA_SPLICING_VIA_SPLICEOSOME

GO Biological Process (43): alternative mRNA splicing, via spliceosome (GO:0000380), osteoblast differentiation (GO:0001649), DNA replication (GO:0006260), chromatin organization (GO:0006325), DNA-templated transcription termination (GO:0006353), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of interferon-alpha production (GO:0032727), positive regulation of interferon-beta production (GO:0032728), positive regulation of interleukin-18 production (GO:0032741), positive regulation of interleukin-6 production (GO:0032755), positive regulation of tumor necrosis factor production (GO:0032760), miRNA-mediated post-transcriptional gene silencing (GO:0035195), DNA-templated viral transcription (GO:0039695), innate immune response (GO:0045087), positive regulation of innate immune response (GO:0045089), positive regulation of DNA repair (GO:0045739), positive regulation of DNA replication (GO:0045740), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of RNA export from nucleus (GO:0046833), positive regulation of fibroblast proliferation (GO:0048146), rhythmic process (GO:0048511), positive regulation of viral transcription (GO:0050434), regulation of mRNA processing (GO:0050684), regulation of defense response to virus by host (GO:0050691), positive regulation of inflammatory response (GO:0050729), mRNA transport (GO:0051028), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), positive regulation of response to cytokine stimulus (GO:0060760), protein-containing complex assembly (GO:0065003), pyroptotic inflammatory response (GO:0070269), RISC complex assembly (GO:0070922), CRD-mediated mRNA stabilization (GO:0070934), cellular response to exogenous dsRNA (GO:0071360), negative regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay (GO:1900152), protein localization to cytoplasmic stress granule (GO:1903608), regulation of cytoplasmic translation (GO:2000765), positive regulation of cytoplasmic translation (GO:2000767), immune system process (GO:0002376), mRNA processing (GO:0006397), regulation of translation (GO:0006417)

GO Molecular Function (41): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), RNA polymerase II complex binding (GO:0000993), regulatory region RNA binding (GO:0001069), DNA binding (GO:0003677), DNA helicase activity (GO:0003678), DNA replication origin binding (GO:0003688), double-stranded DNA binding (GO:0003690), single-stranded DNA binding (GO:0003697), transcription coregulator activity (GO:0003712), transcription coactivator activity (GO:0003713), RNA binding (GO:0003723), RNA helicase activity (GO:0003724), double-stranded RNA binding (GO:0003725), single-stranded RNA binding (GO:0003727), mRNA binding (GO:0003729), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), ribonucleoside triphosphate phosphatase activity (GO:0017111), chromatin DNA binding (GO:0031490), 3’-5’ DNA/RNA helicase activity (GO:0033679), 3’-5’ RNA helicase activity (GO:0034458), siRNA binding (GO:0035197), RNA stem-loop binding (GO:0035613), ribosome binding (GO:0043022), 3’-5’ DNA helicase activity (GO:0043138), triplex DNA binding (GO:0045142), metal ion binding (GO:0046872), nucleoside triphosphate diphosphatase activity (GO:0047429), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), importin-alpha family protein binding (GO:0061676), RNA polymerase binding (GO:0070063), catalytic activity, acting on a nucleic acid (GO:0140640), RISC complex binding (GO:1905172), single-stranded 3’-5’ DNA helicase activity (GO:1990518), sequence-specific mRNA binding (GO:1990825), promoter-specific chromatin binding (GO:1990841), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), helicase activity (GO:0004386), protein binding (GO:0005515)

