DIO3

Summary

DIO3 (iodothyronine deiodinase 3, HGNC:2885) is a protein-coding gene on chromosome 14q32.31, encoding Thyroxine 5-deiodinase (P55073). Plays a crucial role in the metabolism of thyroid hormones (TH) and has specific roles in TH activation and inactivation by deiodination.

The protein encoded by this intronless gene belongs to the iodothyronine deiodinase family. It catalyzes the inactivation of thyroid hormone by inner ring deiodination of the prohormone thyroxine (T4) and the bioactive hormone 3,3’,5-triiodothyronine (T3) to inactive metabolites, 3,3’,5’-triiodothyronine (RT3) and 3,3’-diiodothyronine (T2), respectively. This enzyme is highly expressed in pregnant uterus, placenta, fetal and neonatal tissues, and thought to prevent premature exposure of developing fetal tissues to adult levels of thyroid hormones. It regulates circulating fetal thyroid hormone concentrations, and thus plays a critical role in mammalian development. Knockout mice lacking this gene exhibit abnormalities related to development and reproduction, and increased activity of this enzyme in infants with hemangiomas causes severe hypothyroidism. This protein is a selenoprotein, containing the rare selenocysteine (Sec) amino acid at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3’ UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon rather than as a stop signal.

Source: NCBI Gene 1735 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 33 total
• Druggable target: yes
• MANE Select transcript: NM_001362

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2885
Approved symbol	DIO3
Name	iodothyronine deiodinase 3
Location	14q32.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000197406
Ensembl biotype	protein_coding
OMIM	601038
Entrez	1735

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000510508, ENST00000700173

RefSeq mRNA: 1 — MANE Select: NM_001362 NM_001362

CCDS: CCDS41992

Canonical transcript exons

ENST00000510508 — 1 exons

Exon	Start	End
ENSE00003979028	101561495	101563452

Expression profiles

Bgee: expression breadth ubiquitous, 156 present calls, max score 86.38.

FANTOM5 (CAGE): breadth broad, TPM avg 1.6072 / max 62.9679, expressed in 348 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
141585	1.6072	348

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endocervix	UBERON:0000458	86.38	gold quality
tendon of biceps brachii	UBERON:0008188	84.92	gold quality
right ovary	UBERON:0002118	82.59	gold quality
left ovary	UBERON:0002119	80.83	gold quality
endometrium epithelium	UBERON:0004811	80.80	gold quality
ectocervix	UBERON:0012249	79.75	gold quality
cartilage tissue	UBERON:0002418	79.72	gold quality
parotid gland	UBERON:0001831	77.91	gold quality
left uterine tube	UBERON:0001303	77.51	gold quality
tibial artery	UBERON:0007610	76.47	gold quality
popliteal artery	UBERON:0002250	76.45	gold quality
vagina	UBERON:0000996	76.15	gold quality
Brodmann (1909) area 10	UBERON:0013541	75.60	gold quality
ovary	UBERON:0000992	75.17	gold quality
body of uterus	UBERON:0009853	74.90	gold quality
placenta	UBERON:0001987	73.25	gold quality
buccal mucosa cell	CL:0002336	72.49	gold quality
myometrium	UBERON:0001296	70.88	gold quality
pancreatic ductal cell	CL:0002079	70.34	silver quality
frontal pole	UBERON:0002795	70.20	gold quality
paraflocculus	UBERON:0005351	69.91	gold quality
right lobe of thyroid gland	UBERON:0001119	69.82	gold quality
middle frontal gyrus	UBERON:0002702	69.67	gold quality
omental fat pad	UBERON:0010414	69.66	gold quality
peritoneum	UBERON:0002358	69.63	gold quality
gall bladder	UBERON:0002110	69.41	gold quality
uterine cervix	UBERON:0000002	69.20	gold quality
secondary oocyte	CL:0000655	68.97	gold quality
adipose tissue of abdominal region	UBERON:0007808	68.88	gold quality
subcutaneous adipose tissue	UBERON:0002190	68.65	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-6108	yes	405.30
E-MTAB-8205	yes	169.17
E-MTAB-8271	yes	148.22
E-ANND-3	no	1.15

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, GLI2, HIF1A, HR, JUN

miRNA regulators (miRDB)

