DUOX1

Summary

DUOX1 (dual oxidase 1, HGNC:3062) is a protein-coding gene on chromosome 15q21.1, encoding Dual oxidase 1 (Q9NRD9). Generates hydrogen peroxide (H2O2) which is required for the activity of thyroid peroxidase/TPO and lactoperoxidase/LPO.

The protein encoded by this gene is a glycoprotein and a member of the NADPH oxidase family. The synthesis of thyroid hormone is catalyzed by a protein complex located at the apical membrane of thyroid follicular cells. This complex contains an iodide transporter, thyroperoxidase, and a peroxide generating system that includes proteins encoded by this gene and the similar DUOX2 gene. This protein is known as dual oxidase because it has both a peroxidase homology domain and a gp91phox domain. This protein generates hydrogen peroxide and thereby plays a role in the activity of thyroid peroxidase, lactoperoxidase, and in lactoperoxidase-mediated antimicrobial defense at mucosal surfaces. Two alternatively spliced transcript variants encoding the same protein have been described for this gene.

Source: NCBI Gene 53905 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital hypothyroidism (Limited, GenCC)
• Clinical variants (ClinVar): 259 total — 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_175940

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3062
Approved symbol	DUOX1
Name	dual oxidase 1
Location	15q21.1
Locus type	gene with protein product
Status	Approved
Aliases	NOXEF1, THOX1, LNOX1
Ensembl gene	ENSG00000137857
Ensembl biotype	protein_coding
OMIM	606758
Entrez	53905

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 9 protein_coding, 6 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000321429, ENST00000389037, ENST00000557893, ENST00000558322, ENST00000558446, ENST00000558744, ENST00000558991, ENST00000559219, ENST00000559221, ENST00000559716, ENST00000561166, ENST00000561220, ENST00000682390, ENST00000885347, ENST00000885348, ENST00000957742, ENST00000957743

RefSeq mRNA: 2 — MANE Select: NM_175940 NM_017434, NM_175940

CCDS: CCDS32221

Canonical transcript exons

ENST00000389037 — 34 exons

Exon	Start	End
ENSE00001334579	45129994	45130098
ENSE00001591589	45133864	45133947
ENSE00001609593	45135782	45135948
ENSE00001641785	45136350	45136410
ENSE00001711400	45141975	45142112
ENSE00001731681	45135474	45135675
ENSE00001733023	45139066	45139168
ENSE00001738505	45136529	45136625
ENSE00001760042	45139427	45139599
ENSE00001765730	45135104	45135291
ENSE00001780642	45137924	45138014
ENSE00001792945	45134145	45134309
ENSE00002225467	45131918	45132024
ENSE00002568239	45164779	45165574
ENSE00003461489	45162219	45162377
ENSE00003479087	45143190	45143303
ENSE00003495380	45148272	45148447
ENSE00003514815	45147904	45147997
ENSE00003533446	45163790	45163918
ENSE00003539901	45144895	45145080
ENSE00003547699	45147433	45147658
ENSE00003570389	45144036	45144235
ENSE00003577312	45153380	45153479
ENSE00003577450	45150632	45150701
ENSE00003624616	45153951	45154000
ENSE00003636226	45161738	45161970
ENSE00003645441	45160837	45160990
ENSE00003646880	45140895	45141070
ENSE00003651222	45141292	45141410
ENSE00003654690	45152286	45152516
ENSE00003659944	45163532	45163687
ENSE00003669002	45155802	45155929
ENSE00003674291	45151874	45152052
ENSE00003679092	45151123	45151248

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 98.59.

FANTOM5 (CAGE): breadth broad, TPM avg 2.2398 / max 220.4973, expressed in 235 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
146426	2.0922	202
146425	0.0772	48
146424	0.0704	29

