DIO3 (Iodothyronine Deiodinase 3): The Thyroid Hormone Inactivator
DIO3 encodes the type III iodothyronine deiodinase, a key enzyme that inactivates thyroid hormones, playing a critical role in development, metabolism, and cancer biology.
Gene Information Card
| Symbol | DIO3 |
|---|---|
| Full Name | Iodothyronine Deiodinase 3 |
| Gene Type | Protein coding |
| Chromosomal Location | 14q32.31 |
| NCBI Gene ID | 1735 ncbi.nlm.nih.gov/gene/1735 |
| Ensembl ID | ENSG00000145386 |
| UniProt ID | P55073 |
| OMIM ID | 601038 |
| HGNC ID | 2885 |
| Aliases | DIOIII, D3, TXDI3 |
Description
The DIO3 gene encodes the type III iodothyronine deiodinase (D3), a selenoenzyme that catalyzes the inner-ring deiodination of thyroid hormones. This activity inactivates thyroxine (T4) and triiodothyronine (T3), converting them to reverse T3 (rT3) and 3,3'-diiodothyronine (T2), respectively. DIO3 is highly expressed in fetal tissues, the placenta, and the central nervous system, where it protects developing tissues from excess thyroid hormone. Its expression is tightly regulated and often reactivated in pathological conditions, including cancer, where it can influence cell proliferation and differentiation.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Consumptive Hypothyroidism | Overexpression of DIO3 in large tumors (e.g., hemangiomas, gastrointestinal stromal tumors) leads to excessive degradation of T4 and T3, causing systemic hypothyroidism that is resistant to standard thyroid hormone replacement. | Case reports and clinical studies (PMID: 10946802, 11095477) |
| Hepatocellular Carcinoma (HCC) | DIO3 is re-expressed in HCC tissues, promoting tumor cell proliferation and inhibiting apoptosis. Its expression is associated with poor prognosis and aggressive tumor features. | Expression studies and functional assays (PMID: 21852291, 28925390) |
| Basal Cell Carcinoma (BCC) | DIO3 expression is upregulated in BCC, contributing to the inactivation of thyroid hormones within the tumor microenvironment, which may promote tumor growth and inhibit differentiation. | Gene expression profiling and immunohistochemistry (PMID: 21447717) |
| Proliferative Diabetic Retinopathy | DIO3 is expressed in epiretinal membranes of patients with proliferative diabetic retinopathy, suggesting a role in the local regulation of thyroid hormone levels and angiogenesis. | Expression analysis in surgical specimens (PMID: 21310888) |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Placenta | High | High |
| Fetal Brain | High | High |
| Adult Brain | Low | Low |
| Liver | Not detected | Not detected |
| Kidney | Not detected | Not detected |
| Thyroid | Not detected | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 (Liver cancer) | Low | Re-expressed in some HCC cell lines |
| MCF7 (Breast cancer) | Low | Expression can be induced by hypoxia |
| A549 (Lung cancer) | Low | Expression varies with cellular context |
| SH-SY5Y (Neuroblastoma) | Moderate | Expressed in neuronal cells |
| HUVEC (Endothelial) | Low | Expression may be induced by angiogenic factors |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.278C>T (p.Pro93Leu) | Missense | Rare | Reported in a patient with severe hypothyroidism; reduced enzyme activity in vitro. |
| c.662G>A (p.Arg221His) | Missense | Rare | Identified in a patient with atypical thyroid function tests; functional impact not fully characterized. |
| c.1048C>T (p.Arg350Ter) | Nonsense | Rare | Predicted to result in a truncated, non-functional protein; associated with severe DIO3 deficiency. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in DIO3 are rare and can lead to elevated levels of active thyroid hormones (T3) during development, potentially causing thyrotoxicosis-like effects. However, the clinical phenotype is highly variable and not fully defined.
Gain of Function (GOF)
Gain-of-function is primarily observed at the transcriptional level through gene amplification or promoter activation in cancers. This leads to increased D3 enzyme activity, which inactivates thyroid hormones locally, promoting tumor growth and inhibiting differentiation.
Dominant Negative (DN)
No dominant-negative mutations have been described for DIO3. The enzyme functions as a homodimer, but the clinical significance of dominant-negative effects is not established.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Thyroid hormone synthesis and metabolism
• Selenium metabolism and selenoprotein synthesis
• HIF-1-alpha transcription factor network (in cancer)
Protein Summary
The DIO3 protein is a 278-amino-acid, integral membrane selenoenzyme localized to the endoplasmic reticulum and plasma membrane. It contains a selenocysteine residue at its active site, which is essential for its catalytic activity. D3 catalyzes the inner-ring deiodination of thyroid hormones, inactivating T4 and T3. It plays a critical role in regulating local and systemic thyroid hormone levels, particularly during development and in the adult brain. Its expression is tightly regulated by developmental cues, hormones, and cellular stress, and its aberrant expression is implicated in several cancers.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| DIO3 Knockout HEK293 Cell Line | EDJ-KQ4446 | Human | 1735 | Details Get a Quote |
| DIO3 Knockout HeLa Cell Line | EDJ-KQ53092 | Human | 1735 | Details Get a Quote |
| DIO3 Knockout A-549 Cell Line | EDJ-KQ61559 | Human | 1735 | Details Get a Quote |
| DIO3 Knockout HCT 116 Cell Line | EDJ-KQ70051 | Human | 1735 | Details Get a Quote |
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