41 targeting DIO3, 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-4795-3P	100.00	74.62	4024
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-4777-3P	99.15	68.92	626
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-622	98.99	66.48	1050
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-1257	98.97	68.02	1133
HSA-MIR-5006-5P	98.79	66.92	1246
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-761	98.71	68.07	2051
HSA-MIR-4704-3P	98.28	69.33	1300
HSA-MIR-6787-3P	97.75	66.17	1233
HSA-MIR-6793-3P	97.66	65.78	1084

Literature-anchored findings (GeneRIF, showing 40)

• study demonstrates that D3 is located in the plasma membrane with most of its molecule in the extracellular space, allowing access to inactivate both the hormone T3 and prohormone T4 (PMID:12419801)
• overexpressed iodothyronine deiodinase types 1,2, and 3 can homodimerize probably through disulfide bridges and types 1 and 2 monomeric forms are catalytically active (PMID:12586771)
• the SeC residue in the catalytic center of D3 is essential for efficient inner-ring deiodination of T(3) and in particular T(4) at physiological substrate concentrations. (PMID:12746313)
• D3 contains a glycoside hydrolase clan GH-A-like structure (PMID:12847093)
• identified a conserved enhancer located 3’ of the DIO3 gene containing putative AP-1 and serum response elements, that further increases the serum responsiveness of the Dio3 promoter in a cell-specific manner (PMID:12943987)
• Iodothyronine deiodinases D2 and D3 play important roles in local bioavailability of triiodothyronine T(3). T(3) is produced from thyroxine T(4) by D2, and D3 protects brain regions from excessive T(3) until differentiation is required. (PMID:15240580)
• TGF-beta stimulates transcription of the hDio3 gene via a Smad-dependent pathway. (PMID:16037131)
• structure and function of the type 3 deiodinase gene [review] (PMID:16131329)
• postnatal expression of Dio3 can be reactivated in normal tissues during critical illness and other pathologic conditions [review] (PMID:16131330)
• Deiodinase D3 exists as homo- or heterodimer in living intact cells, a feature that is critical for their catalytic activities. (PMID:18356288)
• The expression of D3 mRNA was more than 10 times higher in the tumor tissue than the mean of placental tissues (PMID:19548001)
• Prx3 knockdown resulted in a 50% decrease in D3-mediated whole-cell deiodination. (PMID:19819956)
• In this case-control study, homozygosity for type 2 deiodinase Thr92Ala polymorphism is associated with increased risk for type 2 diabetes. (PMID:20566590)
• The minor allele of the DIO3 variant rs945006 showed suggestive evidence for protective association in the overall meta-analyses, which was supported by individual osteoarthritis studies and osteoarthritis subtypes. (PMID:20724312)
• [review] progress made in understanding the physiological function and significance of D3; summarizes the intriguing evidence that D3 plays a pivotal role in defining local TH concentration in the developing fetus and in several conditions in adult life. (PMID:21398344)
• coordinate up-regulation of the DLK1-DIO3 miRNA cluster at 14q32.2 may define a novel molecular (stem cell-like) subtype of hepatocellular carcinoma associated with poor prognosis (PMID:21737452)
• D3 expression in perinatal pancreatic beta-cells prevents untimely exposure to thyroid hormone, the absence of which leads to impaired beta-cell function and subsequently insulin secretion and glucose homeostasis (PMID:21828183)
• Deiodinase iodothyronine type III activity was increased in all papillary thyroid carcinomas as compared with that in adjacent thyroid tissue, parallel with ~ 5 times increase in deiodinase iodothyronine type III mRNA levels. (PMID:22823995)
• Reviewed are the microRNAs within the DLK1-DIO3 genomic region, their role in controlling tissue homeostasis and in the pathogenesis of some human diseases, mostly cancer, when aberrantly expressed. [review] (PMID:22825660)
• D3 expression is re-activated in various types of human cancers. It may play a role in carcinogenesis and neoplastic cell proliferation. Review. (PMID:23235188)
• Treatment with high affinity amyloidbeta42 oligomer-binding enantiomeric D3 peptide significantly decreases amyloidbeta deposits and the associated inflammatory response and improves cognition, even when applied only at late stages and high age. (PMID:23271316)
• Data indicate that Na+/I- symporter and type 3 iodothyronine deiodinase genes are expressed in term placenta and amniotic membrane. (PMID:23857380)
• Overall, the data suggest that active expression of the DLK1-DIO3 cluster represents a new biomarker for epigenetic stability of hESCs and indicates the importance of using a proper physiological oxygen level during the derivation and culture of hESCs. (PMID:24123616)
• the microRNA cluster at the Dlk1-Dio3 locus is upregulated in lung adenocarcinoma (PMID:24317514)
• the imprinted DLK1-DIO3 locus is regulated by noncoding RNA IPW in an induced pluripotent stem cell model of Prader-Willi syndrome (PMID:24816254)
• [review] D3 polymorphisms show no relationship with inter-individual variation in serum thyroid hormone parameters. (PMID:24878678)
• Thyroid hormone deiodinases D1, D2, and D3 are differentially expressed in endothelial cells following thyroid hormone exposure. (PMID:25304215)
• D3 is a critical factor in testis development and in testicular protection from thyrotoxicosis. (PMID:26727108)
• MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma (PMID:26825960)
• In neonatal skin, DIO3 exhibited a high degree of monoallelic expression from the paternal allele. (PMID:27329732)
• Presence and subcellular location of D3 in human neutrophils for the first time and propose a model, in which D3 plays a role in the bacterial killing capacity of neutrophils either through generation of iodide for the myeloperoxidase system or through modulation of intracellular Thyroid hormone bioavailability. (PMID:27355490)
• The expression of piRNAs encoded at DLK1-DIO3 enhances the prognostic potential of small non-coding RNAs specific to this locus in predicting lung cancer patient outcome. (PMID:27829231)
• The expression of DIO3 on mRNA/protein levels in the depressive disorders patients was increased in comparison to the control subjects. (PMID:29182613)
• A critical role for reduced intracellular TH concentrations in neutrophil function during infection, for which the TH inactivating enzyme D3 appears essential. (PMID:29186449)
• A direct relationship between DLK1-DIO3 deregulation and replicative senescence of adipose-derived stem cells is reported, involving upregulation of a very significant fraction of its largest miRNA cluster (14q32.31), paralleled by the progressive overexpression of the lncRNA MEG3. (PMID:30395586)
• Downregulation of Type 3 Deiodinase in the Hypothalamus During Inflammation. (PMID:31303139)
• Deiodinases, organic anion transporter polypeptide polymorphisms and ischemic stroke outcomes. (PMID:31677555)
• Effects of methylation of deiodinase 3 gene on gene expression and severity of Kashin-Beck disease. (PMID:32458485)
• Decreased expression of the thyroid hormone-inactivating enzyme type 3 deiodinase is associated with lower survival rates in breast cancer. (PMID:32807826)
• Downregulation of Caveolin-1 and Upregulation of Deiodinase 3, Associated with Hypoxia-Inducible Factor-1alpha Increase, Are Involved in the Oxidative Stress of Graves’ Orbital Adipocytes. (PMID:32977740)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Dio3	ENSMUSG00000075707
rattus_norvegicus	Dio3	ENSRNOG00000052017