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tongue squamous epithelium	UBERON:0006919	98.59	gold quality
lower esophagus mucosa	UBERON:0035834	98.57	gold quality
right lobe of thyroid gland	UBERON:0001119	98.37	gold quality
left lobe of thyroid gland	UBERON:0001120	97.94	gold quality
thyroid gland	UBERON:0002046	97.59	gold quality
esophagus mucosa	UBERON:0002469	97.49	gold quality
right lung	UBERON:0002167	97.39	gold quality
bronchial epithelial cell	CL:0002328	97.15	gold quality
epithelium of bronchus	UBERON:0002031	97.13	gold quality
gingiva	UBERON:0001828	97.05	gold quality
gingival epithelium	UBERON:0001949	97.00	gold quality
right uterine tube	UBERON:0001302	96.82	gold quality
bronchus	UBERON:0002185	96.58	gold quality
skin of abdomen	UBERON:0001416	96.54	gold quality
skin of leg	UBERON:0001511	96.49	gold quality
lower lobe of lung	UBERON:0008949	96.42	gold quality
oral cavity	UBERON:0000167	96.31	gold quality
upper lobe of lung	UBERON:0008948	95.87	gold quality
upper arm skin	UBERON:0004263	95.84	gold quality
upper lobe of left lung	UBERON:0008952	95.74	gold quality
pharyngeal mucosa	UBERON:0000355	95.28	gold quality
nasal cavity epithelium	UBERON:0005384	95.26	gold quality
zone of skin	UBERON:0000014	94.71	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.40	gold quality
mammalian vulva	UBERON:0000997	93.78	gold quality
cauda epididymis	UBERON:0004360	93.17	gold quality
epithelium of esophagus	UBERON:0001976	92.76	gold quality
esophagus squamous epithelium	UBERON:0006920	92.37	gold quality
vagina	UBERON:0000996	92.17	gold quality
squamous epithelium	UBERON:0006914	92.15	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	26.33
E-GEOD-130148	yes	8.94
E-MTAB-6678	yes	4.87

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PAX8, TTF1

miRNA regulators (miRDB)

37 targeting DUOX1, 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-3686	99.90	70.53	2432
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4502	99.65	66.99	1021
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-153-3P	98.96	72.51	1644
HSA-MIR-6871-5P	98.90	66.67	671
HSA-MIR-6760-5P	98.87	66.73	1515
HSA-MIR-5197-3P	98.71	67.05	1905
HSA-MIR-767-3P	98.61	67.69	1192
HSA-MIR-1910-3P	98.44	67.51	1695
HSA-MIR-1262	98.17	66.52	757
HSA-MIR-4701-3P	98.17	66.25	788
HSA-MIR-6736-5P	98.17	66.43	760
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-6511A-5P	98.13	67.47	1770
HSA-MIR-4257	97.86	68.05	1190
HSA-MIR-5699-5P	97.36	67.03	1014

Literature-anchored findings (GeneRIF, showing 40)

