New phenotypes in thyroid dyshormonogenesis: hypothyroidism due to DUOX2 mutations.

Hydrogen peroxide (H(2)O(2)) is an essential compound for the synthesis of thyroid hormone. Its presence in the follicular lumen is required by thyroperoxidase for the iodination of tyrosil residues of thyroglobulin, the initial step in the synthesis of T(3) and T(4). The biochemical requirement of H(2)O(2) for thyroid hormone production has been known for decades and an H(2)O(2)-generating system was predicted to exist in the thyroid gland. In recent years, different research groups have unraveled the molecular nature of the system. Two homologous proteins, the dual oxidases 1 and 2, DUOX1 and DUOX2 (formerly THOX1 and 2, for thyroid oxidases), were identified and shown to contain functional domains typical of NADPH oxidoreductases. However, in vitro reconstitution of H(2)O(2) production could not be obtained in nonthyroidal cell lines expressing these proteins. Evidence of DUOX involvement in thyroidal H(2)O(2) production came from the identification of a DUOX2 nonsense homozygote mutation, which resulted in the absence of all functional domains of the protein, in a patient with permanent and severe congenital hypothyroidism (CH). Recently, an experimental demonstration of H(2)O(2) production by DUOX2 was achieved by coexpression with a novel 'maturation factor' for DUOX2 (DUOXA2). Transient CH has also been linked to heterozygote nonsense DUOX2 mutations, showing for the first time that transitory CH can have a genetic origin. These findings also establish that partial dyshormonogenetic defects can behave biochemically as transient forms of CH. Novel missense and splice-site DUOX2 mutations in compound heterozygosity have been recently reported in association with a wide spectrum of hypothyroid phenotypes, ranging from very mild to severe. Functional analysis of these point mutations using available assays opens now the possibility to ascertain whether transiency or permanency of DUOX2 phenotypes relate exclusively to monoallelic or biallelic inactivation of the gene, or if the degree of pathogenic severity of mutations may also influence the timely outcome of this type of hypothyroidism.