DIO2

Summary

DIO2 (iodothyronine deiodinase 2, HGNC:2884) is a protein-coding gene on chromosome 14q31.1, encoding Type II iodothyronine deiodinase (Q92813). 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 gene belongs to the iodothyronine deiodinase family. It catalyzes the conversion of prohormone thyroxine (3,5,3’,5’-tetraiodothyronine, T4) to the bioactive thyroid hormone (3,5,3’-triiodothyronine, T3) by outer ring 5’-deiodination. This gene is widely expressed, including in thyroid and brain. It is thought to be responsible for the ’local’ production of T3, and thus important in influencing thyroid hormone action in these tissues. It has also been reported to be highly expressed in thyroids of patients with Graves disease, and in follicular adenomas. The intrathyroidal T4 to T3 conversion by this enzyme may contribute significantly to the relative increase in thyroidal T3 production in these patients. This protein is a selenoprotein containing the non-standard amino acid, selenocysteine (Sec), which is encoded by the UGA codon that 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. Unlike the other two members (DIO1 and DIO3) of this enzyme family, the mRNA for this gene contains an additional in-frame UGA codon that has been reported (in human) to function either as a Sec or a stop codon, which can result in two isoforms with one or two Sec residues; however, only the upstream Sec (conserved with the single Sec residue found at the active site in DIO1 and DIO3) was shown to be essential for enzyme activity (PMID:10403186). Alternatively spliced transcript variants have been described for this gene.

Source: NCBI Gene 1734 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 28 total
• Druggable target: yes
• MANE Select transcript: NM_013989

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2884
Approved symbol	DIO2
Name	iodothyronine deiodinase 2
Location	14q31.1
Locus type	gene with protein product
Status	Approved
Aliases	TXDI2, SelY, SELENOY
Ensembl gene	ENSG00000211448
Ensembl biotype	protein_coding
OMIM	601413
Entrez	1734

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000438257, ENST00000553594, ENST00000553968, ENST00000554188, ENST00000555750, ENST00000555844, ENST00000556384, ENST00000556811, ENST00000557010, ENST00000557125

RefSeq mRNA: 4 — MANE Select: NM_013989 NM_000793, NM_001324462, NM_001366496, NM_013989

CCDS: CCDS45146

Canonical transcript exons

ENST00000438257 — 2 exons

Exon	Start	End
ENSE00000000308	80197526	80203288
ENSE00002032108	80211251	80211504

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 96.84.

FANTOM5 (CAGE): breadth broad, TPM avg 10.9361 / max 2056.8508, expressed in 579 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
144272	6.2926	440
144266	3.0609	294
144269	0.6782	173
144267	0.3178	135
144271	0.2455	46
144270	0.2001	107
144277	0.0736	36
144268	0.0243	12
144258	0.0232	8
144257	0.0148	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pharyngeal mucosa	UBERON:0000355	96.84	gold quality
lower esophagus mucosa	UBERON:0035834	96.75	gold quality
tendon of biceps brachii	UBERON:0008188	95.78	gold quality
body of tongue	UBERON:0011876	95.54	gold quality
superior surface of tongue	UBERON:0007371	95.19	gold quality
tongue	UBERON:0001723	95.02	gold quality
oral cavity	UBERON:0000167	94.85	gold quality
thyroid gland	UBERON:0002046	94.71	gold quality
right lobe of thyroid gland	UBERON:0001119	94.69	gold quality
esophagus mucosa	UBERON:0002469	94.61	gold quality
esophagus squamous epithelium	UBERON:0006920	94.47	gold quality
nipple	UBERON:0002030	94.42	gold quality
penis	UBERON:0000989	94.22	gold quality
left lobe of thyroid gland	UBERON:0001120	94.01	gold quality
buccal mucosa cell	CL:0002336	92.76	gold quality
epithelium of esophagus	UBERON:0001976	92.72	gold quality
urethra	UBERON:0000057	91.38	gold quality
squamous epithelium	UBERON:0006914	91.13	gold quality
pituitary gland	UBERON:0000007	90.41	gold quality
minor salivary gland	UBERON:0001830	90.36	gold quality
mouth mucosa	UBERON:0003729	90.20	gold quality
tongue squamous epithelium	UBERON:0006919	89.54	gold quality
tendon	UBERON:0000043	88.46	gold quality
adenohypophysis	UBERON:0002196	88.24	gold quality
endometrium	UBERON:0001295	88.06	gold quality
gingiva	UBERON:0001828	87.79	gold quality
mammalian vulva	UBERON:0000997	87.64	gold quality
amygdala	UBERON:0001876	87.53	gold quality
gingival epithelium	UBERON:0001949	87.05	gold quality
tonsil	UBERON:0002372	87.00	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-23	yes	1598.41
E-MTAB-6701	yes	517.68
E-MTAB-6678	yes	16.75
E-ANND-3	yes	8.84