• Thox1 is expressed in aortic media and either not at all or rarely in unaffected intima, while mRNA expression in cells is greatest in fibrofatty lesions. (PMID:12482831)
• chromosomal organization of hThOX1 and hThOX2 genes and the functional characterization of their respective promoter regions (PMID:15062544)
• EFP1 is a thioredoxin-related protein and partner of duox (PMID:15561711)
• Duox1 plays a critical role in mucin expression by airway epithelial cells through PKCdelta/PKC-Duox1-ROS-TACE-pro-ligand-EGF receptor cascade. (PMID:15640347)
• These data suggest that Duox1 and 2 are the major NADPH oxidases expressed in airway epithelia and therefore contributors of hydrogen peroxide production in the airway lumen. (PMID:15677770)
• Results demonstrate the regulation of Duox1 and 2 expression by Th1 and Th2 cytokines, and suggest a mechanism by which ROS production can be regulated in the respiratory tract as part of the host defense response. (PMID:16111680)
• In conclusion, incubation of normal or GD thyrocytes with Th1 cytokines induces a significant reduction in TSH-increased expression of both TPO and ThOXs, an effect partially mediated by NO. (PMID:16478776)
• Critical role for dual oxidase 1 within the tracheobronchial epithelium, in airway epithelial cell migration and repair following injury. (PMID:17135261)
• there is regulated expression of DUOX1 during alveolar maturation, and DUOX1 mediates alveolar H(2)O(2) and acid secretion by differentiated type II cells (PMID:17337509)
• Results imply that the airway expression of Duox1 is diversely associated with smoking and chronic obstructive pulmonary disease. (PMID:18177232)
• Results suggest that an area on chromosome 15 that includes DUOX1, DUOX2, and their maturation factors is a frequent target for epigenetic silencing in lung cancer. (PMID:18281478)
• a novel, inhibitory function for Noxa1 in Duox1 regulation. (PMID:18606821)
• Activation of dual oxidases Duox1 and Duox2: differential regulation mediated by camp-dependent protein kinase and protein kinase C-dependent phosphorylation. (PMID:19144650)
• Heterodimerization controls localization of Duox-DuoxA NADPH oxidases in airway cells. (PMID:19339556)
• analysis of heme binding and catalytic activity of Caenorhabditis elegans and human dual oxidase 1 (PMID:19460756)
• TPO binds to dualoxidases;defects in this association could impair thyroid hormone synthesis and lead to thyroid insufficiency and cell damage. (PMID:19952225)
• Results found that Pseudomonas aeruginosa triggers H2O2 production by Duox1 in bronchial epithelial cells in a calcium-dependent but predominantly ATP-independent manner. (PMID:20085766)
• activation of Duox1, downstream of proximal TCR signals, generates H(2)O(2) that acts in a positive feedback loop to enhance and sustain further TCR signaling. (PMID:20682913)
• results demonstrate Duox1-mediated redox signaling in bronchial epithelial cells is associated with Lipid raft clustering dependent on the production of ceramide through acid sphingomyelinase (PMID:21389273)
• Data demonstrated that the increased expression of DUOX1 in IL-4/IL-13-treated NHEK augments STAT6 phosphorylation via oxidative inactivation of protein tyrosine phosphatase 1B. (PMID:21411736)
• Data show that comparing with adjacent non-neoplastic tissues, DUOX1, DUOX2, and NOX4 were expressed at higher frequencies in tumor specimens. (PMID:21915726)
• study reports DUOX 1 and 2 are expressed in neuroblastoma SK-N-BE cells as well as in an oligodendrocyte cell line (MO3-13); data unravel a novel mechanism of regulation of DUOX enzymes by reactive oxygen species and identify a circuitry linking NADPH oxidase activity to DUOX1 and 2 levels in neuroblastoma cells (PMID:22523549)
• Report shows that ROS levels in PC3 cells are constitutively maintained by DUOX 1 and 2 enzymes, and these ROS positively regulate AKT signalling through inactivating phosphatases, leading to increased resistance to apoptosis. (PMID:23225414)
• upregulated in chronic rhinosinusitis as a part of inflammatory response (PMID:23281318)
• DUOX1 plays a central role in epithelial defense responses to infection or injury, by mediating oxidative activation of Src and ADAM17 in response to ATP-dependent P2Y(2)R activation as a proximal step in EGFR transactivation and downstream signaling. (PMID:23349873)
• Study indicates a complex profile of protein interactions required for activity and localization of the DUOX1 and DOOX2 enzymes. (PMID:23362256)
• PA-LPS-induced MUC5AC and Clca3 expression is partly through Duox1 (PMID:23691121)
• Further, ROS generated by Duox enzymes localized adjacent to nuclear speckles altered the splicing of viral genes (PMID:24128054)
• Despite the high sequence similarity shared between DUOX1 and DUOX2, the two isoforms present distinct regulations, tissue expression and catalytic functions (PMID:24161126)
• Underscore the importance of DUOX1 and DUOX2 in vesicant-induced IL-6 secretion in human airway epithelial cells. (PMID:24164541)
• DUOX1 is the major H2O2-producing source in NHKs stimulated with Ca(2+), and plays a significant role in regulating the expression of specific markers necessary for the normal differentiation of keratinocytes (PMID:24332816)
• Studies demonstrate the importance of DUOX1 in epithelial redox signaling through reversible S-glutathionylation of a range of proteins, including proteins involved in cytoskeletal regulation and MAPK signaling pathways involved in cell migration. (PMID:24624333)
• Duox1 activity is stimulated by testosterone through GPRC6A in skin keratinocytes (PMID:25164816)
• Duox2 proteins possessing the A-loops of Nox1 or Nox5 co-expressed with DuoxA2 showed enhanced O2 () release, and Duox1 proteins possessing the A-loops of Nox1 or Nox5 co-expressed with DuoxA1 acquired O2 () leakage (PMID:25586178)
• These data reveal a key role of DUOX1-dependent hydrogen peroxide production in long-term persistent radio-induced DNA damage. (PMID:25848056)
• Our findings implicate epithelial DUOX1 as a pivotal mediator of IL-33-dependent activation of innate airway type 2 immune responses to common airborne allergens and indicate that enhanced DUOX1 expression and IL-33 secretion might present important contributing features of allergic asthma. (PMID:26597162)
• Cox multivariate regression analysis demonstrated that DUOX1, GLS2, FBP1 and age were independent risk factors for the prognosis of HCC patients after surgery (PMID:27079415)
• DUOX1 expression in liver tumors is a potential prognostic tool for patients. (PMID:27108801)
• Nox4 and Duox1/Duox2 mediate redox activation of mesenchymal cell migration by PDGF. (PMID:27110716)
• We analyzed the expression of NADPH oxidase isoforms and found both A431 and HaCaT cells to express the calcium-sensitive NADPH oxidase, Dual oxidase 1 (Duox1) and its protein partner Duox activator 1 (DuoxA1).Our observations provide evidence for a new signaling paradigm in which changes of intracellular calcium concentration are transformed into redox signals through the calcium-dependent activation of Duox1. (PMID:27262981)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Duox1	ENSMUSG00000033268
rattus_norvegicus	Duox1	ENSRNOG00000033348

