Thyroglobulin gene mutations producing defective intracellular transport of thyroglobulin are associated with increased thyroidal type 2 iodothyronine deiodinase activity
Thyroglobulin gene mutations producing defective intracellular transport of thyroglobulin are associated with increased thyroidal type 2 iodothyronine deiodinase activity
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DOI：
10.1210/jc.2006-1242
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发表时间：
2007-04-01
影响因子：
5.8
通讯作者：
Murata, Yoshiharu
中科院分区：
文献类型：
--
作者：
Kanou, Yasuhiko;Hishinuma, Akira;Murata, Yoshiharu
背景：大多数甲状腺球蛋白(TG)合成和/或分泌缺陷的患者表现出相对较高的血清游离T-3(FT3)浓度和不成比例的低游离T-4(FT4)水平，导致FT3/FT4比值升高。FT3/FT4比值的这种变化机制尚不清楚。目的：我们假设甲状腺中2型碘甲状腺原氨酸脱碘酶(D2)活性的增加可能解释了在TG合成异常的患者中经常观察到的FT3/FT4比值升高。设计：我们最近发现了一名具有TG G2356R突变的复合杂合型患者(患者A)和一名先前描述的(C1245R)，该患者已知导致TG细胞内运输缺陷。在本研究中，在确定了G2356R引起的异常之后，我们检测了甲状腺中D2的活性及其mRNA水平。我们还检测了3例甘油三酯转运缺陷患者和正常甲状腺组织中的甲状腺D2活性。结果：对患者A的甲状腺进行了形态和生化分析，结合脉冲追逐实验，发现G2356R产生了细胞内甘油三酯转运缺陷。甘油三酯转运异常患者甲状腺组织中D2活性显著高于正常甲状腺组织，而患者A的D2基因表达水平与正常甲状腺组织相当。此外，D2活性与FT3/FT4比值呈正相关。结论：细胞内TG转运缺陷患者甲状腺D2活性升高是FT3/FT4比值升高的原因。
Context: Most patients with defective synthesis and/or secretion of thyroglobulin (Tg) present relatively high serum free T-3 (FT3) concentrations with disproportionately low free T-4 (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.