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DUOX2
dual oxidase 2
The DUOX2 gene provides instructions for the dual oxidase 2 enzyme, which is essential for thyroid hormone synthesis and can be linked to congenital hypothyroidism. The DUOX2 gene encodes dual oxidase 2, an enzyme predominantly found in the thyroid gland where it facilitates the production of hydrogen peroxide.
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, or dual oxidase 2, is crucial for normal thyroid function, particularly in the production of thyroid hormones. Thyroid hormones are vital for regulating growth, brain development, and the body's metabolic rate. The enzyme produced from the DUOX2 gene is primarily active in the thyroid gland, but it is also found in other tissues such as salivary glands, the digestive tract, and airways.
Changes within the DUOX2 gene can impair the function of the dual oxidase 2 enzyme, leading to conditions like congenital hypothyroidism.
What the gene does
The DUOX2 gene is responsible for synthesising the dual oxidase 2 enzyme, a protein that plays a critical role in generating hydrogen peroxide. In the thyroid gland, hydrogen peroxide is a necessary component for the iodination of tyrosine residues on thyroglobulin, a process fundamental to the final steps of thyroid hormone production. This enzyme's activity is therefore directly linked to the body's ability to produce sufficient thyroid hormones.
Beyond the thyroid, dual oxidase 2 also contributes to immune responses and host defence in other tissues. Its ability to produce reactive oxygen species, like hydrogen peroxide, can help fight pathogens in the airways and digestive tract.
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Chromosome location
The DUOX2 gene is situated on chromosome 15, specifically at position 15q21.1. This genomic location helps to categorise and study the gene's role within the broader human genome.
Protein structure
The dual oxidase 2 protein, comprising 1548 amino acids, features several distinct functional regions and domains. It contains a Peroxidase-like region, spanning amino acids 30-596, which is crucial for its peroxidase activity. The protein also includes three EF-hand domains: 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 is found between amino acids 960-1245, alongside a Disordered region from amino acids 971-991. Further, the protein includes a Ferric oxidoreductase domain (amino acids 1084-1266) and a FAD-binding FR-type domain (amino acids 1267-1373), both important for its enzymatic function.
Key variants
Variants in the DUOX2 gene can lead to alterations in the structure or function of the dual oxidase 2 enzyme. These genetic changes can range from subtle alterations in a single amino acid to larger deletions or duplications within the gene. Such variants may result in an abnormally short or non-functional enzyme, affecting its ability to produce hydrogen peroxide and subsequently impacting thyroid hormone synthesis.
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.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.4357C>T | p.Gln1453Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.477del | p.Glu160fs | Pathogenic | ★★☆☆ | Thyroid dyshormonogenesis 6 |
c.618dup | p.Pro207fs | Pathogenic | ★★☆☆ | Congenital hypothyroidism |
c.943G>T | p.Gly315Ter | 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
Pathogenic variants in the DUOX2 gene are primarily associated with Congenital hypothyroidism (dyshormonogenesis). This condition is characterised by a reduced production of thyroid hormones from birth, which can lead to impaired growth and brain development if left untreated. The severity of congenital hypothyroidism can vary depending on the specific DUOX2 variant.
UK clinical status
The DUOX2 gene is included in the NHS Genomic Medicine Service's Green R145 panel for Congenital hypothyroidism, indicating its recognised clinical significance in the UK healthcare system.
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 essential for generating hydrogen peroxide in the thyroid gland. This hydrogen peroxide is a critical component in the production of thyroid hormones.
How do DUOX2 gene variants affect health?
Variants in the DUOX2 gene can lead to a reduced or absent function of the dual oxidase 2 enzyme. This impairment can result in insufficient thyroid hormone production, a condition known as congenital hypothyroidism, which is present from birth.
What is congenital hypothyroidism?
Congenital hypothyroidism is a condition where the thyroid gland does not produce enough thyroid hormones from birth. These hormones are vital for normal growth, brain development, and metabolism, so early diagnosis and treatment are crucial.
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