Paralogs (6): NOX1 (ENSG00000007952), NOX3 (ENSG00000074771), NOX4 (ENSG00000086991), DUOX2 (ENSG00000140279), CYBB (ENSG00000165168), NOX5 (ENSG00000255346)

Protein

Protein identifiers

Dual oxidase 1 — Q9NRD9 (reviewed: Q9NRD9)

Alternative names: Large NOX 1, Long NOX 1, NADPH thyroid oxidase 1, Thyroid oxidase 1

All UniProt accessions (4): Q9NRD9, A0A804HKN9, H0YK19, H0YNR5

UniProt curated annotations — full annotation on UniProt →

Function. Generates hydrogen peroxide (H2O2) which is required for the activity of thyroid peroxidase/TPO and lactoperoxidase/LPO. Plays a role in thyroid hormone synthesis. Also required for lactoperoxidase-mediated antimicrobial defense at the surface of mucosa. Antimicrobial agent hypothiocyanite (OSCN-), which is produced by LPO from DUOX1-derived H2O2, promotes influenza virus inactivation by reducing viral binding to and entry into host cells. Promotes antiviral immunity by increasing airway cytokine levels, promoting innate immune cell recruitment and reducing airway epithelial cell apoptosis. In response to bacterial stimuli, activated by ATP and promotes EGFR/ERK signaling, ADAM17 activation, and EGFR ligand shedding, leading to enhanced CXCL8/IL8 expression and secretion in airway epithelia. Synthesizes NAADP from its reduced NAADPH form which promotes Ca(2+) signaling during T cell activation. In addition to its oxidase activity, has also been shown to have peroxidase activity through its N-terminal peroxidase-like domain. However, another study showed that the isolated peroxidase-like domain does not bind heme and has no intrinsic peroxidase activity.

Subunit / interactions. Heterotetramer with DUOXA1 consisting of 2 DUOX1-DUOXA1 heterodimers. This may represent the inactive state. Has also been detected as a heterodimer with DUOXA1 which has been proposed to be the active state. Interacts with TXNDC11, TPO and CYBA.

Subcellular location. Apical cell membrane.

Tissue specificity. Expressed in thyrocytes and tracheal surface epithelial cells (at protein level). Expressed in thyroid, trachea, bronchium, and to a lower extent, in placenta, testis, prostate, pancreas and heart.

Post-translational modifications. N-glycosylated.

Activity regulation. The NADPH oxidase activity is calcium-dependent. It is activated by release of cellular ATP which is promoted by bacterial infection. Peroxidase activity is inhibited by aminobenzohydrazide.

Induction. By forskolin (at protein level). By thyrotropin and the Th2-specific cytokines IL-4 and IL-13.

Pathway. Hormone biosynthesis; thyroid hormone biosynthesis.

Similarity. In the N-terminal section; belongs to the peroxidase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NRD9-1	1	yes
Q9NRD9-2	2

RefSeq proteins (2): NP_059130, NP_787954* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR010255	Haem_peroxidase_sf	Homologous_superfamily
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR013112	FAD-bd_8	Domain
IPR013121	Fe_red_NAD-bd_6	Domain
IPR013130	Fe3_Rdtase_TM_dom	Domain
IPR017927	FAD-bd_FR_type	Domain
IPR017938	Riboflavin_synthase-like_b-brl	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR019791	Haem_peroxidase_animal	Family
IPR034821	DUOX_peroxidase	Domain
IPR037120	Haem_peroxidase_sf_animal	Homologous_superfamily
IPR039261	FNR_nucleotide-bd	Homologous_superfamily
IPR050369	RBOH/FRE	Family

Pfam: PF00036, PF01794, PF03098, PF08022, PF08030, PF13499

Enzyme classification (BRENDA):

• EC 1.6.3.1 — NAD(P)H oxidase (H2O2-forming) (BRENDA: 39 organisms, 58 substrates, 307 inhibitors, 10 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
NADPH	0.01–0.1	7
NADH	0.1–0.413	3

