Generation of H2O2 at the apical membrane of thyroid cells is essential for iodination of thyroglobulin. Dual oxidase 2 (DUOX2) is the catalytic core of the thyroidal H2O2 generator, and its deficiency leads to congenital hypothyroidism (CH) in humans and mice. The Dual oxidase maturation factor 2 (DUOXA2) is a recently identified endoplasmic reticulum (ER)-resident protein required for expression of DUOX2 activity.
Aims: We aimed the identification of human DUOXA2 defects as a novel cause of dyshormonogenetic thyroid disease.
Patients and methods: Eighty-three CH patients with partial and total iodide organification defects were screened for mutations in the coding regions of DUOX2 and DUOXA2 genes.
Results: Two missense mutations, W132L and G294E, were identified in DUOXA2. Mutations are heterozygous and are located in exons 4 and 6 of the gene, encoding a long intra-ER loop, predicted to interact with DUOX2, and the cytoplasmatic carboxy-terminal tail of the protein, respectively. Cotransfection of DUOX2 and DUOXA2 cDNAs in mammalian COS cells shows that W132L and G294E reduce in vitro H2O2 production capacity to 32% and 16% of wild type DUOXA2, respectively.
W132L was identified in an European Caucasian girl diagnosed with non-goitrous CH, showing TSH of 25 mUI/l at screening and 152 mUI/l at serum confirmation with FreeT4 of 10.5 pmol/l. Reevaluation at 3 years of age showed progressive increase of TSH and T4 treatment was re-introduced. G294E is present in an American-Hispanic girl not subjected to CH screening, consulting at 12 years of age for short stature. She was diagnosed with a large euthyroid goiter, with positive perchlorate test discharge of 24%, and T4 substitution was implemented. DUOX2 gene showed no pathogenic mutations in these patients.
Conclusions: DUOXA2 monoallelic defects are associated with mild but permanent hypothyroidism and /or goiter. DUOXA2 is a novel candidate gene for inheritable dyshormonogenetic thyroid defects.
03 - 07 May 2008
European Society of Endocrinology