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.
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