ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 S20.3

Monoallelic mutations in DUOXA2 are associated with mild permanent hypothyroidism and goiter

Paula Ventura1, Cristina Azcona2, Maria Clemente3, Marian Albisu3, Laura Audí3, Antonio Carrascosa3, Theo Visser1 & Jose C Moreno1

1Erasmus Medical Center, Rotterdam, The Netherlands; 2Clinica Universitaria, Pamplona, Spain; 3Vall d’Hebron Hospital, Barcelona, Spain.

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.

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