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Identification and Functional Studies of Two New Dual-Oxidase 2 (DUOX2) Mutations in a Child with Congenital Hypothyroidism and a Eutopic Normal-Size Thyroid Gland

Dipartimento di Endocrinologia e Metabolismo (M.T., G.D.M., P.A., L.M., C.D.C., A.D., E.F., C.C., F.B., A.P., P.V.), Centro Eccellenza AmbiSEN, Università di Pisa, 56124 Pisa, Italy; Laboratorio de Fisiologia Endocrina (A.C.F.F.), Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-901 Brazil; and Division of Endocrinology and Metabolism (H.E.R.), Department of Medicine, Federal University of Paraná, Curitiba, 80030-110 Brazil

Address all correspondence and requests for reprints to: Massimo Tonacchera, Dipartimento di Endocrinologia, Università di Pisa, Via Paradisa 2, 56124, Cisanello, Pisa, Italy. E-mail: mtonacchera{at}hotmail.com

Context: Some cases of congenital hypothyroidism (CH) are associated with a gland of normal size.

Objective: To explore the cause of organification defect in one child with CH and a eutopic thyroid gland, genetic analyses of TPO, DUOX2, and DUOXA2 genes were performed.

Patient: One child with CH, a eutopic thyroid gland, and a partial organification defect was shown after ¹²³I scintigraphy and perchlorate test.

Methods: In the child with the organification defect, TPO, DUOX2, and DUOXA2 genes were analyzed. The functional activity of the DUOX2 mutants was studied after expression in eukaryotic cells.

Results: No TPO or DUOXA2 gene mutations were identified. Direct sequencing of the DUOX2 gene revealed a compound heterozygous genotype for S911L and C1052Y substitutions. S911L and C1052Y caused a partial defect in H₂O₂ production after transient expression in HeLa cells.

Conclusions: We performed a genetic analysis in one child with CH and a eutopic thyroid gland. Two new mutations in DUOX2 gene responsible for the partial deficit in the organification process were identified.