Catalyzed reactions (Rhea), 3 shown:

• NADPH + O2 + H(+) = H2O2 + NADP(+) (RHEA:11260)
• NADH + O2 + H(+) = H2O2 + NAD(+) (RHEA:11264)
• NAADPH + O2 + H(+) = NAADP(+) + H2O2 (RHEA:86235)

UniProt features (203 total): helix 59, binding site 47, strand 38, turn 13, topological domain 8, transmembrane region 7, mutagenesis site 6, domain 5, glycosylation site 5, region of interest 3, disulfide bond 3, sequence variant 3, splice variant 2, sequence conflict 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7D3F	ELECTRON MICROSCOPY	2.6
7D3E	ELECTRON MICROSCOPY	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NRD9-F1	85.72	0.61

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 (47): 109; 170; 172; 174; 176; 828; 830; 832; 834; 839; 864; 866 …

Disulfide bonds (3): 118–1165, 345–565, 364–579

Glycosylation sites (5): 94, 342, 354, 461, 534

Mutagenesis-validated functional residues (6):

Position	Phenotype
50	severely reduces tetramer formation.
109	fails to assemble with duoxa1; when associated with a-174.
174	fails to assemble with duoxa1; when associated with a-109.
332	fails to assemble with duoxa1; when associated with a-397.
397	fails to assemble with duoxa1; when associated with a-332.
507	severely reduces tetramer formation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-209968	Thyroxine biosynthesis

MSigDB gene sets: 170 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BENPORATH_ES_WITH_H3K27ME3, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_POSITIVE_REGULATION_OF_INTERLEUKIN_8_PRODUCTION, GOBP_RESPONSE_TO_PEPTIDE, JAEGER_METASTASIS_DN, GOBP_HYDROGEN_PEROXIDE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOCC_CELL_SURFACE, GOBP_SUPEROXIDE_METABOLIC_PROCESS, GOBP_THYROID_HORMONE_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_WOUND_HEALING

GO Biological Process (15): thyroid hormone generation (GO:0006590), defense response (GO:0006952), response to oxidative stress (GO:0006979), cytokine-mediated signaling pathway (GO:0019221), cuticle development (GO:0042335), hormone biosynthetic process (GO:0042446), superoxide anion generation (GO:0042554), hydrogen peroxide catabolic process (GO:0042744), hydrogen peroxide biosynthetic process (GO:0050665), response to cAMP (GO:0051591), positive regulation of wound healing (GO:0090303), positive regulation of cell motility (GO:2000147), cellular response to cytokine stimulus (GO:0071345), reactive oxygen species metabolic process (GO:0072593), cellular oxidant detoxification (GO:0098869)

GO Molecular Function (13): peroxidase activity (GO:0004601), calcium ion binding (GO:0005509), NAD(P)H oxidase H2O2-forming activity (GO:0016174), superoxide-generating NAD(P)H oxidase activity (GO:0016175), heme binding (GO:0020037), protein heterodimerization activity (GO:0046982), NADP binding (GO:0050661), NADPH binding (GO:0070402), FAD binding (GO:0071949), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), oxidoreductase activity, acting on NAD(P)H, oxygen as acceptor (GO:0050664)

GO Cellular Component (7): endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), cell surface (GO:0009986), apical plasma membrane (GO:0016324), cell leading edge (GO:0031252), NADPH oxidase complex (GO:0043020), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of amine-derived hormones	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
response to stress	2
hydrogen peroxide metabolic process	2
oxidoreductase activity, acting on NAD(P)H, oxygen as acceptor	2
thyroid hormone metabolic process	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
multicellular organism development	1
anatomical structure development	1
biosynthetic process	1
hormone metabolic process	1
superoxide metabolic process	1
catabolic process	1
reactive oxygen species biosynthetic process	1
response to purine-containing compound	1
response to organophosphorus	1
response to oxygen-containing compound	1
wound healing	1
regulation of wound healing	1
positive regulation of response to wounding	1
positive regulation of locomotion	1
positive regulation of cellular process	1
cell motility	1
regulation of cell motility	1
response to cytokine	1
metabolic process	1
cellular detoxification	1
antioxidant activity	1
oxidoreductase activity, acting on peroxide as acceptor	1
metal ion binding	1
tetrapyrrole binding	1
protein dimerization activity	1
adenyl nucleotide binding	1
anion binding	1
NADP binding	1
flavin adenine dinucleotide binding	1
binding	1
catalytic activity	1
cation binding	1
oxidoreductase activity, acting on NAD(P)H	1

