DIO1

Summary

DIO1 (iodothyronine deiodinase 1, HGNC:2883) is a protein-coding gene on chromosome 1p32.3, encoding Type I iodothyronine deiodinase (P49895). 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 activation, as well as the inactivation of thyroid hormone by outer and inner ring deiodination, respectively. The activation reaction involves the conversion of the prohormone thyroxine (3,5,3’,5’-tetraiodothyronine, T4), secreted by the thyroid gland, to the bioactive thyroid hormone (3,5,3’-triiodothyronine, T3) by 5’-deiodination. This protein provides most of the circulating T3, which is essential for growth, differentiation and basal metabolism in vertebrates. This protein is a selenoprotein, containing the rare amino acid selenocysteine (Sec) 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. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 1733 — RefSeq curated summary.

At a glance

• Gene–disease (curated): thyroid hormone metabolism, abnormal, 2 (Moderate, GenCC)
• Clinical variants (ClinVar): 33 total — 2 pathogenic
• Phenotypes (HPO): 4
• Druggable target: yes
• MANE Select transcript: NM_000792

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2883
Approved symbol	DIO1
Name	iodothyronine deiodinase 1
Location	1p32.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000211452
Ensembl biotype	protein_coding
OMIM	147892
Entrez	1733

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 7 protein_coding, 5 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000322679, ENST00000361921, ENST00000388876, ENST00000524406, ENST00000525044, ENST00000525202, ENST00000526329, ENST00000527060, ENST00000528946, ENST00000529329, ENST00000529589, ENST00000530084, ENST00000532493, ENST00000534069

RefSeq mRNA: 5 — MANE Select: NM_000792 NM_000792, NM_001039715, NM_001039716, NM_001324316, NM_213593

CCDS: CCDS30722, CCDS41339, CCDS41340, CCDS53320, CCDS81328

Canonical transcript exons

ENST00000361921 — 4 exons

Exon	Start	End
ENSE00001434650	53909931	53911086
ENSE00002144768	53894187	53894547
ENSE00003531248	53904666	53904809
ENSE00003786550	53906095	53906294

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 96.33.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4454 / max 82.9550, expressed in 59 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2931	0.4454	59

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of thyroid gland	UBERON:0001119	96.33	gold quality
nephron tubule	UBERON:0001231	95.63	gold quality
liver	UBERON:0002107	95.61	gold quality
left lobe of thyroid gland	UBERON:0001120	95.35	gold quality
thyroid gland	UBERON:0002046	94.89	gold quality
right lobe of liver	UBERON:0001114	94.63	gold quality
kidney epithelium	UBERON:0004819	93.64	gold quality
renal glomerulus	UBERON:0000074	91.95	gold quality
adult organism	UBERON:0007023	91.39	gold quality
metanephric glomerulus	UBERON:0004736	90.66	gold quality
adult mammalian kidney	UBERON:0000082	90.62	gold quality
kidney	UBERON:0002113	85.90	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.08	gold quality
cortex of kidney	UBERON:0001225	82.78	gold quality
metanephros	UBERON:0000081	75.49	gold quality
bronchial epithelial cell	CL:0002328	73.45	gold quality
right uterine tube	UBERON:0001302	72.23	gold quality
renal medulla	UBERON:0000362	69.81	gold quality
epithelium of bronchus	UBERON:0002031	69.69	gold quality
bronchus	UBERON:0002185	68.65	gold quality
metanephros cortex	UBERON:0010533	67.54	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	65.20	gold quality
endometrium epithelium	UBERON:0004811	63.93	gold quality
gall bladder	UBERON:0002110	61.99	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	61.63	gold quality
pancreatic ductal cell	CL:0002079	61.05	silver quality
granulocyte	CL:0000094	59.72	gold quality
stromal cell of endometrium	CL:0002255	59.01	gold quality
monocyte	CL:0000576	58.54	gold quality
mononuclear cell	CL:0000842	58.48	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.42

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXA1, FOXA2, GATA4, HNF4A, IFNG, IL1B, KAT7, KLF9, NCOA1, NCOR1, NCOR2, TNF, USF1

miRNA regulators (miRDB)

