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Thyroglobulin Gene Mutations Producing Defective Intracellular Transport of Thyroglobulin Are Associated with Increased Thyroidal Type 2 Iodothyronine Deiodinase Activity

Department of Genetics (Y.K., Y.Miz., H.F., Y.Mu.), Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; Department of Clinical Laboratory Medicine (A.H., T.Ie.), Dokkyo University School of Medicine, Mibu, Tochigi 321-0923, Japan; Department of Clinical Laboratory Medicine (K.T., K.S., M.M.), Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan; and Departments of Endocrinology and Transplantation (Y.Miz., T.Im.), Endocrinology and Diabetology (Y.Miu., C.Y.), and Clinical Pathology (T.N.), Nagoya University Graduate School of Medicine, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan

Address all correspondence and requests for reprints to: Yoshiharu Murata, M.D., Ph.D., Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. 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 that 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 three 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 type 1 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.

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