GO Cellular Component (18): nucleus (GO:0005634), nucleoplasm (GO:0005654), perichromatin fibrils (GO:0005726), nucleolus (GO:0005730), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), actin cytoskeleton (GO:0015629), membrane (GO:0016020), RISC complex (GO:0016442), nuclear body (GO:0016604), protein-containing complex (GO:0032991), cytoplasmic ribonucleoprotein granule (GO:0036464), RISC-loading complex (GO:0070578), CRD-mediated mRNA stability complex (GO:0070937), nuclear stress granule (GO:0097165), ribonucleoprotein complex (GO:1990904), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
ZBP1(DAI) mediated induction of type I IFNs	1
Cytosolic sensors of pathogen-associated DNA	1
mRNA Splicing	1
mRNA 3’-end processing	1
Antimicrobial mechanism of IFN-stimulated genes	1
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
RNA binding	4
DNA binding	3
intracellular membraneless organelle	3
transcription by RNA polymerase II	2
positive regulation of type I interferon production	2
positive regulation of cytokine production	2
positive regulation of DNA metabolic process	2
positive regulation of DNA-templated transcription	2
nucleic acid binding	2
helicase activity	2
nuclear lumen	2
cytoplasm	2
mRNA splicing, via spliceosome	1
ossification	1
cell differentiation	1
DNA metabolic process	1
DNA biosynthetic process	1
cellular component organization	1
DNA-templated transcription	1
RNA biosynthetic process	1
regulation of DNA-templated transcription	1
interferon-alpha production	1
regulation of interferon-alpha production	1
interferon-beta production	1
regulation of interferon-beta production	1
interleukin-18 production	1
regulation of interleukin-18 production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
regulatory ncRNA-mediated post-transcriptional gene silencing	1
viral transcription	1
immune response	1
defense response to symbiont	1
positive regulation of response to biotic stimulus	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1

Protein interactions and networks

STRING

4828 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DHX9	EWSR1	Q01844	991
DHX9	BRCA1	P38398	967
DHX9	HNRNPU	Q00839	965
DHX9	AGO2	Q9UKV8	960
DHX9	HNRNPC	P07910	959
DHX9	DDX5	P17844	935
DHX9	SYNCRIP	O60506	905
DHX9	ILF2	Q12905	901
DHX9	AKAP8L	Q9ULX6	873
DHX9	IGF2BP2	Q9Y6M1	867
DHX9	MAVS	Q7Z434	864
DHX9	HNRNPM	P52272	863
DHX9	YBX1	P16990	863
DHX9	ADAR	P55265	852
DHX9	MYD88	P78397	836

IntAct

388 interactions, top by confidence:

A	B	Type	Score
STAU1	RPLP0	psi-mi:“MI:0914”(association)	0.750
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
STAU1	DHX9	psi-mi:“MI:0403”(colocalization)	0.680
FUS	HNRNPA1	psi-mi:“MI:0914”(association)	0.670
IGF2BP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
FUS	DHX9	psi-mi:“MI:0403”(colocalization)	0.630
C1QBP	DDX6	psi-mi:“MI:0915”(physical association)	0.620
DDX6	RPLP0	psi-mi:“MI:0915”(physical association)	0.620
IGF2BP1	SYNCRIP	psi-mi:“MI:0914”(association)	0.580
IGF2BP1	DHX9	psi-mi:“MI:0403”(colocalization)	0.580
CHEK2	PPM1G	psi-mi:“MI:0914”(association)	0.560
DHX9		psi-mi:“MI:0915”(physical association)	0.540
DHX9		psi-mi:“MI:0403”(colocalization)	0.540
DDX6	HSP90AA1	psi-mi:“MI:0915”(physical association)	0.540
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
DHX9	XPO1	psi-mi:“MI:0915”(physical association)	0.500
XPO1	DHX9	psi-mi:“MI:0914”(association)	0.500
FMR1	ACOT7	psi-mi:“MI:0914”(association)	0.500
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480

BioGRID (1039): DHX9 (Affinity Capture-MS), DHX9 (Affinity Capture-MS), DHX9 (Affinity Capture-RNA), DHX9 (Affinity Capture-RNA), DHX9 (Affinity Capture-RNA), DHX9 (Affinity Capture-MS), DHX9 (Affinity Capture-MS), DHX9 (Affinity Capture-MS), DHX9 (Affinity Capture-MS), DHX9 (Affinity Capture-MS), DHX9 (Affinity Capture-MS), DHX9 (Affinity Capture-MS), DHX9 (Affinity Capture-Western), DHX9 (Affinity Capture-MS), DHX9 (Reconstituted Complex)

ESM2 similar proteins: A0A2R8QFQ6, A0A2R8RWN9, D3Z7P3, E9PV86, G3MWR8, O54865, O60907, O89050, O94925, P13264, P16068, P20595, P58058, Q02153, Q08211, Q12800, Q13042, Q14722, Q28141, Q28D01, Q3MHJ2, Q3ULA2, Q4R8H1, Q4ZHR9, Q5R874, Q5RB35, Q5SP67, Q5SRY7, Q5ZHN3, Q6DN14, Q7RTP6, Q7T2U9, Q7Z6J6, Q8BTG7, Q8C6G8, Q8CJ19, Q8K4Q0, Q8N122, Q8N2K0, Q8R349

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

7 interactions.