Protein interactions and networks

STRING

1736 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DUOX1	DUOXA1	Q1HG43	990
DUOX1	NOX4	Q9NPH5	985
DUOX1	DUOXA2	Q1HG44	985
DUOX1	NOX1	Q9Y5S8	985
DUOX1	NOX5	Q96PH1	984
DUOX1	NOX3	Q9HBY0	981
DUOX1	CYBB	P04839	972
DUOX1	NCF1	P14598	968
DUOX1	CYBA	P13498	956
DUOX1	NCF2	P19878	955
DUOX1	NCF4	Q15080	933
DUOX1	NOXO1	Q8NFA2	767
DUOX1	SLC28A2	O43868	764
DUOX1	NOXA1	Q86UR1	756
DUOX1	SLC30A4	O14863	733

IntAct

16 interactions, top by confidence:

A	B	Type	Score
DUOX1	DUOXA1	psi-mi:“MI:0407”(direct interaction)	0.600
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
PBXIP1	KCNN4	psi-mi:“MI:0914”(association)	0.530
DUOX1	TXNDC11	psi-mi:“MI:0403”(colocalization)	0.460
DUOX1	TXNDC11	psi-mi:“MI:0915”(physical association)	0.460
DUOX1	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
DUOX1	TXNDC11	psi-mi:“MI:0915”(physical association)	0.370
LDLRAD1	ZNF316	psi-mi:“MI:0914”(association)	0.350
MBNL1	A2ML1	psi-mi:“MI:0914”(association)	0.350
SMPD2	A2ML1	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350

BioGRID (10): DUOX1 (Affinity Capture-MS), DUOX1 (Proximity Label-MS), DUOX1 (Proximity Label-MS), DUOX1 (Affinity Capture-RNA), DUOX1 (Affinity Capture-RNA), DUOX1 (Affinity Capture-MS), DUOX1 (Affinity Capture-MS), DUOX1 (Affinity Capture-MS), DUOX1 (Affinity Capture-MS), DUOX1 (Affinity Capture-MS)

ESM2 similar proteins: A1A5Y0, A1KZ92, A2AJ76, B0S5N4, D3YXG0, D3ZPX4, F1MMS9, O00187, O55005, O60500, O75093, O88279, O88280, P11627, P17852, P26006, P32004, P51805, P57110, P59511, P70208, P85171, Q05695, Q0PMG2, Q13219, Q3UH53, Q4KMG0, Q62470, Q62918, Q7Z5N4, Q80TR4, Q8AV58, Q8AXZ4, Q8CIY2, Q8HZK2, Q8HZK3, Q8NDA2, Q8R4K8, Q8TE57, Q91WP0

Diamond homologs: A0A1Y9G8H0, A0A452E9Y6, A1XQX2, G5EG78, O02768, O19183, O62664, O62698, O62725, O97554, P05164, P05979, P22079, P22437, P23219, P27607, P35354, P35355, P70682, P79208, P90820, Q05769, Q63921, Q6TMK4, Q8HYB7, Q8HZR1, Q9NRD9, Q8R481, O46522, O48538, O81209, O81210, O81211, P04839, P52649, Q2HXK9, Q2HXL0, Q3KTM0, Q5ZAJ0, Q61093

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
PRKACA	up-regulates	DUOX1	phosphorylation
DUOX1	up-regulates	ROS
DUOX1	“up-regulates quantity”	superoxide	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	200
Likely benign	19
Benign	12

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
547142	GRCh37/hg19 15q21.1(chr15:45360338-45437443)x2	Likely pathogenic

SpliceAI

5886 predictions. Top by Δscore:

