Mice deficient in dual oxidase maturation factors are severely hypothyroid

Helmut Grasberger, Xavier de Deken, Olga Barca Mayo, Houssam Raad, Mia Weiss, Xiao Hui Liao, Samuel Refetoff

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


Dual oxidases (DUOX1 and DUOX2) are evolutionary conserved reduced nicotinamide adenine dinucleotide phosphate oxidases responsible for regulated hydrogen peroxide (H 2O 2) release of epithelial cells. Specific maturation factors (DUOXA1 and DUOXA2) are required for targeting of functional DUOX enzymes to the cell surface. Mutations in the single-copy Duox and Duoxa genes of invertebrates cause developmental defects with reduced survival, whereas knockdown in later life impairs intestinal epithelial immune homeostasis. In humans, mutations in both DUOX2 and DUOXA2 can cause congenital hypothyroidism with partial iodide organification defects compatible with a role of DUOX2-generated H 2O 2 in driving thyroid peroxidase activity. The DUOX1/ DUOXA1 system may account for residual iodide organification in patients with loss of DUOX2, but its physiological function is less clear. To provide a murine model recapitulating complete DUOX deficiency, we simultaneously targeted both Duoxa genes by homologous recombination. Knockout of Duoxa genes (Duoxa -/- mice) led to a maturation defect of DUOX proteins lacking Golgi processing of N-glycans and to loss of H 2O 2 release from thyroid tissue. Postnatally, Duoxa -/- mice developed severe goitreous congenital hypothyroidism with undetectable serum T4 and maximally disinhibited TSH levels. Heterozygous mice had normal thyroid function parameters. 125I uptake and discharge studies and probing of iodinated TG epitopes corroborated the iodide organification defect in Duoxa -/- mice. Duoxa -/- mice on continuous T4 replacement from P6 showed normal growth without an overt phenotype. Our results confirm in vivo the requirement of DUOXA for functional expression of DUOX-based reduced nicotinamide adenine dinucleotide phosphate oxidases and the role of DUOX isoenzymes as sole source of hormonogenic H 2O 2.

Original languageEnglish
Pages (from-to)481-492
Number of pages12
JournalMolecular Endocrinology
Issue number3
StatePublished - Mar 1 2012


Dive into the research topics of 'Mice deficient in dual oxidase maturation factors are severely hypothyroid'. Together they form a unique fingerprint.

Cite this