72 targeting DIO1, 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-3662	99.99	73.82	5684
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-3975	99.62	65.97	697
HSA-MIR-182-3P	99.57	67.57	825
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-217-5P	99.49	69.93	1419
HSA-MIR-122B-5P	99.46	70.81	1457
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-519D-5P	99.41	69.30	2057

Literature-anchored findings (GeneRIF, showing 40)

• 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)
• 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)
• D1 contains a glycoside hydrolase clan GH-A-like structure (PMID:12847093)
• DIO1 and DIO2 were underexpressed in nearly all papillary thyroid carcinomas (PMID:15785240)
• many factors interact in complex ways to establish D1 levels, contributing to the circulating concentrations of thyroxine (T(4)) and T(3) [review] (PMID:16131326)
• association of D1a-C/T and D1b-A/G polymorphisms with iodothyronine levels in the elderly (PMID:17105838)
• presence of type 1 5’-deiodinase in well-differentiated breast cancer tissue (PMID:17274741)
• 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)
• HNF4alpha regulates thyroid hormone homeostasis through transcriptional regulation of the Dio1 gene with GATA4 and KLF9 (PMID:18426912)
• common genetic variation in DIO1 alters deiodinase function, resulting in an alteration in the balance of circulating free T(3) to free T(4). (PMID:18492748)
• The D1-C785T polymorphism is significantly associated with serum thyroid hormone levels. (PMID:18793344)
• A functional polymorphism in type 1 deiodinase is associated with enhanced potentiation of the antidepressant effect of sertraline by triiodothyronine (PMID:19064291)
• lower enzymatic activity in hemangiomas in relation to healthy liver tissue (PMID:20049650)
• [review] aims at presenting an updated picture of the recent advances made in the biochemical and molecular properties of D1 as well as its role in human physiology (PMID:21415143)
• we report that SNP at the DIO1 variant rs11206244 is associated with lifetime major depression in White females in high-risk cohorts. (PMID:21563302)
• a novel miRNA-mediated regulatory mechanism of Type 1 iodothyronine deiodinase expression in clear cell Renal Cell Carcinoma (PMID:21912701)
• Short interfering RNA-mediated knockdown of FOXA1 decreased the expression of DIO1 mRNA, but knockdown of both FOXA1 and FOXA2 restored it. (PMID:22067325)
• investigation of DIO1 and DIO2 activities in 66 thyroid tissue samples from follicular thyroid adenoma, toxic diffuse goiter, nontoxic multinodular goiter, papillary thyroid carcinoma, and surrounding normal tissues (PMID:22207295)
• D1-C785T polymorphism correlates with the severity of pre-eclampsia (PMID:22339181)
• Data indicate that type 1 deiodinase is subject to catalysis-induced loss of activity. (PMID:22544951)
• a new mechanism of posttranscriptional regulation of DIO1 and show deregulation of DIO1 expression in pituitary adenoma, possibly resulting from disturbed expression of SF2/ASF. (PMID:23462647)
• The pattern of expression and role of triiodothyronine (T3) receptors and type I 5’-deiodinase in breast carcinomas, benign breast diseases, lactational change, and normal breast epithelium. (PMID:24162265)
• [review] Deiodinase type 1 polymorphisms particularly show moderate-to-strong relationships with thyroid hormone parameters, insulin-like growth factor (IGF)1 protein production, and risk for depression. (PMID:24878678)
• Thyroid hormone deiodinases D1, D2, and D3 are differentially expressed in endothelial cells following thyroid hormone exposure. (PMID:25304215)
• Functional variants within the DIO1 gene that affect triiodothyronine (T3) levels seem not to be associated with cognitive functions. (PMID:26866568)
• All these results indicate that the oxidative stress downregulates the conversion of T4 to T3 through DIO1 function in HepG2 cells. (PMID:26947333)
• The DIO1 gene is related to the depression. (PMID:27351946)
• wW observed that the DIO1 rs2235544 SNP modified the association between exposure to some of the organochlorine compounds (OCs) (specifically HCB and PCB153) and maternal thyroid hormone levels. These results strengthen the hypothesis that the deiodinase enzymes play a role in explaining the disruption of thyroid hormones in relation to exposure to OCs. (PMID:28395858)
• Minor variations in iodothyronine deiodinase 1 were associated with decreased well-being in the Korean hypothyroid population, whereas iodothyronine deiodinase 2 and 3 were not. (PMID:28466400)
• results indicated that LXRalpha plays a specific and important role in activation of TH by regulating D1, and that LXRalpha binds to and regulates the hDIO1 promoter, competing with TRbeta on specific sequences within the promoter. (PMID:28617824)
• The expression of DIO1 on mRNA/protein levels in the depressive disorder patients was reduced in comparison to the control subjects. (PMID:29182613)
• data supports the notion that suppressed DIO1 expression and changes in local availability of thyroid hormones might favor a shift from a differentiated to a more proliferation-prone state of cancer tissues and cell lines (PMID:29272308)
• Multivariate linear regression analysis revealed that the DIO1 concentration and FT3 level were not associated with the concentration of serum 8-Isoprostane (PMID:29894998)
• this current study found that the serum DIO-1 concentration was inversely correlated with the concentration of TNF-alpha, which suggests that DIO-1 might inhibit the production of serum TNF-alpha in patients with chronic renal failure (PMID:30152254)
• Our results indicate that increased thyroidal D1 and D2 activities may be responsible for the higher serum FT3/FT4 ratio in patients with huge goitrous Hashimoto’s thyroiditis. (PMID:30737677)
• polymorphisms in DIO1 are associated with aerobic endurance performance (PMID:31250614)
• Human Type 1 Iodothyronine Deiodinase (DIO1) Mutations Cause Abnormal Thyroid Hormone Metabolism. (PMID:32718224)
• Deiodinases, organic anion transporter polypeptide polymorphisms and symptoms of anxiety and depression after ischemic stroke. (PMID:32807452)
• Novel DIO1 Gene Mutation Acting as Phenotype Modifier for Novel Compound Heterozygous TPO Gene Mutations Causing Congenital Hypothyroidism. (PMID:34128397)
• Association between phenols and thyroid hormones: The role of iodothyronine deiodinase genes. (PMID:35964788)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Dio1	ENSMUSG00000034785
rattus_norvegicus	Dio1	ENSRNOG00000061237

