Genetic and functional analysis of two missense DUOX2 mutations in congenital hypothyroidism and goiter

Mutations in the dual oxidase 2 gene (DUOX2) impair hydrogen peroxide (H2O2) production and cause dyshormonogenesis. In addition, these mutations have been implicated in autosomal recessive congenital hypothyroidism (CH) with goiter. In this study, we identified DUOX2 mutations that were causative for CH and explored the effects of these mutations on DUOX2 function. Blood samples were collected from 10 infants born with CH and goiter to unrelated parents. We extracted genomic DNA and sequenced all exons by polymerase chain reaction direct sequencing. The effects of DUOX2 mutations were characterized by H2O2 production assays and cycloheximide (CHX) chase experiments. Sequence analysis revealed one novel DUOX2 mutation and one known DUOX2 mutation in unrelated families: c.1060C>T (p.R354W) and c.3616 G>A (p.A1206T). Both mutations impaired H2O2 production. CHX chase experiments demonstrated the DUOX2 mutants had shorter half-lives and degraded more rapidly than wild-type DUOX2. Our study identified two novel DUOX2 mutations in Chinese patients with CH and goiter, which were responsible for the deficit in the organification process.