Paralogs (2): DIO2 (ENSG00000211448), DIO1 (ENSG00000211452)

Protein

Protein identifiers

Thyroxine 5-deiodinase — P55073 (reviewed: P55073)

Alternative names: 5DIII, DIOIII, Type 3 DI, Type III iodothyronine deiodinase

All UniProt accessions (2): A0A8V8TPY2, P55073

UniProt curated annotations — full annotation on UniProt →

Function. Plays a crucial role in the metabolism of thyroid hormones (TH) and has specific roles in TH activation and inactivation by deiodination. Catalyzes the deiodination of L-thyroxine (T4) to 3,3’,5’-triiodothyronine (rT3), 3,5,3’-triiodothyronine (T3) to 3,3’-diiodothyronine (3,3’-T2), 3,5-diiodothyronine (3,5-T2) to 3-monoiodothyronine (3-T1), rT3 to 3’,5’-diiodothyronine (3’,5’-T2) and 3,3’-T2 to 3’-monoiodothyronine (3’-T1) via inner-ring deiodination (IRD). Catalyzes the deiodination of 3-T1 to L-thyronine (T0) via outer-ring deiodination (ORD). Catalyzes the tyrosyl ring deiodinations of 3,3’,5,5’-tetraiodothyronamine, 3,3’,5’-triiodothyronamine, 3,5,3’-triiodothyronamine, 3,5-diiodothyronamine, 3,3’-diiodothyronamine and 3-iodothyronamine.

Subunit / interactions. Monomer. Homodimer. May undergo minor heretodimerization with DIO1 and DIO2.

Subcellular location. Cell membrane. Endosome membrane.