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
MYOD1	Activation

Upstream regulators (CollecTRI, top): AP1, CEBPA, CEBPB, CEBPG, CREB1, CTNNB1, FOSL2, FOXO3, GATA2, GATA4, HNF4A, JUN, MEF2A, MITF, NFATC1, NFKB, NKX2-5, NR1H3, PRDM16, RBPJ, SP1, SP3, STAT3, STAT5A, TBP, TTF1

miRNA regulators (miRDB)

224 targeting DIO2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062

Literature-anchored findings (GeneRIF, showing 40)

• Type 2 iodothyronine deiodinase expression is upregulated by the protein kinase A-dependent pathway and is downregulated by the protein kinase C-dependent pathway in cultured human thyroid cells. (PMID:11716036)
• The effects of TNF-alpha, interleukin-6 and interferon gamma were studied on the activity of type 2,5’-deiodinase and on the binding of [125I] T(4) to proteins in human thyroid cytosolic (supernatant) and membrane (pellet) fractions (PMID:11716958)
• mutants with a cysteine or serine two-residue amino terminal to the SeC are enzymatically active and displayed similar Michaelis-Menten constant values for T(4) and reverse T(3) as the wild-type D2 enzyme (PMID:11897672)
• The inhibition by D2 5’UTR is localized to a region of the first short open reading frame encoding a tripeptide-MKG (PMID:12089359)
• finding that normal pituitary tissue and pituitary adenomas expressed 5’-deiodinase activity implies that both enzymes are active in tumors and local deiodination is important for function and feedback regulation of anterior pituitary (PMID:12153750)
• Ubc6p and Ubc7p are required for normal and substrate-induced ubiquitination and proteolysis of D2 (PMID:12198238)
• 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)
• transcription factor Pax-8 could be involved in the upregulation of DIO2 expression in the thyroid of Graves’ patients (PMID:12699588)
• Nkx-2.5 and GATA-4 play prime roles in Dio2 gene regulation in the human heart and suggests that it is their synergistic action in humans that causes the differential expression of the cardiac Dio2 gene between humans and rats. (PMID:12775767)
• D2 contains a glycoside hydrolase clan GH-A-like structure (PMID:12847093)
• In endoplasmic reticulum, degradation proceeds via an association with UBC7. (PMID:12933904)
• 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)
• Variation in the DIO2 gene may affect the availability Triiodothyronine and a iodine deficiency that may partly determin and overall risk of mental retardation in china. (PMID:15286152)
• characterisation of the CRE/TATA box unit of type 2 deiodinase gene promoter in a human choriocarcinoma cell line (PMID:15291742)
• We hypothesize that this might be explained by the decline in skeletal muscle size during aging, resulting in a relative decrease in the contribution of D2 to serum T(3) production. (PMID:15727947)
• DIO1 and DIO2 were underexpressed in nearly all papillary thyroid carcinomas (PMID:15785240)
• Single nucleotide polymorphism is associated with greater insulin resistance in type 2 diabetes mellitus patients and with lower D2 velocity in tissue samples. (PMID:15797963)
• Results suggest that impairment of type 2 iodothyronine deiodinase-generated triiodothyronine (T3) is the major cause of the reduced T3 production in the euthyroid sick syndrome. (PMID:16127464)
• analysis of the pretranslational regulation of D2 [review] (PMID:16131328)
• D2 expression is increased by BPS and suppressed by PDGF in hCASMCs, and that intracellular thyroid hormone activation may be involved in the suppression of DNA synthesis and migration activity of hCASMCs. (PMID:16140305)
• results indicate that inflammatory signals regulate iodothyronine deiodinase type II expression predominantly via the nuclear factor-kappa B pathway in a direct transcriptional manner (PMID:16728495)
• analysis of a human type-2 deiodinase polymorphism (PMID:16889485)
• the instability loop in D2, but not its subcellular localization, is the key determinant of D2 susceptibility to ubiquitination and rapid turnover rate (PMID:16928685)
• DIO2 variants were not associated with serum thyroid parameters in the elderly (PMID:17105838)
• The Ala92 allele of the type 2 iodothyronine deiodinase increases risk for the development of hypertension. (PMID:17224473)
• Increased thyroidal D2 activity in the thyroid gland is responsible for the higher serum-free levels in patients with defective thyroglobin transport. (PMID:17244789)
• there is no association of the DIO2 A/G polymorphism with diabetes intermediate trait levels or DM2 risk (PMID:17381351)
• Ubiquitination can also regulate proteins by transiently inactivating enzymatic function through conformational change in a dimeric enzyme, which can be reversed upon deubiquitination. (PMID:17452445)
• reduced D2 activity does not play a role in the pathogenesis of the low triiodothyronine syndrome of critical illness (PMID:17504898)
• EGF modulates transcription of human type II deiodinase gene (Dio2) through distinct signaling pathways, leading to the assembly of a heterogeneous transcription factor complex (PMID:17991726)
• D2 Thr92Ala polymorphism seems to predict the need for higher T4 intake in thyroidectomized patients. (PMID:18073314)
• There is a combined effect of DIO2 T92A and PPARgamma2 P12A polymorphisms on insulin resistance-related features in non-diabetic whites. (PMID:18198294)
• Results indicate a new susceptibility gene (DIO2) conferring risk to osteoarthritis. (PMID:18334578)
• The role of type 1 and type 2 5’-deiodinase in the pathophysiology of the 3,5,3’-triiodothyronine toxicosis of McCune-Albright syndrome. (PMID:18349068)
• D2 is highly expressed in human medullary thyroid carcinoma (PMID:18514391)
• The D2-Thr92Ala polymorphism is not associated with blood thyroid hormone levels. (PMID:19018782)
• The D2-Thr92Ala, D2-ORFa-Gly3Asp and TSHR-Asp727Glu polymorphisms were not associated with blood pressure or the risk of hypertension. (PMID:19178511)
• commonly inherited variation in the DIO2 gene is associated both with impaired baseline psychological well-being on thryoxine and enhanced response to combination triiodothyronine therapy (PMID:19190113)
• Human skeletal muscle D2 mRNA expression is modulated by fasting and insulin, but not by hypothyroidism. (PMID:19293265)
• Genetic variations of type II deiodinase are associated with bipolar disorder in a subset of a Chinese Han population. (PMID:19427350)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dio2	ENSDARG00000094857
mus_musculus	Dio2	ENSMUSG00000007682
rattus_norvegicus	Dio2	ENSRNOG00000062383

