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This version published online on January 23, 2007
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-1242
A more recent version of this article appeared on April 1, 2007
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*THYROGLOBULIN

Submitted on June 9, 2006
Accepted on January 16, 2007

Thyroglobulin gene mutations producing defective intracellular transport of thyroglobulin are associated with increased thyroidal type 2 iodothyronine deiodinase activity

Yasuhiko Kanou, Akira Hishinuma, Katsuhiko Tsunekawa, Koji Seki, Yutaka Mizuno, Haruki Fujisawa, Tsuneo Imai, Yoshitaka Miura, Tetsuro Nagasaka, Chizumi Yamada, Tamio Ieiri, Masami Murakami, and Yoshiharu Murata*

Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601; Department of Clinical Laboratory Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0923, Japan; Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; Department of Endocrinology and Transplantation, Endocrinology and Diabetologyand Clinical Pathology, Nagoya University Graduate School of Medicine, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan

* To whom correspondence should be addressed. E-mail: ymurata{at}riem.nagoya-u.ac.jp.

Context: Most patients with defective synthesis and/or secretion of thyroglobulin (Tg) present relatively high serum free T3 (FT3) concentrations with disproportionately low free T4 (FT4) resulting in a high FT3/FT4 ratio. The mechanism of this change in FT3/FT4 ratio remains unknown.

Objective: We hypothesize that increased type 2 iodothyronine deiodinase (D2) activity in the thyroid gland may explain the higher FT3/FT4 ratio which is frequently observed in patients with abnormal Tg synthesis.

Design: We recently identified a compound heterozygous patient (Patient A) with a Tg G2356R mutation and one previously described (C1245R) that is known to cause a defect in intracellular transport of Tg. In the current study, after determining the abnormality caused by G2356R, we measured D2 activity as well as its mRNA level in the thyroid gland. We also measured the thyroidal D2 activity in 3 patients with Tg transport defect and in normal thyroid tissue.

Results: Morphological and biochemical analysis of the thyroid gland from Patient A, complemented by a pulse chase experiment revealed that G2356R produces a defect in intracellular Tg transport. D2 activity but not type1 deiodinase in thyroid glands of patients with abnormal Tg transport was significantly higher than in normal thyroid glands, whereas D2 mRNA level in Patient A was comparable with that in normal thyroid glands. Furthermore, there was a positive correlation between D2 activity and FT3/FT4 ratios.

Conclusion: Increased thyroidal D2 activity in the thyroid gland is responsible for the higher FT3/FT4 ratios in patients with defective intracellular Tg transport.
Key words: type 2 iodothyronine deiodinase • thyroglobulin • mutation • thyroid gland • goiter






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