Paralogs (2): DIO3 (ENSG00000197406), DIO2 (ENSG00000211448)

Protein

Protein identifiers

Type I iodothyronine deiodinase — P49895 (reviewed: P49895)

Alternative names: 5DI, DIOI, Type 1 DI, Type-I 5’-deiodinase

All UniProt accessions (6): P49895, A0A182DWI2, C6ZRC2, E9PI35, E9PM07, F6RP93

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 deiodination of T4 to 3,3’,5’-triiodothyronine (rT3) via inner-ring deiodination (IRD). Catalyzes the deiodination of T3 to 3,3’-T2, 3,5-diiodothyronine (3,5-T2) to 3- monoiodothyronine (3-T1) and 3,3’-T2 to 3-T1 via IRD. Catalyzes the phenolic ring deiodinations of 3,3’,5’-triiodothyronamine and 3’,5’-diiodothyronamine. Catalyzes the phenolic ring deiodination of 3,3’-diiodothyronamine and tyrosyl ring deiodinations of 3,5,3’-triiodothyronamine and 3,5-diiodothyronamine. Catalyzes the deiodination of L-thyroxine sulfate and 3,3’,5-triiodo-L-thyronine sulfate via IRD and of 3,3’,5’-triiodo-L-thyronine sulfate via ORD.

Subunit / interactions. Predominantly monomer. Can form homodimers but homodimerization is not essential for enzyme activity.

Subcellular location. Cell membrane. Endoplasmic reticulum membrane. Basolateral cell membrane.

Disease relevance. Thyroid hormone metabolism, abnormal, 2 (THMA2) [MIM:619855] An autosomal dominant disorder characterized by slightly increased thyroid-stimulating hormone levels, and elevated serum reverse triiodothyronine (rT3) levels and rT3/T3 ratios. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Deiodination of substrates 3,3’,5’-triiodothyronine, 3,3’,5’-triiodothyronamine and 3’,5’- diiodothyronamine are inhibited by 6n-propyl-2-thiouracil (PTU).

Miscellaneous. The UGA codon in position 83 may either function as a selenocysteine codon or a translation termination codon. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. The UGA codon in position 34 may either function as a selenocysteine codon or a translation termination codon. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. The UGA codon in position 59 may either function as a selenocysteine codon or a translation termination codon. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. The UGA codon in position 59 may either function as a selenocysteine codon or a translation termination codon.

