Zebrafish mutations provide a model for human congenital hypothyroidism.

Thyroid dyshormonogenesis is a leading cause of congenital hypothyroidism, a highly prevalent but treatable condition. Thyroid hormone (TH) synthesis is dependent on the formation of reactive oxygen species (ROS). In humans, the primary sources for ROS production during thyroid hormone synthesis are the NADPH oxidases DUOX1 and DUOX2. Indeed, mutations in and have been linked with congenital hypothyroidism. Unlike humans, zebrafish has a single orthologue for and In this study, we investigated the phenotypes associated with two nonsense mutant alleles, and , of the single gene in zebrafish. Both alleles gave rise to readily observable phenotypes reminiscent of congenital hypothyroidism, from the larval stages through to adulthood. By using various methods to examine external and internal phenotypes, we discovered a strong correlation between TH synthesis and function, beginning from an early larval stage, when T levels are already noticeably absent in the mutants. Loss of T production resulted in growth retardation, pigmentation defects, ragged fins, thyroid hyperplasia/external goiter and infertility. Remarkably, all of these defects associated with chronic congenital hypothyroidism could be rescued with T treatment, even when initiated when the fish had already reached adulthood. Our work suggests that these zebrafish mutants may provide a powerful model to understand the aetiology of untreated and treated congenital hypothyroidism even in advanced stages of development.This article has an associated First Person interview with the first author of the paper.