A	Effect	B	Mechanism
DHX9	“up-regulates activity”	NfKb-p65/p50	binding
DHX9	up-regulates	mRNA_nuclear_export
AKAP8L	“up-regulates activity”	DHX9	binding
DHX9	“up-regulates activity”	NUP98	binding
MYD88	“up-regulates activity”	DHX9	binding
FUS	“down-regulates activity”	DHX9	relocalization
LARP6	“up-regulates activity”	DHX9	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 197 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
Regulation of PLK1 Activity at G2/M Transition	11	10.2×	8e-06
AURKA Activation by TPX2	9	10.0×	1e-04
Loss of Nlp from mitotic centrosomes	8	9.3×	4e-04
Loss of proteins required for interphase microtubule organization from the centrosome	8	9.3×	4e-04
mRNA 3’-end processing	6	8.6×	5e-03
Recruitment of mitotic centrosome proteins and complexes	8	7.9×	1e-03
Recruitment of NuMA to mitotic centrosomes	8	6.8×	3e-03
Processing of Capped Intron-Containing Pre-mRNA	11	6.6×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of cytoplasmic translation	7	40.1×	3e-07
mRNA stabilization	8	16.9×	7e-06
mRNA export from nucleus	8	13.7×	3e-05
intrinsic apoptotic signaling pathway	6	12.4×	9e-04
positive regulation of G1/S transition of mitotic cell cycle	5	11.6×	5e-03
negative regulation of translation	9	10.2×	5e-05
autophagosome maturation	5	10.2×	7e-03
regulation of protein localization	7	8.3×	2e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — HCC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	6
Uncertain significance	119
Likely benign	15
Benign	3

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
2579538	NM_001357.5(DHX9):c.1557+1G>A	Pathogenic
3359027	NM_001357.5(DHX9):c.1876C>T (p.Gln626Ter)	Pathogenic
3367218	NM_001357.5(DHX9):c.3497G>C (p.Arg1166Pro)	Pathogenic
3367220	NM_001357.5(DHX9):c.685C>T (p.Arg229Ter)	Pathogenic
3501760	NM_001357.5(DHX9):c.3384dup (p.Glu1129Ter)	Pathogenic
3501762	NM_001357.5(DHX9):c.2290C>T (p.Arg764Ter)	Pathogenic
3501764	NM_001357.5(DHX9):c.3154C>T (p.Arg1052Ter)	Pathogenic
3501765	NM_001357.5(DHX9):c.1704C>A (p.Tyr568Ter)	Pathogenic
3911810	NM_001357.5(DHX9):c.1133del (p.Leu378fs)	Pathogenic
4011532	NM_001357.5(DHX9):c.2299C>T (p.Arg767Ter)	Pathogenic
2627913	NM_001357.5(DHX9):c.2291G>A (p.Arg764Gln)	Likely pathogenic
2663910	NM_001357.5(DHX9):c.710dup (p.Leu237fs)	Likely pathogenic
3253104	NM_001357.5(DHX9):c.2282G>A (p.Arg761Gln)	Likely pathogenic
3341006	NM_001357.5(DHX9):c.1420C>T (p.Arg474Ter)	Likely pathogenic
3367217	NM_001357.5(DHX9):c.422G>A (p.Arg141Gln)	Likely pathogenic
3899565	NM_001357.5(DHX9):c.3745C>T (p.Arg1249Ter)	Likely pathogenic

SpliceAI

3315 predictions. Top by Δscore:

Variant	Effect	Δscore
1:182839444:G:GT	donor_gain	1.0000
1:182842611:G:GT	donor_gain	1.0000
1:182843431:TGGG:T	donor_gain	1.0000
1:182843432:GGG:G	donor_gain	1.0000
1:182843432:GGGG:G	donor_gain	1.0000
1:182843433:GG:G	donor_gain	1.0000
1:182843433:GGG:G	donor_gain	1.0000
1:182843434:GG:G	donor_gain	1.0000
1:182843434:GGT:G	donor_loss	1.0000
1:182843435:G:GG	donor_gain	1.0000
1:182843435:GTA:G	donor_loss	1.0000
1:182852228:T:TA	acceptor_gain	1.0000
1:182852231:A:AG	acceptor_gain	1.0000
1:182852231:A:AT	acceptor_loss	1.0000
1:182852231:AG:A	acceptor_gain	1.0000
1:182852232:G:GA	acceptor_gain	1.0000
1:182852232:GG:G	acceptor_gain	1.0000
1:182852232:GGT:G	acceptor_gain	1.0000
1:182852232:GGTA:G	acceptor_gain	1.0000
1:182852340:AGCAG:A	donor_gain	1.0000
1:182852341:GCAG:G	donor_gain	1.0000
1:182852341:GCAGG:G	donor_gain	1.0000
1:182852343:AG:A	donor_gain	1.0000
1:182852343:AGGTA:A	donor_loss	1.0000
1:182852344:GG:G	donor_gain	1.0000
1:182852345:G:GA	donor_loss	1.0000
1:182852345:G:GG	donor_gain	1.0000
1:182853301:A:AG	acceptor_gain	1.0000
1:182853302:A:G	acceptor_gain	1.0000
1:182853302:ACAG:A	acceptor_loss	1.0000

AlphaMissense

8336 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:182842666:T:C	F34L	1.000
1:182842668:C:A	F34L	1.000
1:182842668:C:G	F34L	1.000
1:182843327:G:A	G49R	1.000
1:182843327:G:C	G49R	1.000
1:182843328:G:A	G49E	1.000
1:182843344:A:C	K54N	1.000
1:182843344:A:T	K54N	1.000
1:182843364:C:A	A61D	1.000
1:182843367:C:A	A62D	1.000
1:182854073:G:A	G174E	1.000
1:182854078:T:A	W176R	1.000
1:182854078:T:C	W176R	1.000
1:182854093:G:C	A181P	1.000
1:182854094:C:A	A181D	1.000
1:182854106:T:C	L185P	1.000
1:182856536:T:C	F211L	1.000
1:182856538:T:A	F211L	1.000
1:182856538:T:G	F211L	1.000
1:182856542:G:C	A213P	1.000
1:182856543:C:A	A213E	1.000
1:182858125:G:A	G232E	1.000
1:182858135:G:C	K235N	1.000
1:182858135:G:T	K235N	1.000
1:182858143:C:A	A238E	1.000
1:182858156:T:G	C242W	1.000
1:182858158:C:A	A243D	1.000
1:182858161:T:C	L244P	1.000
1:182858826:T:A	W332R	1.000
1:182858826:T:C	W332R	1.000

dbSNP variants (sampled 300 via entrez): RS1000001138 (1:182865032 A>G), RS1000038236 (1:182852562 A>G), RS1000074146 (1:182852246 C>T), RS1000118325 (1:182865307 G>C), RS1000160347 (1:182877812 G>A,C), RS1000443438 (1:182877560 G>A,C), RS1000458287 (1:182858335 T>G), RS1000502648 (1:182863182 A>G), RS1000567231 (1:182870179 A>G), RS1000574746 (1:182862850 A>G), RS1000694738 (1:182855006 A>G), RS1000735357 (1:182839986 C>A,G), RS1000973277 (1:182861247 C>A,G), RS1001008043 (1:182866314 T>G), RS1001080331 (1:182850914 A>G)

Disease associations

OMIM: gene MIM:603115 | disease phenotypes: MIM:620988, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease	Strong	Autosomal dominant
intellectual developmental disorder, autosomal dominant 75	Strong	Autosomal dominant