Tissue specificity. Expressed in placenta and several fetal tissues.

Similarity. Belongs to the iodothyronine deiodinase family.

RefSeq proteins (1): NP_001353* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000643	Iodothyronine_deiodinase	Family
IPR008261	Iodothyronine_deiodinase_AS	Active_site
IPR027252	Iodothyronine_deiodinase_I/III	Family
IPR036249	Thioredoxin-like_sf	Homologous_superfamily

Pfam: PF00837

Enzyme classification (BRENDA):

• EC 1.21.99.3 — thyroxine 5-deiodinase (BRENDA: 14 organisms, 68 substrates, 93 inhibitors, 33 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
3,3’,5-TRIIODO-L-THYRONINE	—	13
3,3’,5’-TRIIODO-L-THYRONINE	—	7
L-THYROXINE	—	5
L-3,5’,3’-TRIIODOTHYRONINE	0.003–0.57	3
3,5,3’-TRIIODO-L-THYRONINE	—	2

Catalyzed reactions (Rhea), 12 shown:

• 3,3’,5’-triiodo-L-thyronine + iodide + A + H(+) = L-thyroxine + AH2 (RHEA:18897)
• 3,3’-diiodo-L-thyronine + iodide + A + H(+) = 3,3’,5-triiodo-L-thyronine + AH2 (RHEA:82571)
• 3-iodo-L-thyronine + iodide + A + H(+) = 3,5-diiodo-L-thyronine + AH2 (RHEA:82895)
• L-thyronine + iodide + A + H(+) = 3-iodo-L-thyronine + AH2 (RHEA:83771)
• 3’,5’-diiodo-L-thyronine + iodide + A + H(+) = 3,3’,5’-triiodo-L-thyronine + AH2 (RHEA:83775)
• 3’-iodo-L-thyronine + iodide + A + H(+) = 3,3’-diiodo-L-thyronine + AH2 (RHEA:83779)
• 3’,5’-diiodothyronamine + iodide + A + H(+) = 3,3’,5’-triiodothyronamine + AH2 (RHEA:83799)
• 3,3’,5’-triiodothyronamine + iodide + A + H(+) = 3,3’,5,5’-tetraiodothyronamine + AH2 (RHEA:83807)
• 3,3’-diiodothyronamine + iodide + A + H(+) = 3,3’,5-triiodothyronamine + AH2 (RHEA:83811)
• 3’-iodothyronamine + iodide + A + H(+) = 3,3’-diiodothyronamine + AH2 (RHEA:83815)
• thyronamine + iodide + A + H(+) = 3-iodothyronamine + AH2 (RHEA:83819)
• 3-iodothyronamine + iodide + A + H(+) = 3,5-diiodothyronamine + AH2 (RHEA:83823)

UniProt features (12 total): topological domain 2, sequence conflict 2, region of interest 2, chain 1, transmembrane region 1, compositionally biased region 1, active site 1, non-standard amino acid 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for P55073 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Catalytic / active sites (1): 170

Mutagenesis-validated functional residues (1):

Position	Phenotype
170	complete loss of enzyme activity towards 3,5,3’-triiodothyronine.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-350864	Regulation of thyroid hormone activity
R-HSA-1430728	Metabolism
R-HSA-209776	Metabolism of amine-derived hormones
R-HSA-209968	Thyroxine biosynthesis
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 117 (showing top): RNGTGGGC_UNKNOWN, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, E2F_Q4_01, BENPORATH_ES_WITH_H3K27ME3, MODULE_255, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, PEREZ_TP63_TARGETS, GOBP_MODIFIED_AMINO_ACID_CATABOLIC_PROCESS, GOBP_GROWTH, MODULE_317, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_THYROID_HORMONE_METABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_NEURAL_RETINA_DEVELOPMENT, EFC_Q6

GO Biological Process (9): response to hypoxia (GO:0001666), positive regulation of multicellular organism growth (GO:0040018), thyroid hormone metabolic process (GO:0042403), thyroid hormone catabolic process (GO:0042404), hormone biosynthetic process (GO:0042446), retinal cone cell development (GO:0046549), brown fat cell proliferation (GO:0070342), retinal cone cell apoptotic process (GO:0097474), apoptotic process (GO:0006915)

GO Molecular Function (3): thyroxine 5’-deiodinase activity (GO:0004800), thyroxine 5-deiodinase activity (GO:0033798), oxidoreductase activity (GO:0016491)