Paralogs (2): DIO3 (ENSG00000197406), DIO1 (ENSG00000211452)

Protein

Protein identifiers

Type II iodothyronine deiodinase — Q92813 (reviewed: Q92813)

Alternative names: 5DII, DIOII, Type 2 DI, Type-II 5’-deiodinase

All UniProt accessions (6): A0A024R6J8, Q92813, G3V2A7, G3V3A8, H0YJ42, H0YJQ8

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 3,5,3’-triiodothyronine (T3), 3,3’,5’-triiodothyronine (rT3) to 3,3’-diiodothyronine (3,3’-T2) and 3’,5’-diiodothyronine (3’,5’-T2) to 3’-monoiodothyronine (3’-T1) via outer-ring deiodination (ORD). Catalyzes the phenolic ring deiodinations of 3,3’,5’-triiodothyronamine and 3’,5’- diiodothyronamine.

Subunit / interactions. Predominantly monomer. Can form homodimers but homodimerization is not essential for enzyme activity. Interacts with USP20 and USP33. Interacts with MARCHF6.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Isoform 1 is expressed in the lung, trachea, kidney, heart, skeletal muscle, placenta, fetal brain and several regions of the adult brain. Isoform 2 is expressed in the brain, heart, kidney and trachea.

Post-translational modifications. Ubiquitinated by MARCHF6, leading to its degradation by the proteasome. Deubiquitinated by USP20 and USP33.