Variant	Effect	Δscore
15:45135760:T:TA	acceptor_gain	1.0000
15:45135762:C:CA	acceptor_gain	1.0000
15:45135769:ACGTC:A	acceptor_gain	1.0000
15:45135944:ACCAG:A	donor_loss	1.0000
15:45135945:CCAGG:C	donor_loss	1.0000
15:45135946:CAG:C	donor_loss	1.0000
15:45135947:AGGTC:A	donor_loss	1.0000
15:45135948:GG:G	donor_loss	1.0000
15:45135949:G:A	donor_loss	1.0000
15:45135950:T:A	donor_loss	1.0000
15:45136408:CAGG:C	donor_loss	1.0000
15:45136409:AGGT:A	donor_loss	1.0000
15:45136410:GGTGA:G	donor_loss	1.0000
15:45136411:G:C	donor_loss	1.0000
15:45136412:T:A	donor_loss	1.0000
15:45136519:A:AG	acceptor_gain	1.0000
15:45136520:T:G	acceptor_gain	1.0000
15:45136526:CAG:C	acceptor_loss	1.0000
15:45136527:A:AG	acceptor_gain	1.0000
15:45136527:A:C	acceptor_loss	1.0000
15:45136527:AG:A	acceptor_gain	1.0000
15:45136528:G:A	acceptor_gain	1.0000
15:45136528:G:GA	acceptor_gain	1.0000
15:45136528:GGA:G	acceptor_gain	1.0000
15:45136528:GGAT:G	acceptor_gain	1.0000
15:45136528:GGATA:G	acceptor_gain	1.0000
15:45136622:TGAG:T	donor_loss	1.0000
15:45136623:GAG:G	donor_gain	1.0000
15:45136623:GAGG:G	donor_loss	1.0000
15:45136624:AG:A	donor_loss	1.0000

AlphaMissense

10137 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:45164800:A:C	S1519R	1.000
15:45164802:C:A	S1519R	1.000
15:45164802:C:G	S1519R	1.000
15:45161794:T:A	W1305R	0.999
15:45161794:T:C	W1305R	0.999
15:45162325:T:C	L1399P	0.999
15:45163544:T:A	W1421R	0.999
15:45163544:T:C	W1421R	0.999
15:45163574:T:A	W1431R	0.999
15:45163574:T:C	W1431R	0.999
15:45164795:T:A	V1517E	0.999
15:45164896:T:C	F1551L	0.999
15:45164898:C:A	F1551L	0.999
15:45164898:C:G	F1551L	0.999
15:45161796:G:C	W1305C	0.998
15:45161796:G:T	W1305C	0.998
15:45161836:C:G	H1319D	0.998
15:45162258:T:A	W1377R	0.998
15:45162258:T:C	W1377R	0.998
15:45162280:T:A	V1384E	0.998
15:45155888:T:C	F1221L	0.997
15:45155890:C:A	F1221L	0.997
15:45155890:C:G	F1221L	0.997
15:45161750:T:C	L1290P	0.997
15:45161788:G:T	G1303W	0.997
15:45161789:G:A	G1303E	0.997
15:45161905:T:A	W1342R	0.997
15:45161905:T:C	W1342R	0.997
15:45162237:T:C	F1370L	0.997
15:45162239:T:A	F1370L	0.997

dbSNP variants (sampled 300 via entrez): RS1000072131 (15:45145431 T>C), RS1000090683 (15:45152863 A>C), RS1000173854 (15:45163449 A>G), RS1000210494 (15:45128723 T>C), RS1000300746 (15:45159404 G>A,C), RS1000358399 (15:45165677 C>T), RS1000483424 (15:45131866 C>A,G,T), RS1000524687 (15:45145172 A>G), RS1000608979 (15:45150267 T>C), RS1000842622 (15:45165300 T>C), RS1000865006 (15:45130248 G>A), RS1000967585 (15:45137814 G>A,T), RS1001010793 (15:45134063 T>A,C), RS1001168559 (15:45137847 C>A), RS1001189416 (15:45156583 C>A,T)

Disease associations

OMIM: gene MIM:606758 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital hypothyroidism	Limited	Unknown

Mondo (1): congenital hypothyroidism (MONDO:0018612)

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003409	Congenital Hypothyroidism	C05.116.099.343.347; C05.116.132.256; C16.320.240.625; C19.297.155; C19.874.482.281

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465362 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — NADPH oxidases

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.16	IC50	700	nM	CHEMBL4210329