GO Cellular Component (4): plasma membrane (GO:0005886), endosome membrane (GO:0010008), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Thyroxine biosynthesis	1
Metabolism of amino acids and derivatives	1
Metabolism of amine-derived hormones	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
hormone metabolic process	2
oxidoreductase activity, acting on X-H and Y-H to form an X-Y bond	2
response to stress	1
response to decreased oxygen levels	1
multicellular organism growth	1
regulation of multicellular organism growth	1
positive regulation of developmental growth	1
positive regulation of multicellular organismal process	1
modified amino acid metabolic process	1
phenol-containing compound metabolic process	1
phenol-containing compound catabolic process	1
modified amino acid catabolic process	1
thyroid hormone metabolic process	1
hormone catabolic process	1
biosynthetic process	1
eye photoreceptor cell development	1
retinal cone cell differentiation	1
fat cell proliferation	1
neuron apoptotic process	1
retinal cell apoptotic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
catalytic activity	1
membrane	1
cell periphery	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
endomembrane system	1
cytoplasmic vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

484 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DIO3	DLK1	P15803	924
DIO3	SLC16A2	P36021	836
DIO3	TRH	P20396	830
DIO3	RTL1	A6NKG5	791
DIO3	SLCO1C1	Q9NYB5	704
DIO3	GPX2	P18283	676
DIO3	GPX3	P22352	673
DIO3	SLC7A8	Q9UHI5	665
DIO3	THRB	P10828	645
DIO3	GPX7	Q96SL4	634
DIO3	GPX6	P59796	630
DIO3	TSHB	P01222	621
DIO3	TSHR	P16473	616
DIO3	DIO2	Q92813	615
DIO3	SERPINA7	P05543	590

IntAct

2 interactions, top by confidence:

A	B	Type	Score
DIO3	BLTP3B	psi-mi:“MI:0914”(association)	0.350

BioGRID (20): DIO3 (Affinity Capture-MS), PLSCR1 (Affinity Capture-MS), ATP1A3 (Affinity Capture-MS), UHRF1BP1L (Affinity Capture-MS), SURF4 (Affinity Capture-MS), TARSL2 (Affinity Capture-MS), SLC12A7 (Affinity Capture-MS), XPO5 (Affinity Capture-MS), HERC3 (Affinity Capture-MS), ATP13A1 (Affinity Capture-MS), SLC5A3 (Affinity Capture-MS), ANKRD13A (Affinity Capture-MS), CNNM4 (Affinity Capture-MS), SOAT1 (Affinity Capture-MS), CNNM2 (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8Y7D0, A3KMV1, A6NDN8, B9EHT4, D3YWQ0, F1MAB7, O23702, O54788, O75426, O76075, P04413, P0C5J9, P49897, P55073, Q1LZC5, Q28969, Q2T9Z2, Q2VPJ9, Q39491, Q3MHJ7, Q3TGW2, Q4R327, Q57VU6, Q58CZ0, Q5BIR3, Q5I3B1, Q5R4R7, Q5R686, Q5SPX3, Q5XI74, Q6DN07, Q6NXT1, Q6P7W2, Q6QN11, Q6X4W1, Q7L9B9, Q7TPD7, Q80TL4, Q8K485, Q8TBC3

Diamond homologs: A4GT88, A7YD35, L7WGA7, O42411, O42412, O42449, P24389, P49894, P49895, P49896, P49897, P49898, P49899, P55073, P70551, P79747, Q2QEI3, Q5I3B1, Q5I3B2, Q61153, Q6DN07, Q6QN11, Q6QN12, Q6QN13, Q6U6H1, Q6V915, Q804E1, Q8UVX8, Q91ZI8, Q92813, Q95N00, Q9IAX2, Q9Z1Y9

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
DIO3	“down-regulates quantity”	L-thyroxine	“chemical modification”
DIO3	“up-regulates quantity”	3,3’,5’-triiodothyronine	“chemical modification”
DIO3	“up-regulates quantity”	iodide	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

85 predictions. Top by Δscore:

Variant	Effect	Δscore
14:101562050:C:CG	donor_gain	0.5000
14:101562094:G:GT	donor_gain	0.4900
14:101562149:A:AG	acceptor_gain	0.4800
14:101562150:G:GG	acceptor_gain	0.4800
14:101562046:GTCAC:G	donor_gain	0.4300
14:101562047:TCACT:T	donor_gain	0.4300
14:101562050:C:G	donor_gain	0.4300
14:101562150:GCACC:G	acceptor_gain	0.4300
14:101562253:GCC:G	donor_gain	0.4000
14:101562150:GC:G	acceptor_gain	0.3900
14:101561701:A:AG	acceptor_gain	0.3700
14:101561702:A:G	acceptor_gain	0.3600
14:101562185:GG:G	donor_gain	0.3600
14:101562186:GG:G	donor_gain	0.3600
14:101562349:C:G	donor_gain	0.3600
14:101561522:T:A	donor_gain	0.3500
14:101561916:G:GA	donor_gain	0.3400
14:101561915:T:TA	donor_gain	0.3200
14:101562185:G:A	donor_gain	0.3100
14:101561526:G:GA	donor_gain	0.3000
14:101561967:G:T	donor_gain	0.3000
14:101562203:C:CG	donor_gain	0.3000
14:101561700:CA:C	acceptor_gain	0.2900
14:101561701:AA:A	acceptor_gain	0.2900
14:101562122:C:CT	acceptor_gain	0.2900
14:101562189:ACTGC:A	donor_gain	0.2900
14:101562374:A:G	donor_gain	0.2900
14:101562095:A:T	donor_gain	0.2800
14:101562201:TGC:T	donor_gain	0.2800
14:101562054:G:GG	donor_gain	0.2700

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000106689 (14:101559469 T>C), RS1000227493 (14:101562706 A>G), RS1001107414 (14:101560676 G>A,T), RS1001117243 (14:101560810 C>A), RS1001925252 (14:101563588 G>A), RS1002272804 (14:101563763 A>G), RS1002469076 (14:101560554 C>A), RS1002624007 (14:101560891 A>G), RS1002655376 (14:101559725 T>C), RS1003043577 (14:101561075 C>A), RS1003637243 (14:101562217 C>G), RS1004245138 (14:101562566 C>A), RS1005867829 (14:101561086 G>A,C), RS1006496611 (14:101559436 A>C), RS1007757275 (14:101561692 T>C,G)

Disease associations

OMIM: gene MIM:601038 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000539_2	Type 1 diabetes	1.000000e-10
GCST006626_46	Pulse pressure	8.000000e-10
GCST009391_1030	Metabolite levels	2.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement
EFO:0009775	threonine measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3542431 (PROTEIN FAMILY), CHEMBL3611 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Thyroid hormone turnover

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
xanthohumol	decreases activity, affects metabolic processing	2
entinostat	decreases expression, affects cotreatment	2
2,2’,4,4’-tetrabromodiphenyl ether	increases methylation, decreases activity, decreases expression, increases expression, increases abundance	2
Resveratrol	decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Diethylhexyl Phthalate	increases expression, affects expression, decreases expression	2
Estradiol	affects expression, increases activity	2
Triiodothyronine	affects metabolic processing, decreases activity, affects abundance, affects cotreatment, increases expression	2
Valproic Acid	decreases expression, increases methylation	2
cyclopamine	decreases expression	1
4,5-dichloro-1,2-dithiol-3-one	decreases activity	1
captafol	decreases activity	1
methylmercuric chloride	increases expression	1
tetrachloroisophthalonitrile	decreases activity	1
bisphenol A	increases methylation	1
chrysophenine	decreases activity	1
dichlone	decreases activity	1
dinocap	decreases activity	1
morin	decreases activity	1
decabromobiphenyl ether	decreases expression, decreases reaction	1
hydroxyhydroquinone	increases expression	1
beta-lapachone	decreases expression	1
hexachlorocyclopentadiene	decreases activity	1
mono-(2-ethylhexyl)phthalate	decreases expression, decreases methylation	1
2,2’-dihydroxy-6,6’-dinaphthyldisulfide	decreases activity	1
bisphenol A diglycidyl ether	decreases activity	1
tetrabromobisphenol A	increases expression	1
didecyldimethylammonium	decreases activity	1
6-O-palmitoylascorbic acid	decreases activity	1
2-n-octyl-4-isothiazolin-3-one	decreases activity	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL699716	Binding	Inhibition of Human Placenta Inner-Ring Iodothyronine 5-deiodinase at the compound concentration of 5 mM	Synthesis of 6-anilino-2-thiouracils and their inhibition of human placenta iodothyronine deiodinase. — J Med Chem

Clinical trials (associated diseases)

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