Zebrafishduoxmutations provide a model for human congenital hypothyroidism

ABSTRACT Thyroid dyshormonogenesis is a leading cause of congenital hypothyroidism, a highly prevalent but treatable condition. Thyroid hormone 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 oxidase, DUOX1 and DUOX2. Indeed mutations in DUOX1 and DUOX2 have been linked with congenital hypothyroidism. Unlike humans, zebrafish has a single orthologue for DUOX1 and DUOX2 . In this study, we investigated the phenotypes associated with two nonsense mutant alleles of the single duox gene in zebrafish, sa9892 and sa13017 . 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 the external and internal phenotypes, we discovered a strong correlation between TH synthesis and duox function, beginning from the early larval stage, when T 4 levels are already noticeably absent in the mutants. Loss of T 4 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 4 treatment, even when initiated when the fish had already reached adulthood. Our work suggests that these zebrafish duox mutants may provide a powerful model to understand the aetiology of untreated and treated congenital hypothyroidism even in advance stages of development.