Miscellaneous. Has a Sec in positions 90, 169 and 302. Has a Sec in position 37.

Similarity. Belongs to the iodothyronine deiodinase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q92813-1	1, hDII-a	yes
Q92813-2	2, hDII-b
Q92813-3	3, hDII-c

RefSeq proteins (4): NP_000784, NP_001311391, NP_001353425, NP_054644* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000643	Iodothyronine_deiodinase	Family
IPR008261	Iodothyronine_deiodinase_AS	Active_site
IPR036249	Thioredoxin-like_sf	Homologous_superfamily

Pfam: PF00837

Enzyme classification (BRENDA):

• EC 1.21.99.4 — thyroxine 5’-deiodinase (BRENDA: 17 organisms, 66 substrates, 73 inhibitors, 76 Km, 3 kcat entries)

Substrate kinetics (BRENDA)

10 substrates with measured Km, best-characterized 10. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
3,3’,5’-TRIIODOTHYRONINE	0.0067–2.7	25
L-THYROXINE	—	20
3,3’,5-TRIIODO-L-THYRONINE SULFATE	0.0015–0.0045	11
REVERSE TRIIODOTHYRONINE	—	5
3,3’,5-TRIIODOTHYRONINE	0.0026–0.005	2
L-3,5’,3’-TRIIODOTHYRONINE	0.003–0.57	2
THYROXINE	—	2
3,3’,5’-TRIIODO-L-THYRONINE	0.02	1
3,5’-DIIODO-L-THYRONINE	0.01	1
SULFATED REVERSE TRIIODOTHYRONINE	0.0007	1

Catalyzed reactions (Rhea), 5 shown:

• 3,3’,5-triiodo-L-thyronine + iodide + A + H(+) = L-thyroxine + AH2 (RHEA:19745)
• 3,3’-diiodo-L-thyronine + iodide + A + H(+) = 3,3’,5’-triiodo-L-thyronine + AH2 (RHEA:82575)
• 3’-iodo-L-thyronine + iodide + A + H(+) = 3’,5’-diiodo-L-thyronine + AH2 (RHEA:82899)
• 3,3’-diiodothyronamine + iodide + A + H(+) = 3,3’,5’-triiodothyronamine + AH2 (RHEA:83795)
• 3’-iodothyronamine + iodide + A + H(+) = 3’,5’-diiodothyronamine + AH2 (RHEA:83803)

UniProt features (17 total): splice variant 4, mutagenesis site 3, topological domain 2, sequence variant 2, non-standard amino acid 2, chain 1, sequence conflict 1, transmembrane region 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q92813 — 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): 133

Mutagenesis-validated functional residues (3):

Position	Phenotype
133	complete loss of enzyme activity towards l-thyroxine.
133	1000-fold increase of km and vmax value for l-thyroxine.
266	no effect on enzyme activity towards l-thyroxine.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-350864	Regulation of thyroid hormone activity
R-HSA-9844594	Transcriptional regulation of brown and beige adipocyte differentiation by EBF2
R-HSA-1266738	Developmental Biology
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
R-HSA-9843743	Transcriptional regulation of brown and beige adipocyte differentiation
R-HSA-9843745	Adipogenesis

MSigDB gene sets: 257 (showing top): ATF_B, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, TSUNODA_CISPLATIN_RESISTANCE_UP, AAGCAAT_MIR137, JAEGER_METASTASIS_DN, AREB6_03, GOBP_MODIFIED_AMINO_ACID_CATABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GCAAGGA_MIR502, GOBP_THYROID_HORMONE_METABOLIC_PROCESS, BRUECKNER_TARGETS_OF_MIRLET7A3_DN, GOBP_TRANSLATION, PAX8_B, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION

GO Biological Process (7): selenocysteine incorporation (GO:0001514), thyroid hormone generation (GO:0006590), response to lipopolysaccharide (GO:0032496), thyroid hormone metabolic process (GO:0042403), thyroid hormone catabolic process (GO:0042404), hormone biosynthetic process (GO:0042446), positive regulation of cold-induced thermogenesis (GO:0120162)

GO Molecular Function (5): thyroxine 5’-deiodinase activity (GO:0004800), selenium binding (GO:0008430), ubiquitin protein ligase binding (GO:0031625), thyroxine 5-deiodinase activity (GO:0033798), oxidoreductase activity (GO:0016491)

