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DUOX2
dual oxidase 2
The DUOX2 gene provides instructions for the dual oxidase 2 enzyme, which plays a vital role in thyroid hormone synthesis, and variants in this gene are associated with congenital hypothyroidism. DUOX2 encodes an enzyme called dual oxidase 2, primarily active in the thyroid gland where it is essential for producing hydrogen peroxide needed for thyroid hormone formation.
DUOX2 is located on the long (q) arm of chromosome 15, at band 15q21.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The DUOX2 gene, also known as dual oxidase 2, carries the genetic blueprint for an enzyme central to human physiological processes. This enzyme is primarily found in the thyroid gland, a butterfly-shaped organ in the neck, but also in salivary glands, the digestive tract, and airways. Its main function involves the generation of hydrogen peroxide, a critical molecule for various biochemical reactions [PMID:17403039].
Dysfunction of the DUOX2 gene is often linked to congenital hypothyroidism, a condition marked by insufficient thyroid hormone production from birth [PMID:16825490]. Thyroid hormones are essential regulators of growth, brain development, and metabolism throughout the body.
What the gene does
The dual oxidase 2 enzyme, encoded by the DUOX2 gene, is indispensable for the final stages of thyroid hormone synthesis. Within the thyroid gland, this enzyme facilitates the production of hydrogen peroxide. The hydrogen peroxide subsequently enables the completion of thyroid hormone synthesis by participating in the concluding biochemical reactions [PMID:18096688].
Beyond the thyroid, DUOX2 is also expressed in other tissues such as the salivary glands, the gastrointestinal tract, and the respiratory system. Maintaining adequate thyroid hormone levels is crucial for normal growth, neurological development, and regulating the body's metabolic rate.
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Chromosome location
The DUOX2 gene is situated on chromosome 15 at band 15q21.1. This specific location on the long arm of chromosome 15 houses the genetic instructions for the dual oxidase 2 enzyme, which is composed of 1548 amino acids.
Protein structure
The dual oxidase 2 protein, encoded by the DUOX2 gene, has a complex structure comprising several functional domains. It features a Peroxidase-like region, located from amino acids 30-596, which mediates the protein's peroxidase activity. Further along, three distinct EF-hand domains are present: EF-hand 1 (amino acids 819-854), EF-hand 2 (amino acids 855-890), and EF-hand 3 (amino acids 899-934).
An Interaction with TXNDC11 region spans amino acids 960-1245. Within this region, there is also a Disordered region from amino acids 971-991. The protein includes a Ferric oxidoreductase domain (amino acids 1084-1266) and a FAD-binding FR-type domain (amino acids 1267-1373), both critical for its enzymatic function.
Key variants
Variants within the DUOX2 gene can lead to alterations in the structure or function of the dual oxidase 2 enzyme. These genetic changes can range from small alterations in the DNA sequence to larger structural rearrangements. The impact of a specific variant depends on its location and type, potentially affecting the enzyme's ability to produce hydrogen peroxide or its overall stability. Many identified variants result in an abnormally short enzyme or alter critical amino acids, thus impairing its function.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1275T>G | p.Tyr425Ter | Pathogenic | ★★☆☆ | Thyroid dyshormonogenesis 6 |
c.1464del | p.Leu489fs | Pathogenic/Likely pathogenic | ★★☆☆ | Thyroid dyshormonogenesis 6 |
c.1871del | p.Gly624fs | Pathogenic/Likely pathogenic | ★★☆☆ | Thyroid dyshormonogenesis 6 |
c.2109C>A | p.Cys703Ter | Pathogenic/Likely pathogenic | ★★☆☆ | DUOX2-related disorders |
c.3085C>T | p.Gln1029Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Thyroid dyshormonogenesis 6 |
c.316dup | p.Val106fs | Pathogenic/Likely pathogenic | ★★☆☆ | Thyroid dyshormonogenesis 6 |
c.3285_3286del | p.Ile1097fs | Pathogenic | ★★☆☆ | Thyroid dyshormonogenesis 6 |
c.3901C>T | p.Gln1301Ter | Pathogenic/Likely pathogenic | ★★☆☆ | DUOX2-related disorders |
c.4357C>T | p.Gln1453Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.477del | p.Glu160fs | Pathogenic | ★★☆☆ | Thyroid dyshormonogenesis 6 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the DUOX2 gene are primarily associated with inherited conditions affecting thyroid function. The most notable condition is Congenital hypothyroidism (dyshormonogenesis), which is often inherited in an autosomal recessive manner. This condition is characterised by a reduced production of thyroid hormones from birth, which can impact development if not treated early. The inheritance pattern for DUOX2-related conditions can vary.
UK clinical status
The DUOX2 gene is included in the UK NHS Genomic Medicine Service's PanelApp, specifically within the green R145 panel for Congenital hypothyroidism. A 'green' rating indicates that there is strong evidence supporting the gene's association with this condition for diagnostic purposes.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the DUOX2 gene?
The DUOX2 gene provides instructions for creating the dual oxidase 2 enzyme, which is crucial for producing hydrogen peroxide in the thyroid gland. This hydrogen peroxide is essential for the final steps of thyroid hormone synthesis.
Which medical condition is most commonly associated with DUOX2 variants?
Variants in the DUOX2 gene are most commonly associated with congenital hypothyroidism (dyshormonogenesis). This condition is characterised by insufficient thyroid hormone levels from birth, which can affect growth and brain development.
Is DUOX2 relevant to UK clinical testing?
Yes, DUOX2 is listed on the UK NHS Genomic Medicine Service's PanelApp. It is part of the R145 panel for Congenital hypothyroidism, indicating its significance in diagnostic testing for this condition within the UK.
References
- Wang F, Lu K, Yang Z. Genotypes and phenotypes of congenital goitre and hypothyroidism caused by mutations in dual oxidase 2 genes. Clinical endocrinology. 2014. PMID: 24735383
- Jin HY, Heo SH, Kim YM. High frequency of DUOX2 mutations in transient or permanent congenital hypothyroidism with eutopic thyroid glands. Hormone research in paediatrics. 2014. PMID: 25248169
- Varela V, Rivolta CM, Esperante SA. Three mutations (p.Q36H, p.G418fsX482, and g.IVS19-2A>C) in the dual oxidase 2 gene responsible for congenital goiter and iodide organification defect. Clinical chemistry. 2006. PMID: 16322276
- El Hassani RA, Benfares N, Caillou B. Dual oxidase2 is expressed all along the digestive tract. American journal of physiology. Gastrointestinal and liver physiology. 2005. PMID: 15591162
- Forteza R, Salathe M, Miot F. Regulated hydrogen peroxide production by Duox in human airway epithelial cells. American journal of respiratory cell and molecular biology. 2005. PMID: 15677770
- Geiszt M, Witta J, Baffi J. Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2003. PMID: 12824283
- De Deken X, Wang D, Dumont JE. Characterization of ThOX proteins as components of the thyroid H(2)O(2)-generating system. Experimental cell research. 2002. PMID: 11822874