Mondo (2): intellectual developmental disorder, autosomal dominant 75 (MONDO:0975838), Charcot-Marie-Tooth disease (MONDO:0015626)

Orphanet (1): Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166)

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000369	Low-set ears
HP:0000431	Wide nasal bridge
HP:0000582	Upslanted palpebral fissure
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001518	Small for gestational age
HP:0001999	Abnormal facial shape
HP:0002020	Gastroesophageal reflux
HP:0002119	Ventriculomegaly
HP:0002342	Moderate intellectual disability
HP:0003477	Peripheral axonal neuropathy
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0004322	Short stature
HP:0006889	Borderline intellectual disability
HP:0008936	Axial hypotonia
HP:0010864	Severe intellectual disability
HP:0011968	Feeding difficulties

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067223 (SINGLE PROTEIN)

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

ChEMBL bioactivities

80 potent at pChembl≥5 of 90 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.70	EC50	2	nM	CHEMBL6171019
8.70	EC50	2	nM	CHEMBL6151216
8.52	EC50	3	nM	CHEMBL6173215
8.40	EC50	4	nM	CHEMBL6170706
8.05	EC50	9	nM	CHEMBL6159637
7.96	EC50	11	nM	CHEMBL6167466
7.82	EC50	15	nM	CHEMBL6152606
7.82	EC50	15	nM	CHEMBL6151216
7.70	EC50	20	nM	CHEMBL6167116
7.57	Kd	27	nM	CHEMBL6151698
7.41	EC50	39	nM	CHEMBL6167466
7.39	EC50	41	nM	CHEMBL6149290
7.38	EC50	42	nM	CHEMBL6159825
7.35	EC50	45	nM	CHEMBL6148688
7.34	EC50	46	nM	CHEMBL6163626
7.28	EC50	52	nM	CHEMBL6171019
7.27	EC50	54	nM	CHEMBL6144055
7.24	Kd	57	nM	CHEMBL6144128
7.22	EC50	60	nM	CHEMBL6173215
7.21	EC50	62	nM	CHEMBL6167227
7.21	EC50	62	nM	CHEMBL6159637
7.13	EC50	74	nM	CHEMBL6167633
7.13	IC50	74	nM	CHEMBL6167116
7.12	EC50	75	nM	CHEMBL6173634
7.07	EC50	86	nM	CHEMBL6144128
7.04	EC50	91	nM	CHEMBL6171220
7.00	EC50	99	nM	CHEMBL6151212
6.97	EC50	108	nM	CHEMBL6150890
6.96	EC50	111	nM	CHEMBL6175070
6.95	Kd	112.1	nM	CHEMBL3752910
6.95	ED50	112.1	nM	CHEMBL3752910
6.94	EC50	116	nM	CHEMBL6172065
6.89	EC50	130	nM	CHEMBL6148688
6.85	EC50	141	nM	CHEMBL6142275
6.85	Kd	142	nM	CHEMBL6169039
6.81	EC50	156	nM	CHEMBL6151698
6.81	EC50	154	nM	CHEMBL6152606
6.65	EC50	223	nM	CHEMBL6169039
6.65	IC50	225	nM	CHEMBL6151698
6.59	EC50	254	nM	CHEMBL6174592
6.48	Kd	330	nM	CHEMBL6162165
6.47	EC50	338	nM	CHEMBL6164076
6.47	EC50	335	nM	CHEMBL6173425
6.40	Kd	400	nM	CHEMBL6162165
6.39	EC50	410	nM	CHEMBL6167633
6.36	IC50	440	nM	CHEMBL6149290
6.31	IC50	490	nM	CHEMBL6144055
6.25	IC50	565	nM	CHEMBL6170706
6.22	IC50	602	nM	CHEMBL6171220
6.19	IC50	643	nM	CHEMBL6144128