Similarity. Belongs to the iodothyronine deiodinase family.

Isoforms (9)

UniProt ID	Names	Canonical?
P49895-1	1, a	yes
P49895-2	2, b
P49895-3	3, c/f
P49895-4	4, d
P49895-5	5, e
P49895-6	6, k
P49895-7	7, l
P49895-8	8, m
P49895-9	9, s

RefSeq proteins (5): NP_000783, NP_001034804, NP_001034805, NP_001311245, NP_998758 (=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 1.21.99.4 — 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), 12 shown:

• 3,3’,5’-triiodo-L-thyronine + iodide + A + H(+) = L-thyroxine + AH2 (RHEA:18897)
• 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:82571)
• 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:82895)
• 3’-iodo-L-thyronine + iodide + A + H(+) = 3’,5’-diiodo-L-thyronine + AH2 (RHEA:82899)
• 3,3’-diiodo-L-thyronine sulfate + iodide + A + H(+) = 3,3’,5-triiodo-L-thyronine sulfate + AH2 (RHEA:83751)
• 3-iodo-L-thyronine + iodide + A + H(+) = 3,3’-diiodo-L-thyronine + AH2 (RHEA:83783)
• 3,3’-diiodothyronamine + iodide + A + H(+) = 3,3’,5’-triiodothyronamine + AH2 (RHEA:83795)
• 3’-iodothyronamine + iodide + A + H(+) = 3’,5’-diiodothyronamine + AH2 (RHEA:83803)
• 3,3’-diiodothyronamine + iodide + A + H(+) = 3,3’,5-triiodothyronamine + AH2 (RHEA:83811)
• 3-iodothyronamine + iodide + A + H(+) = 3,5-diiodothyronamine + AH2 (RHEA:83823)

UniProt features (21 total): splice variant 13, topological domain 2, sequence variant 2, chain 1, transmembrane region 1, active site 1, non-standard amino acid 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for P49895 — 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): 126

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: 135 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, MODULE_93, MODULE_516, CMYB_01, GOBP_MODIFIED_AMINO_ACID_CATABOLIC_PROCESS, MODULE_445, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_THYROID_HORMONE_METABOLIC_PROCESS, MORF_ZNF10, SMID_BREAST_CANCER_LUMINAL_B_UP, DELYS_THYROID_CANCER_DN, GOBP_HORMONE_BIOSYNTHETIC_PROCESS, MORF_EPHA7, MORF_RAB3A

GO Biological Process (5): amino acid metabolic process (GO:0006520), thyroid hormone generation (GO:0006590), thyroid hormone metabolic process (GO:0042403), thyroid hormone catabolic process (GO:0042404), hormone biosynthetic process (GO:0042446)

GO Molecular Function (4): thyroxine 5’-deiodinase activity (GO:0004800), selenium binding (GO:0008430), thyroxine 5-deiodinase activity (GO:0033798), oxidoreductase activity (GO:0016491)

GO Cellular Component (5): endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), basolateral plasma membrane (GO:0016323), endoplasmic reticulum (GO:0005783), 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
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
primary metabolic 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
hormone catabolic process	1
biosynthetic process	1
small molecule 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
basal plasma membrane	1
plasma membrane region	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

328 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DIO1	SEPHS2	Q99611	860
DIO1	SEPHS1	P49903	822
DIO1	GPX6	P59796	740
DIO1	GPX5	O75715	739
DIO1	GPX2	P18283	738
DIO1	GPX3	P22352	738
DIO1	GPX7	Q96SL4	731
DIO1	GPX8	Q8TED1	727
DIO1	GPBAR1	Q8TDU6	715
DIO1	TRH	P20396	646
DIO1	SERPINA7	P05543	630
DIO1	THRB	P10828	598
DIO1	TSHR	P16473	564
DIO1	SELENOO	Q9BVL4	532
DIO1	SELENOT	P62341	515

IntAct

0 interactions, top by confidence:

BioGRID (1): DIO1 (Negative Genetic)

ESM2 similar proteins: A0A0U1RQE8, F1S5L4, O43010, O77512, P06592, P13233, P14714, P42498, P49895, P55004, P97564, Q07071, Q09305, Q0P464, Q0P4Y1, Q1LYL8, Q2KHV5, Q2KIR7, Q3UW68, Q5BK10, Q5FW57, Q5GJ77, Q5PQT3, Q5RFP0, Q60462, Q61586, Q62240, Q64112, Q6IB77, Q6MZZ7, Q6P5U7, Q6QN13, Q6QR59, Q6V915, Q7L7V1, Q804E1, Q8CBA2, Q8T773, Q8WU03, Q91754

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

7 interactions.