PubChem BioAssay actives

1 with measured affinity, of 1 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
2-(3-benzyltriazolo[4,5-d]pyrimidin-7-yl)sulfanyl-1,3-benzoxazole	2013286: Inhibition of human DUOX1 transfected in HEK cells assessed as PMA-induced hydrogen peroxide production preincubated for 15 mins and measured after 10 mins by Amplex-red based fluorescence assay	ic50	0.7000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases secretion, increases expression, decreases reaction, affects methylation (+2 more)	5
Particulate Matter	increases expression, decreases reaction, decreases expression, increases abundance	4
Benzo(a)pyrene	affects methylation, increases expression	3
Aflatoxin B1	decreases methylation, increases expression	3
Resveratrol	affects cotreatment, decreases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Paraquat	decreases reaction, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
GSK-J4	decreases expression	1
sotorasib	affects cotreatment, increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
kaempferol	decreases reaction, increases expression	1
bisphenol A	decreases expression	1
titanium dioxide	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
zinc chloride	affects reaction, increases secretion	1
cerous chloride	affects cotreatment, increases expression, decreases expression	1
lanthanum chloride	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
cyfluthrin	increases expression	1
salvianolic acid A	decreases reaction, increases abundance, increases expression	1
trametinib	increases expression, affects cotreatment	1
NVP-BKM120	affects cotreatment, increases expression	1
Aerosols	decreases expression	1
Antimony Potassium Tartrate	decreases reaction, increases expression, decreases expression	1
Arsenic	affects reaction, decreases expression, increases abundance, increases expression, decreases reaction	1
Calcitriol	increases expression, affects cotreatment	1
Copper	affects cotreatment, decreases expression	1
Deferoxamine	increases expression, decreases reaction	1
Estradiol	affects cotreatment, decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5367019	Binding	Inhibition of human DUOX1 transfected in HEK cells assessed as PMA-induced hydrogen peroxide production preincubated for 15 mins and measured after 10 mins by Amplex-red based fluorescence assay	NADPH Oxidases: From Molecular Mechanisms to Current Inhibitors. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05228184	PHASE4	TERMINATED	Use of Tirosint®-SOL or Tablet Formulations of Levothyroxine in Pediatric Patients With Congenital Hypothyroidism (CH)
NCT05371262	PHASE4	COMPLETED	Influence of Initial Levothyroxine Dose on Neurodevelopmental and Growth Outcomes in Congenital Hypothyroidism
NCT00403390	Not specified	COMPLETED	Generic vs. Name-Brand Levothyroxine
NCT00493103	Not specified	COMPLETED	TG Gene Mutations and Congenital Hypothyroidism
NCT00497575	Not specified	COMPLETED	Diagnosis and Follow-up of Patients With Subclinical Hypothyroidism
NCT00505479	Not specified	UNKNOWN	Iodine Status in Pregnant Women and Their Newborns: is Congenital Hypothyroidism Related to Iodine Deficiency in Pregnancy?
NCT01223638	Not specified	WITHDRAWN	The Prevalence of Hearing Loss Among Children With Congenital Hypothyroidism
NCT01349634	Not specified	COMPLETED	The Effects of Iodized Salt on Cognitive Development in Ethiopia
NCT01488721	Not specified	COMPLETED	Clinical Evaluation of NeoPlex4 Assay and NeoPlex System
NCT01916018	Not specified	COMPLETED	Clinical and Genetic Analysis in Congenital Hypothyroidism Due to Thyroid Dysgenesis.
NCT02307175	Not specified	COMPLETED	A Study of 99m Tc Pertechnetate Produced in High Energy Cyclotron in Patients With Thyroid Scan Indication
NCT02374593	Not specified	COMPLETED	Targeted Levothyroxine Dosing in Infants With Congenital Hypothyroidism
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04712760	Not specified	UNKNOWN	Congenital Hypothyroidism in Children With Eutopic Gland or Thyroid Hemiagenesis: Predictive Factors for Transient vs Permanent Hypothyroidism.
NCT04734457	Not specified	UNKNOWN	Final Height in Patients With CH Diagnosed by the Screening
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06724224	Not specified	RECRUITING	Comparison of Levothyroxine Formulations in the Treatment of Congenital Hypothyroidism
NCT06728735	Not specified	RECRUITING	Role of Next Generation Sequencing in the Etiological Diagnosis of Permanent Congenital Hypothyroidism With in Situ Thyroid
NCT06864039	Not specified	ENROLLING_BY_INVITATION	Quality of Life and Long-term Outcome of Adequately Treated Congenital Hypothyroidism
NCT06864351	Not specified	RECRUITING	Prospective Evaluation of OptiThyDose
NCT07126353	Not specified	NOT_YET_RECRUITING	Metabolic Risk Assessment in Prepubertal Children With Congenital Hypothyroidism
NCT07280104	Not specified	RECRUITING	Infants With Primary Congenital Hypothyroidism and Development
NCT07425028	Not specified	NOT_YET_RECRUITING	Evaluation of an Intensified Systematic Screening for Congenital Hypothyroidism in Premature Newborns
NCT07579988	Not specified	NOT_YET_RECRUITING	Ultrasound Measurement of Thyroid Volume in Term Newborns