Alternative titles; symbols
HGNC Approved Gene Symbol: DUOX2
Cytogenetic location: 15q21.1 Genomic coordinates (GRCh38) : 15:45,092,650-45,114,172 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q21.1 | Thyroid dyshormonogenesis 6 | 607200 | Autosomal recessive | 3 |
The synthesis of thyroid hormone is catalyzed by a protein complex located at the apical membrane of thyroid follicular cells. Contained within this complex is an iodide transporter (605646), thyroperoxidase (TPO; 274500), and a peroxide-generating system that includes DUOX1 (606758) and DUOX2 (De Deken et al., 2000).
Using a probe for a leukocyte NADPH oxidase, De Deken et al. (2000) cloned a DUOX2 cDNA from a primary human thyroid cell cDNA library. The deduced 1,548-amino acid protein has a calculated molecular mass of 177 kD. It contains several domains characteristic of flavoproteins including NADPH- and FAD-binding domains, and 4 specific histidines and a conserved arginine predicted to bind a heme prosthetic group. DUOX2 also contains 2 EF-hand motifs, 4 putative N-glycosylation sites, and 7 hydrophobic stretches. It shares 83% and 47% sequence similarity with DUOX1 and gp91-phox (300481), respectively, and significant similarity to other NADPH oxidases. DUOX1 and DUOX2 share 53% and 61% sequence similarity, respectively, with a predicted protein in C. elegans. Northern blot analysis detected a 6.4-kb DUOX2 transcript in cultured human thymocytes. Immunolocalization studies demonstrated that DUOX2 colocalizes with thyroperoxidase at the supranuclear apical pole of all thyroid cells.
De Deken et al. (2000) demonstrated upregulated expression of DUOX1 and DUOX2 mRNA in cultured human thymocytes stimulated with cAMP agonists. In a study of thyroid carcinomas, Lacroix et al. (2001) showed that levels of DUOX1 and DUOX2 were maintained in parallel and were more frequently seen in neoplastic tissues expressing other thyroid differentiation markers.
Caillou et al. (2001) investigated the gene and protein expression of DUOX1 and DUOX2 in normal and pathologic human thyroid tissues using real-time kinetic quantitative PCR and antipeptide antibodies, respectively. In normal tissue, DUOX1 and DUOX2 localized at the apical pole of thyrocytes. Immunostaining for DUOX1 and DUOX2 was heterogeneous, inside a given follicle, with 40 to 60% of positive follicular cells. Among normal and pathologic tissues, variations of DUOX1 and DUOX2 mRNA levels were parallel, suggesting a similar regulation of both gene expressions. The authors concluded that DUOX proteins are apical glycoproteins with a regulation of expression that differs from that of other thyroid markers. Because DUOX1 and DUOX2 are not absolutely thyroid-specific, and because they constitute a novel family of long homologs of the NOX flavoproteins and were predicted to form a part of NADPH:O(2)-oxidoreductase systems, Caillou et al. (2001) referred to the DUOX proteins as LNOX (for 'long NOX') 1 and 2.
DUOX2 is a component of the thyroid H2O2 generator crucial for hormone synthesis at the apical membrane. By transfection in HeLa cells, Grasberger and Refetoff (2006) found that coexpression of DUOX2 and DUOXA2 (612772), but not expression of DUOX2 alone, was required for plasma membrane localization of DUOX2 and H2O2 generation. H2O2 release triggered by DUOX2/DUOXA2 cotransfection was completely blocked by the flavoprotein inhibitor DPI.
Niethammer et al. (2009) probed the role of hydrogen peroxide (H2O2) during the early events of wound responses in zebrafish larvae expressing the genetically encoded H2O2 sensor. This reporter revealed a sustained rise in H2O2 concentration at the wound margin, starting approximately 3 minutes after wounding and peaking at approximately 20 minutes, which extended 100 to 200 microns into the tail fin epithelium as a decreasing concentration gradient. Using pharmacologic and genetic inhibition, they showed that this gradient is created by dual oxidase (Duox1, 606758 and Duox2) and that it is required for rapid requirement of leukocytes to the wound. Niethammer et al. (2009) concluded that this was the first observation of a tissue-scale H2O2 pattern, and the first evidence that H2O2 signals to leukocytes in tissues, in addition to its known antiseptic role.
By FISH, Dupuy et al. (1999) mapped the DUOX2 gene to chromosome 15q15. By radiation hybrid analysis, De Deken et al. (2000) colocalized the DUOX2 and DUOX1 genes on 15q15.3.
Moreno et al. (2002) studied the thyroid oxidase system in 9 patients with idiopathic congenital hypothyroidism (1 with permanent and 8 with transient hypothyroidism) and an iodide organification defect (607200) who had been identified by the screening program for congenital hypothyroidism. The DNA of the patients and their relatives was analyzed for mutations in the genes for DUOX1 and DUOX2. One patient with permanent and severe thyroid hormone deficiency and a complete iodide organification defect had a homozygous nonsense mutation (606759.0001) in the DUOX2 gene that eliminated all functional domains of the protein. Three of the 8 patients with mild transient congenital hypothyroidism and a partial iodide organification defect had heterozygous mutations in the DUOX2 gene that prematurely terminated the protein, thus abolishing its functional domains. Moreno et al. (2002) observed that monoallelic mutations, associated with mild, transient hypothyroidism, resulted in insufficient thyroid production of hydrogen peroxide, which prevented the synthesis of sufficiently large quantities of thyroid hormones required at the beginning of life.
