title: Thyroglobulin gene mutations producing defective intracellular transport of thyroglobulin are associated with increased thyroidal type 2 iodothyronine deiodinase activity.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Increased thyroidal D2 activity in the thyroid gland is responsible for the higher FT3/FT4 ratios in patients with defective intracellular Tg transport.
authors.affiliation: Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kanou
authors.forename: Akira
authors.initials: A
authors.lastname: Hishinuma
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Tsunekawa
authors.forename: Koji
authors.initials: K
authors.lastname: Seki
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Haruki
authors.initials: H
authors.lastname: Fujisawa
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Imai
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Miura
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Nagasaka
authors.forename: Chizumi
authors.initials: C
authors.lastname: Yamada
authors.forename: Tamio
authors.initials: T
authors.lastname: Ieiri
authors.forename: Masami
authors.initials: M
authors.lastname: Murakami
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Murata
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D001692:Biological Transport; D002460:Cell Line; D006580:Genetic Carrier Screening; D006801:Humans; D007453:Iodide Peroxidase / Q000378:metabolism*; D007668:Kidney; D008297:Male; D009154:Mutation; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D013954:Thyroglobulin / Q000235:genetics* / Q000378:metabolism; D013961:Thyroid Gland / Q000201:enzymology*; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D012313:RNA; D013954:Thyroglobulin; D000097564:Iodothyronine Deiodinase Type II