Disease relevance of DUOX2

• Mutations in DUOX2 produce congenital hypothyroidism in humans [1].
• We investigated both DUOX1 and DUOX2 gene expressions using quantitative reverse transcription-polymerase chain reaction (RT-PCR) in 47 thyroid carcinomas, including 10 paired normal/tumoral tissues [2].
• Persistent mild hypothyroidism associated with novel sequence variants of the DUOX2 gene in two siblings [3].
• 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 [4].
• Duox2 expression was also elevated by polyinosine-polycytidylic acid (poly(I:C)) and rhinovirus infection [5].

Psychiatry related information on DUOX2

• Our observations suggest that Duox1 and Duox2 are novel H2O2 sources that can support LPO-mediated antimicrobial defense mechanisms on mucosal surfaces [6].

High impact information on DUOX2

• By data mining of a massively parallel signature sequencing tissue expression data base, we identified an uncharacterized gene named DUOX maturation factor (DUOXA2) arranged head-to-head to and co-expressed with DUOX2 [1].
• Dual oxidase 2 (DUOX2), an NADPH:O(2) oxidoreductase flavoprotein, is a component of the thyroid H(2)O(2) generator crucial for hormone synthesis at the apical membrane [1].
• Duox2 (and probably Duox1) is a glycoflavoprotein involved in thyroid hormone biosynthesis, as the thyroid H2O2 generator functionally associated with Tpo (thyroperoxidase) [7].
• Using a spin-trapping technique combined with electron paramagnetic resonance spectroscopy, we confirmed this result but also demonstrated that the partially glycosylated form of Duox2, located in the endoplasmic reticulum, generates superoxide in a calcium-dependent manner [7].
• These results suggest that post-translational modifications during the maturation process of Duox2 could be implicated in the mechanism of H2O2 formation by favoring intramolecular superoxide dismutation [7].

Chemical compound and disease context of DUOX2

• CONCLUSIONS: Biallelic inactivating mutations in the THOX2 gene result in complete disruption of thyroid-hormone synthesis and are associated with severe and permanent congenital hypothyroidism [8].

Biological context of DUOX2

• METHODS: We studied the complete coding sequence of the human DUOX2 gene by single-strand conformational polymorphism (SSCP) analysis of DNA from 17 unrelated patients with iodide organification defects [4].
• Both siblings resulted compound heterozygotes for two novel DUOX2 variants, a nonsense mutation (c.2524C>T, p.Arg842X) and a missense substitution (c.1126C>T, p.Arg376Trp), undetected in 140 control alleles [3].
• Different neonatal iodine supply apparently acted as disease modifier, justifying the discrepant results at TSH screening in the two siblings with same DUOX2 genotype and suggesting that mild dyshormonogenic defects may remain undisclosed in areas characterized by elevated iodine intake [3].
• The function of DUOX2 in thyroid hormonogenesis has been firmly established by linking the congenital hypothyroid phenotype "total iodide organification defect" to biallelic inactivating DUOX2 mutations [9].
• In addition, missense mutations of four cysteines (Cys-351, -370, -568, or -582) completely inhibited the emergence of pig Duox2-Q686X from the ER compartment, indicating their importance in Duox2 maturation [10].

Anatomical context of DUOX2

• We demonstrate that co-expression of DUOXA2, an ER-resident transmembrane protein, allows ER-to-Golgi transition, maturation, and translocation to the plasma membrane of functional DUOX2 in a heterologous system [1].
• DUOX2 mRNA was recently detected by RT-PCR and in-situ hybridization experiments in other tissues, such as rat colon and rat and human epithelial cells from the salivary excretory ducts and rectal glands [11].
• A marked increase in DUOX2 expression was also found during spontaneous differentiation of postconfluent Caco-2 cells [11].
• Epithelial cells in salivary excretory ducts and rectal glands express Duox2, whereas tracheal and bronchial epithelial cells express Duox1 [6].
• We examined Duox1 and Duox2 expression in secretory glands and on mucosal surfaces and give evidence for their presence and activity in salivary glands, rectum, trachea, and bronchium [6].

Associations of DUOX2 with chemical compounds

• CONCLUSIONS: Two previously unknown compound heterozygous mutations in the DUOX2 gene, p.Q36H/p.S965fsX994 and p.G418fsX482/g.IVS19-2A>C, are responsible for iodide organification defects in 2 unrelated families [4].
• Carbohydrate content analysis revealed that complex type-specific Golgi apparatus (GA) oligosaccharides were present on pig Duox2-Q686X, whereas human truncated Duox2 carried only high mannose-type sugar chains characteristic of the ER [10].
• BACKGROUND: Iodide organification defects are associated with mutations in the dual oxidase 2 (DUOX2) gene and are characterized by a positive perchlorate discharge test [4].
• Increasing evidence supports the hypothesis that the dual function NAD(P)H oxidases/peroxidases, Duox1 and Duox2, are important sources of regulated H2O2 production in respiratory tract epithelium [5].
• Differential regulation of dual NADPH oxidases/peroxidases, Duox1 and Duox2, by Th1 and Th2 cytokines in respiratory tract epithelium [5].

Other interactions of DUOX2

• A Ca2+/NADPH-dependent H2O2-generating system was associated with Duox2 protein expression, which had the same biochemical characteristics as the NADPH oxidase in the thyroid [11].

Analytical, diagnostic and therapeutic context of DUOX2

• Northern blot analysis of 23 different human tissues demonstrated that LNOX2 messenger RNA (mRNA) is strongly expressed only in the thyroid gland, although blast analysis of expressed sequence tags databases indicated that LNOX genes are also expressed in some nonthyroid cells [12].
• Western blot analysis identified Duox2 as the same two molecular species (M(r) 165 and 175 kDa) as detected in the thyroid [11].
• Accordingly, we examined Duox1 and Duox2 mRNA expression by real-time PCR in primary respiratory tract epithelial cultures after treatment with multiple cytokines [5].

References