GO Cellular Component (5): endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), membrane (GO:0016020), endoplasmic reticulum (GO:0005783), endomembrane system (GO:0012505)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Thyroxine biosynthesis	1
Transcriptional regulation of brown and beige adipocyte differentiation	1
Metabolism of amino acids and derivatives	1
Metabolism of amine-derived hormones	1
Metabolism	1
Adipogenesis	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
thyroid hormone metabolic process	2
hormone metabolic process	2
oxidoreductase activity, acting on X-H and Y-H to form an X-Y bond	2
cellular anatomical structure	2
translational readthrough	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	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
hormone catabolic process	1
biosynthetic process	1
positive regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
small molecule binding	1
ubiquitin-like protein ligase binding	1
catalytic activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

1226 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DIO2	SECISBP2	Q96T21	916
DIO2	SLC16A2	P36021	894
DIO2	TRH	P20396	846
DIO2	UCP1	P25874	845
DIO2	GPBAR1	Q8TDU6	834
DIO2	CIDEA	O60543	808
DIO2	SLCO1C1	Q9NYB5	794
DIO2	TSHB	P01222	787
DIO2	TSHR	P16473	781
DIO2	PRDM16	Q9HAZ2	778
DIO2	THRB	P10828	774
DIO2	TG	P01266	748
DIO2	PPARGC1A	Q9UBK2	733
DIO2	ELOVL3	Q9HB03	722
DIO2	TXNRD2	Q9NNW7	691

IntAct

0 interactions, top by confidence:

BioGRID (29): DIO2 (Biochemical Activity), DIO2 (Affinity Capture-RNA), USP33 (Reconstituted Complex), DIO2 (Affinity Capture-Western), DIO2 (Affinity Capture-Western), TOMM22 (Co-fractionation), DIO2 (Co-fractionation), USP33 (Two-hybrid), DIO2 (Affinity Capture-Western), DIO2 (FRET), UBE2G1 (FRET), WSB1 (FRET), USP33 (FRET), TCEB2 (Affinity Capture-Western), CUL5 (Affinity Capture-Western)

ESM2 similar proteins: A4GT88, A7YD35, O02734, O14349, O42411, O42412, O42449, O95822, P09543, P12617, P13233, P13807, P13834, P24389, P49894, P49895, P49896, P49897, P49898, P49899, P51639, P54310, P55073, P70551, P79747, P97564, Q07071, Q0P4Y1, Q2QEI3, Q5I3B1, Q5I3B2, Q5R9H0, Q5RFD0, Q61153, Q6DN07, Q6QN11, Q6QN12, Q6QN13, Q6U6H1, Q6V915

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

9 interactions.

A	Effect	B	Mechanism
DIO2	“up-regulates quantity by expression”	MYOD1	“transcriptional regulation”
DIO2	“down-regulates quantity”	L-thyroxine	“chemical modification”
DIO2	“up-regulates quantity”	iodide	“chemical modification”
“3’,5’-cyclic AMP”	“up-regulates quantity by expression”	DIO2
UBE2J1	“down-regulates quantity by destabilization”	DIO2	ubiquitination
UBE2G2	“down-regulates quantity by destabilization”	DIO2	ubiquitination
FOXO3	“up-regulates quantity by expression”	DIO2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	21
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

457 predictions. Top by Δscore:

Variant	Effect	Δscore
14:80211247:TCA:T	donor_loss	1.0000
14:80211248:CACCT:C	donor_loss	1.0000
14:80211249:A:AC	donor_gain	1.0000
14:80211249:A:AT	donor_loss	1.0000
14:80211250:C:CC	donor_gain	1.0000
14:80211250:CCT:C	donor_gain	0.9900
14:80211250:CCTG:C	donor_gain	0.9900
14:80211250:CCTGT:C	donor_gain	0.9900
14:80203287:ACC:A	acceptor_loss	0.9800
14:80203288:CCTGA:C	acceptor_loss	0.9800
14:80203289:C:CA	acceptor_loss	0.9800
14:80203289:C:CC	acceptor_gain	0.9800
14:80203290:T:A	acceptor_loss	0.9800
14:80203293:CGG:C	acceptor_gain	0.9800
14:80203294:G:T	acceptor_gain	0.9800
14:80203295:G:C	acceptor_gain	0.9800
14:80203295:G:GC	acceptor_gain	0.9800
14:80211249:AC:A	donor_gain	0.9800
14:80211250:CC:C	donor_gain	0.9800
14:80203284:TTCAC:T	acceptor_gain	0.9700
14:80203285:TCAC:T	acceptor_gain	0.9700
14:80203286:CAC:C	acceptor_gain	0.9700
14:80203286:CACC:C	acceptor_gain	0.9700
14:80203287:AC:A	acceptor_gain	0.9700
14:80203288:CC:C	acceptor_gain	0.9700
14:80208806:TGAAG:T	donor_gain	0.9700
14:80211240:G:C	donor_gain	0.9600
14:80202327:C:A	donor_gain	0.9500
14:80206493:T:TA	donor_gain	0.9500
14:80199418:CCAA:C	acceptor_gain	0.9400

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000006287 (14:80231295 C>G), RS1000071624 (14:80218153 A>G), RS1000093203 (14:80204520 C>G), RS1000119649 (14:80221820 G>A), RS1000316799 (14:80210795 T>C), RS1000375757 (14:80215301 A>G), RS1000404287 (14:80222080 C>A), RS1000455005 (14:80223664 C>T), RS1000675537 (14:80228500 C>T), RS1000713327 (14:80216227 G>A,C), RS1000728637 (14:80224076 C>A,T), RS1000746489 (14:80215126 C>T), RS1001021224 (14:80229525 C>A,T), RS1001057751 (14:80209565 A>T), RS1001160489 (14:80202276 T>A,C)

Disease associations

OMIM: gene MIM:601413 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005352_26	Paclitaxel disposition in epithelial ovarian cancer	5.000000e-06
GCST005790_31	Rosacea symptom severity	4.000000e-09
GCST006896_12	Free thyroxine concentration	5.000000e-17
GCST009391_887	Metabolite levels	8.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009180	rosacea severity measurement
EFO:0010439	triacylglycerol 58:12 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3542431 (PROTEIN FAMILY)

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs225014	DIO2		0.00	0
rs12885300	DIO2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Thyroid hormone turnover

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Thyroxine	decreases activity, decreases expression, decreases reaction, increases chemical synthesis, increases metabolic processing (+1 more)	5
Estradiol	affects cotreatment, decreases expression, increases expression	4
bisphenol A	decreases expression, increases methylation, affects cotreatment, increases expression	3
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression, affects cotreatment, increases reaction, decreases activity, decreases reaction (+2 more)	3
Triiodothyronine	increases reaction, decreases reaction, increases chemical synthesis, increases metabolic processing, affects abundance (+3 more)	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	3
Particulate Matter	increases abundance, increases expression, decreases expression	3
decabromobiphenyl ether	increases ubiquitination, decreases reaction, increases degradation, increases reaction, decreases expression (+4 more)	2
sodium arsenite	decreases expression	2
xanthohumol	decreases activity, affects metabolic processing	2
2,2’,4,4’,5-brominated diphenyl ether	decreases reaction, increases chemical synthesis, increases metabolic processing, decreases activity, increases degradation (+3 more)	2
Resveratrol	affects cotreatment, decreases expression, decreases activity	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Cycloheximide	decreases activity, decreases reaction, affects cotreatment, increases reaction	2
Lipopolysaccharides	increases expression, increases reaction, increases activity, affects response to substance, affects cotreatment (+1 more)	2
Progesterone	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
Medroxyprogesterone Acetate	affects cotreatment, decreases expression	2
bisphenol F	increases expression, affects cotreatment	1
4,5-dichloro-1,2-dithiol-3-one	decreases activity	1
sotorasib	affects cotreatment, increases expression	1
captafol	decreases activity	1
tetrachloroisophthalonitrile	decreases activity	1
kaempferol	increases expression, increases abundance, increases activity, increases reaction	1
chrysophenine	decreases activity	1
dichlone	decreases activity	1
dinocap	decreases activity	1
sodium arsenate	decreases expression, increases abundance	1
dodecyldimethylamine oxide	decreases expression	1
hexachlorocyclopentadiene	decreases activity	1

Clinical trials (associated diseases)

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