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, Yoshiharu Murata

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

Abstract

Context: Most patients with defective synthesis and/or secretion of thyroglobulin (Tg) present relatively high serum free T3 (FT 3) 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/FT 4 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.

Original languageEnglish
Pages (from-to)1451-1457
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Volume92
Issue number4
DOIs
Publication statusPublished - 04-2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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