Congenital hypothyroidism, dwarfism, and hearing impairment caused by a missense mutation in the mouse dual oxidase 2 gene, Duox2.

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Amino-Acid-Substitution, Animals, Base-Sequence, Body-Weight, Cochlea, Congenital-Hypothyroidism, DNA-Primers, Disease-Models-Animal, Dwarfism, Female, Flavoproteins, Hearing-Loss, Homozygote, Humans, Insulin-Like-Growth-Factor-I, Male, Mice-Inbred-C57BL, Mice-Mutant-Strains, Molecular-Sequence-Data, Mutation-Missense, NADPH-Oxidase, Phenotype, Pregnancy, Sequence-Homology-Amino-Acid, Thyrotropin, Thyroxine

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Mol Endocrinol 2007 Jul; 21(7):1593-602.


Dual oxidases generate the hydrogen peroxide needed by thyroid peroxidase for the incorporation of iodine into thyroglobulin, an essential step in thyroid hormone synthesis. Mutations in the human dual oxidase 2 gene, DUOX2, have been shown to underlie several cases of congenital hypothyroidism. We report here the first mouse Duox2 mutation, which provides a new genetic model for studying the specific function of DUOX2 in the thyroid gland and in other organ systems where it is hypothesized to play a role. We mapped the new spontaneous mouse mutation to chromosome 2 and identified it as a T>G base pair change in exon 16 of Duox2. The mutation changes a highly conserved valine to glycine at amino acid position 674 (V674G) and was named "thyroid dyshormonogenesis" (symbol thyd) to signify a defect in thyroid hormone synthesis. Thyroid glands of mutant mice are goitrous and contain few normal follicles, and anterior pituitaries are dysplastic. Serum T(4) in homozygotes is about one-tenth the level of controls and is accompanied by a more than 100-fold increase in TSH. The weight of adult mutant mice is approximately half that of littermate controls, and serum IGF-I is reduced. The cochleae of mutant mice exhibit abnormalities characteristic of hypothyroidism, including a delayed formation of the inner sulcus and tunnel of Corti and an abnormally thickened tectorial membrane. Hearing thresholds of adult mutant mice are on average 50-60 decibels (dB) above those of controls.