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148238: Binding affinity to human DHX9 incubated for 45 mins by Kinobead based pull down assay	kd	0.1121	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Valproic Acid	decreases expression, increases methylation	3
trichostatin A	affects cotreatment, decreases expression	2
bisphenol S	increases expression, increases methylation	2
Air Pollutants	increases oxidation, affects expression, affects cotreatment, increases abundance	2
Dinitrochlorobenzene	affects binding, increases metabolic processing	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance, affects expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
TAK-243	decreases sumoylation	1
geldanamycin	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization, increases expression	1
5-chloro-2-methyl-4-isothiazolin-3-one	increases metabolic processing	1
beta-lapachone	decreases expression	1
methylparaben	increases expression	1
afimoxifene	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cypermethrin	increases expression	1
cobaltous chloride	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
cyclic 3’,5’-uridine monophosphate	affects binding	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	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
CHEMBL5651280	Binding	Binding affinity to human DHX9 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT01289704	PHASE2/PHASE3	UNKNOWN	Treadmill, Stretching and Proprioceptive Exercise (TreSPE) Rehabilitation Program for Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A)
NCT00541164	PHASE1/PHASE2	COMPLETED	Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease
NCT05361031	PHASE1/PHASE2	COMPLETED	The Safety and Tolerability of Engensis (VM202) in Patients With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A)
NCT07223632	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Treatment of Charcot-Marie-Tooth Disease, Axonal, Type 2S (CMT2S) in an Individual Patient
NCT00149045	Not specified	COMPLETED	Follow up and Observation of Charcot Marie Tooth Disease in Families
NCT01193075	Not specified	RECRUITING	Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others
NCT01203085	Not specified	COMPLETED	Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale for Children With CMT
NCT01455623	Not specified	COMPLETED	Development and Validation of a Disability Severity Index for CMT
NCT01918826	Not specified	UNKNOWN	Evaluation of the Analgesic Efficiency of the Transcutaneous Neurostimulation in the Charcot Syndrome Marie Tooth on the Pains of Lower Limbs
NCT02001038	Not specified	COMPLETED	Survey of Current Management of Orthopaedic Complications in CMT Patients
NCT02011204	Not specified	COMPLETED	Study of Electrical Impedance Myography (EIM) in ALS
NCT02194010	Not specified	COMPLETED	Disability Severity Scale (DSI) and Hereditary Motor and Sensory Neuropathy Overall Disability Scale (HMSN-R-ODS)
NCT02429947	Not specified	COMPLETED	An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients
NCT02532244	Not specified	COMPLETED	Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02788734	Not specified	COMPLETED	Patient Reported Outcomes Measures (PROM) in Carpal Tunnel Therapies in Patients With Inherited Neuropathies
NCT02979145	Not specified	UNKNOWN	Charcot-Marie-Tooth Disease (CMT) Infant Scale (INC-6611)
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03460951	Not specified	COMPLETED	Diffusion Tensor Imaging in Chronic Inflammatory Demyelinating Polyneuropathy (PIDC)
NCT03715283	Not specified	COMPLETED	Change in MUNIX in Patients With CMT1A Undergoing a Home Ankle Strengthening Program Versus Standard of Care
NCT03782883	Not specified	COMPLETED	The Impact of Charcot-Marie-Tooth Disease in the Real World
NCT03810508	Not specified	TERMINATED	A Natural History Study of Charcot-Marie-Tooth 4J (CMT4J)
NCT03966287	Not specified	COMPLETED	Analysis of Pain and Quality of Life in Patients With Charcot-Marie-Tooth Neuropathy (CMT)
NCT04010188	Not specified	RECRUITING	A Registered Cohort Study on Charcot-Marie-Tooth Disease
NCT04283175	Not specified	COMPLETED	Validation Study of Posturology Platforms for Evaluating Postural Control of Hemiparetic and Neuro-muscular Patients
NCT04461613	Not specified	UNKNOWN	Physical Activity in Persons With Charcot-Marie-Tooth: Developing a Measurement Instrument
NCT04786522	Not specified	COMPLETED	Irisin Levels in Patients With Charcot-Marie-Tooth (CMT) Disease
NCT04967716	Not specified	UNKNOWN	Genetics of Charcot-Marie-Tooth Dystrophy and Related Diseases
NCT04980807	Not specified	COMPLETED	Observational Study of Neuromuscular Function in CMT Type 1&2 and Healthy Controls
NCT05011006	Not specified	NOT_YET_RECRUITING	NT-3 Levels and Function in Individuals With CMT