Thyroid Research Thyroid Research Archive Thyroid Hormone Production

Genetic deficiency of type 3 iodothyronine deiodinase in mice results in fetal and neonatal hyperthyroidism followed by central hypothyroidism

(March 2006)

The background of the study. Normal growth and development are dependent on adequate amounts of thyroxine (T4) and triiodothyronine (T3). The availability of these substances is dependent on normal pituitary–thyroid function and on the activity of several enzymes that convert T4 to the more active T3 (types 1 and 2 deiodinase) or convert both T3 and T4 to inactive compounds (type 3 deiodinase). The effects of deletion of the gene for type 3 deiodinase (Diol3) on growth and development; serum T4, T3, and thyrotropin (TSH) concentrations; and T3 action in mice were determined in this study.

How the study was done and the results of the study. The studies were done in mice carrying a Diol3 gene that had been mutated so that the enzyme was inactive (D3KO mice). D3KO mice were less fertile than expected, and their growth was impaired

In the normal mice, serum T3 and T4 concentrations were low at birth, reached a peak on the 15th postnatal day, and then declined. Their serum TSH concentrations on postnatal days 21, 90, and 240 to 390 days were approximately 200 ng/ml. The D3KO mice had slightly higher serum T3 concentrations at birth and considerably higher (325 percent) concentrations on postnatal day 5, due to slow breakdown of T3, after which they declined to low values. Their serum T4 concentrations were never more than 50 percent of the concentrations in normal mice. Serum TSH concentrations were also low initially, and later were only slightly higher than in normal mice.

On postnatal days 1 to 3, the T3 concentration in the brain was almost three times higher in the D3KO mice than in normal mice and the brain content of two T3-stimulated genes was increased. Later, there was evidence of hypothyroidism in the tissues of the D3KO mice.

The conclusions of the study. Deletion of the Diol3 gene results in high serum T3 concentrations and increased T3 action in tissue in fetal and newborn mice, and hypothyroidism with low serum TSH concentrations in older mice.

The original article. Hernandez A, Martinez ME, Fiering S, Galton VA, St Germain D. Type 3 deiodinase is critical for the maturation and function of the thyroid axis. J Clin Invest 2006;116:476-84.