Endocrine Abstracts

Generation of hydrogen peroxide (H₂O₂) in thyroid cells is essential for the synthesis of thyroid hormone. H₂O₂ is produced by the Dual Oxidase 2 (DUOX2) at the apical membrane of the thyrocyte, where it is required by thyroperoxidase for the iodination of thyroglobulin. A dual oxidase maturation factor 2 (DUOXA2) was recently identified as an endoplasmic reticulum-resident protein required for expression of DUOX2 activity. DUOX2 and DUOXA2 genes are located in immediate vicinity at human chromosome 15q, and constitute a functional unit evolved from ancient prokaryotic operons.

Deficiency of DUOX2 leads to congenital hypothyroidism (CH) in humans and mice. We described biallelic inactivating mutations in DUOX2 in patients with severe and permanent CH, while monoallelic defects cause milder and transient CH. These findings represented the first proof of a direct involvement of DUOX2 in human thyroid hormonogenesis, and showed that a (permanent) genetic defect could cause a transient CH phenotype. Missense DUOX2 defects in compound heterozygosity with nonsense mutations were later shown to contribute to permanent but milder forms of CH, adding to the hypothesis that biallelic defects are necessary for permanency of the disease. However, transient CH was recently reported in children with biallelic mutations in the gene, albeit not functionally tested.

We performed a large-scale screening in 102 patients with thyroid dyshormonogenesis and identified DUOX2 mutations in 33% of the cohort, and a much lower prevalence of DUOXA2 defects of only 2%. Even when DUOX2-DUOXA2 genes are also expressed in other tissues as the lung or the gastrointestinal tract, we did not identify any extra-thyroidal symptoms in patients with DUOX2 or DUOXA2 genetic defects. This probably reflects the tight and complex tissue-specific regulation of H₂O₂/superoxide generation systems, including overlapping functions of the DUOX1/DUOXA1 paralog pair in human mucosal host defence.