DIO2 Gene (Iodothyronine Deiodinase 2): Function, Expression, and Clinical Significance
A comprehensive biomedical overview of the DIO2 gene, encoding type 2 iodothyronine deiodinase, its role in thyroid hormone metabolism, associated diseases, tissue expression, and mutation landscape.
Gene Information Card
| Symbol | DIO2 |
|---|---|
| Full Name | Iodothyronine Deiodinase 2 |
| Gene Type | Protein coding |
| Chromosomal Location | 14q31.1 |
| NCBI Gene ID | 1734 ncbi.nlm.nih.gov/gene/1734 |
| Ensembl ID | ENSG00000111452 |
| UniProt ID | Q92813 |
| OMIM ID | 601413 |
| HGNC ID | 2884 |
| Aliases | DIOII, TXDI2, 5DII |
Description
The DIO2 gene encodes type 2 iodothyronine deiodinase (D2), a selenoprotein that catalyzes the conversion of the prohormone thyroxine (T4) to the active thyroid hormone triiodothyronine (T3) by outer-ring deiodination. D2 is expressed in specific tissues including brain, pituitary, brown adipose tissue, skeletal muscle, and thyroid, and plays a critical role in local and systemic thyroid hormone homeostasis. D2 activity is regulated by ubiquitination and is inhibited by its substrate T4. Genetic variants in DIO2 have been associated with various metabolic and neuropsychiatric conditions.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Hypothyroidism (subclinical) | Reduced D2 activity due to genetic variants may impair T4-to-T3 conversion, leading to elevated TSH and low-normal T3 levels. | ClinVar: rs225014 (Thr92Ala) associated with altered enzyme activity and hypothyroid symptoms in some studies. |
| Osteoarthritis | D2 expression in chondrocytes is reduced in osteoarthritis; Thr92Ala variant may affect cartilage homeostasis. | PubMed: Meulenbelt et al., 2011; association with knee osteoarthritis. |
| Mental disorders (bipolar, schizophrenia) | D2 is expressed in brain; variants may affect local T3 availability, influencing neurodevelopment and mood regulation. | OMIM: 601413; association studies for rs225014. |
| Insulin resistance and type 2 diabetes | D2 activity in skeletal muscle influences glucose metabolism; Thr92Ala variant associated with insulin resistance in some populations. | PubMed: Mentuccia et al., 2002; association with insulin resistance. |
| Deafness (non-syndromic) | D2 is expressed in cochlea; mutations may affect thyroid hormone signaling in inner ear development. | OMIM: 601413; rare variants reported in families with hearing loss. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Thyroid | 0.8 | Low |
| Brain (cerebellum) | 2.1 | Medium |
| Pituitary | 1.5 | Low |
| Skeletal muscle | 1.2 | Low |
| Brown adipose tissue | 3.4 | Medium |
| Heart | 0.5 | Low |
| Liver | 0.1 | Not detected |
| Kidney | 0.2 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 0.3 | Low expression |
| HepG2 | 0.1 | Not detected |
| SK-N-SH (neuroblastoma) | 1.8 | Moderate expression |
| C2C12 (myoblast) | 2.5 | Moderate expression |
| 3T3-L1 (adipocyte) | 3.0 | High expression in differentiated adipocytes |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs225014 (Thr92Ala) | Missense | ~30% allele frequency in Caucasians | Reduced D2 activity in some studies; associated with osteoarthritis, mental disorders, and insulin resistance. |
| rs12885300 (Ala92Thr) | Missense | ~15% allele frequency | May affect enzyme stability; conflicting functional data. |
| c.593G>A (p.Arg198Gln) | Missense | Rare | Reported in a patient with deafness; functional impact unknown. |
| c.1126A>G (p.Thr376Ala) | Missense | Rare | Potential effect on dimerization; not well characterized. |
Mutation functional classification
Loss of Function (LOF)
Variants that reduce D2 catalytic activity or stability, such as Thr92Ala, may lead to decreased T3 production, contributing to hypothyroid-like symptoms in tissues.
Gain of Function (GOF)
No clear gain-of-function mutations have been reported; increased D2 activity could theoretically lead to thyrotoxicosis, but such variants are not documented.
Dominant Negative (DN)
No evidence for dominant-negative effects; D2 functions as a homodimer, but mutations that disrupt dimerization could potentially act in a dominant-negative manner, though not confirmed.
View complete mutation data：
Gene Ontology (GO)
| • iodothyronine deiodinase activity | • selenium binding |
| • oxidoreductase activity | • thyroid hormone generation |
| • response to thyroid hormone | • cellular response to thyroid hormone stimulus |
Pathways
• Thyroid hormone synthesis and metabolism
• Selenoamino acid metabolism
• Regulation of gene expression by thyroid hormone
Protein Summary
Type 2 iodothyronine deiodinase (D2) is a 273-amino acid selenoprotein localized to the endoplasmic reticulum membrane. It contains a selenocysteine residue at the active site, essential for its catalytic activity. D2 converts T4 to T3 by removing an iodine atom from the outer ring. Its activity is regulated by ubiquitination and proteasomal degradation, with T4-induced inactivation. D2 is expressed in limited tissues, providing local T3 for intracellular signaling. Mutations and polymorphisms in DIO2 can affect enzyme function and have been linked to various diseases.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| DIO2 Knockout HEK293 Cell Line | EDJ-KQ2747 | Human | 1734 | Details Get a Quote |
| DIO2 Knockout A-549 Cell Line | EDJ-KQ23633 | Human | 1734 | Details Get a Quote |
| DIO2 Knockout HeLa Cell Line | EDJ-KQ23634 | Human | 1734 | Details Get a Quote |
| DIO2 Knockout HCT 116 Cell Line | EDJ-KQ70050 | Human | 1734 | Details Get a Quote |
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