Grasberger and Refetoff (2006) found that the DUOX/DUOXA arrangement is highly conserved. The bidirectional association of Duox and Duoxa emerged before the divergence of echinoderms. Teleosts have single copies of the Duox and Duoxa genes, and these underwent tandem duplication to an inverted repeat (Duox2/Duoxa2/Duoxa1 (612771)/Duox1) in vertebrates before the amphibian divergence.
In a patient with congenital hypothyroidism (TDH6; 607200) detected in neonatal screening, Moreno et al. (2002) discovered homozygosity for a 1300C-T transition in the DUOX2 gene, resulting in an arg434-to-ter (R434X) mutation that truncated the protein. The patient had thyroxine levels below the limit of detection and very high thyrotropin levels. Subsequent diagnostic procedures showed a properly located gland with a high uptake of iodine-123 and complete discharge of iodide in the perchlorate test. The patient required continued thyroid hormone therapy. The patient was the product of a consanguineous marriage. The father, mother, and brother were heterozygous for the mutation and had normal thyroid function.
In a patient with congenital hypothyroidism (TDH6; 607200) detected in newborn screening and showing mildly decreased thyroxine and elevated thyrotropin levels, Moreno et al. (2002) identified a 2056C-T transition resulting in a gln686-to-ter (Q686X) mutation. After several adjustments in dosage, the patient was given very low doses of thyroxine, and after the age of 3 years therapy was stopped for diagnostic purposes. The patient remained euthyroid during the follow-up of 12 months. Whereas a patient with permanent hypothyroidism was homozygous for a DUOX2 mutation (606759.0001), the patient with the 2056C-T mutant DUOX2 allele was heterozygous, as was the father; the mother was homozygous wildtype.
In 2 brothers with congenital hypothyroidism (TDH6; 607200), Vigone et al. (2005) identified compound heterozygosity for a 2524C-T transition in exon 18 of the DUOX2 gene, resulting in an arg842-to-ter (R842X) substitution, and a 1126C-T transition in exon 9 of the DUOX2 gene, resulting in an arg376-to-trp (R376W) substitution (606759.0004). The euthyroid parents were heterozygotes, the mother for R842X and the father for R376W.
For discussion of the arg376-to-trp (R376W) mutation in the DUOX2 gene that was found in compound heterozygous state in patients with congenital hypothyroidism (TDH6; 607200) by Vigone et al. (2005), see 606759.0003.
Caillou, B., Dupuy, C., Lacroix, L., Nocera, M., Talbot, M., Ohayon, R., Deme, D., Bidart, J.-M., Schlumberger, M., Virion, A. Expression of reduced nicotinamide adenine dinucleotide phosphate oxidase (ThoX, LNOX, Duox) genes and proteins in human thyroid tissues. J. Clin. Endocr. Metab. 86: 3351-3358, 2001. [PubMed: 11443211] [Full Text: https://doi.org/10.1210/jcem.86.7.7646]
De Deken, X., Wang, D., Many, M.-C., Costagliola, S., Libert, F., Vassart, G., Dumont, J. E., Miot, F. Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family. J. Biol. Chem. 275: 23227-23233, 2000. [PubMed: 10806195] [Full Text: https://doi.org/10.1074/jbc.M000916200]
Dupuy, C., Ohayon, R., Valent, A., Noel-Hudson, M.-S., Deme, D., Virion, A. Purification of a novel flavoprotein involved in the thyroid NADPH oxidase: cloning of the porcine and human cDNAs. J. Biol. Chem. 274: 37265-37269, 1999. [PubMed: 10601291] [Full Text: https://doi.org/10.1074/jbc.274.52.37265]
Grasberger, H., Refetoff, S. Identification of the maturation factor for dual oxidase: evolution of an eukaryotic operon equivalent. J. Biol. Chem. 281: 18269-18272, 2006. [PubMed: 16651268] [Full Text: https://doi.org/10.1074/jbc.C600095200]
Lacroix, L., Nocera, M., Mian, C., Caillou, B., Virion, A., Dupuy, C., Filetti, S., Bidart, J. M., Schlumberger, M. Expression of nicotinamide adenine dinucleotide phosphate oxidase flavoprotein DUOX genes and proteins in human papillary and follicular thyroid carcinomas. Thyroid 11: 1017-1023, 2001. [PubMed: 11762710] [Full Text: https://doi.org/10.1089/105072501753271699]
Moreno, J. C., Bikker, H., Kempers, M. J. E., van Trotsenburg, A. S. P., Baas, F., de Vijlder, J. J. M., Vulsma, T., Ris-Stalpers, C. Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. New Eng. J. Med. 347: 95-102, 2002. [PubMed: 12110737] [Full Text: https://doi.org/10.1056/NEJMoa012752]
Niethammer, P., Grabher, C., Look, A. T., Mitchison, T. J. A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature 459: 996-999, 2009. [PubMed: 19494811] [Full Text: https://doi.org/10.1038/nature08119]
Vigone, M. C., Fugazzola, L., Zamproni, I., Passoni, A., Di Candia, S., Chiumello, G., Persani, L., Weber, G. Persistent mild hypothyroidism associated with novel sequence variants of the DUOX2 gene in two siblings. Hum. Mutat. 26: 395, 2005. Note: Electronic Article. [PubMed: 16134168] [Full Text: https://doi.org/10.1002/humu.9372]