A	Effect	B	Mechanism
DIO1	“down-regulates quantity”	L-thyroxine	“chemical modification”
DIO1	“up-regulates quantity”	3,3’,5’-triiodothyronine	“chemical modification”
DIO1	“up-regulates quantity”	iodide	“chemical modification”
6-propyl-2-thiouracil	“down-regulates activity”	DIO1	“chemical inhibition”
TNF	“down-regulates quantity by repression”	DIO1	“transcriptional regulation”
IL1B	“down-regulates quantity by repression”	DIO1	“transcriptional regulation”
IFNG	“down-regulates quantity by repression”	DIO1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	24
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1686838	NM_000792.7(DIO1):c.282C>A (p.Asn94Lys)	Pathogenic
1686839	NM_000792.7(DIO1):c.603G>A (p.Met201Ile)	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000023199 (1:53899934 G>A), RS1000099611 (1:53901246 G>C), RS1000674210 (1:53911220 T>C), RS1000811227 (1:53907098 C>G), RS1000845038 (1:53904252 C>G), RS1000863398 (1:53903961 T>C), RS1001165203 (1:53892557 A>G), RS1001216176 (1:53892341 C>A), RS1001314615 (1:53898809 G>T), RS1001388063 (1:53900249 C>G), RS1001514569 (1:53893126 G>A), RS1001807159 (1:53898609 G>A), RS1001852838 (1:53903513 C>T), RS1001905845 (1:53905530 C>G,T), RS1001962891 (1:53909586 T>C)

Disease associations

OMIM: gene MIM:147892 | disease phenotypes: MIM:619855

GenCC curated gene-disease

Disease	Classification	Inheritance
thyroid hormone metabolism, abnormal, 2	Moderate	Autosomal dominant

Mondo (1): thyroid hormone metabolism, abnormal, 2 (MONDO:0030839)

Orphanet (0):

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0003124	Hypercholesterolemia
HP:0034288	Elevated circulating reverse T3 concentration
HP:0034289	Elevated circulating rT3/T3 ratio

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2019 (SINGLE PROTEIN), CHEMBL3542431 (PROTEIN FAMILY)

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2235544	DIO1		0.00	0
rs11206244	DIO1		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Thyroid hormone turnover

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression	5
Propylthiouracil	decreases activity, affects metabolic processing	4
Triiodothyronine	increases chemical synthesis, increases abundance, increases metabolic processing, decreases reaction, increases expression (+2 more)	4
Cyclosporine	decreases expression	4
Aflatoxin B1	decreases expression, decreases methylation, affects expression	4
fipronil	affects cotreatment, increases expression, decreases activity	3
Tetrachlorodibenzodioxin	decreases expression, affects expression	3
captafol	decreases activity	2
tetrachloroisophthalonitrile	decreases activity	2
triflumizol	decreases activity	2
fluazinam	decreases activity	2
zoxamide	decreases activity	2
Aurothioglucose	decreases activity, affects metabolic processing	2
Thyroxine	affects abundance, increases metabolic processing, increases abundance, decreases reaction	2
Triiodothyronine, Reverse	increases metabolic processing, increases abundance, decreases reaction, affects metabolic processing, decreases activity	2
Genistein	decreases activity, affects metabolic processing	2
aristolochic acid I	increases expression	1
6-methyl-2-thiouracil	decreases activity	1
4,5-dichloro-1,2-dithiol-3-one	decreases activity	1
dicrotophos	decreases expression	1
clorophene	decreases activity	1
methyleugenol	decreases expression	1
captax	decreases activity	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	affects expression	1
chrysophenine	decreases activity	1
dichlone	decreases activity	1
dinocap	decreases activity	1
morin	decreases activity	1
decabromobiphenyl ether	increases expression	1

Clinical trials (associated diseases)

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