Thyroid Hormone Resistance Syndrome
Thyroid Hormone Resistance Syndrome
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甲状腺激素抵抗综合症
DOI：
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发表时间：
1991
期刊：
影响因子：
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通讯作者：
L. Jameson
中科院分区：
文献类型：
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作者：
V. Chatterjee;T. Nagaya;L. Madison;S. Datta;A. Rentoumis;L. Jameson
在大多数情况下，甲状腺激素（T3）抵抗是遗传性的。
常染色体显性方式。该疾病的特点是
游离甲状腺激素水平升高和部分抵抗
细胞水平的甲状腺激素。独特的单一氨基酸
ft 形式的配体结合结构域中的取代
甲状腺激素受体已被描述为两种
患有这种疾病。我们使用瞬时表达测定来表征
这些受体突变体的功能特性，
340 号氨基酸 (G340R) 处含有甘氨酸 (Gly) 至精氨酸 (Arg) 的变化
另一个在氨基酸 448 (P448H) 处由 Pro 变为 His。
九个氨基酸羧基末端缺失 (A448456)，类似
还研究了 v-erbA 中发生的改变
与 T3 抗性中发生的突变进行比较
综合症。没有一个受体突变体能够介导
甲状腺激素依赖性激活 (TreTKCAT) 或抑制
报告基因（TSHaCAT）与
野生型受体。此外，突变体抑制了活性
在共表达中检查时正常 a 和 (3 受体亚型
化验。这种活动称为显性负性
抑制，在积极和消极方面都很明显
负调控的报告基因。虽然突变受体
配体结合研究显示，与 DNA 的结合不受影响
G340R和A448456突变体未能结合T3，
而 P448H 突变体结合激素的亲和力降低
与野生型受体相比（- 正常值的 10%）。一致
根据这一发现，P448H 突变受体部分被
在较高的 T3 浓度下具有活性。此外，占主导地位的
P448H 受体突变体引起的负抑制
在较高的 T3 浓度下，在高浓度的存在下发生逆转。
T3的剂量。这些发现表明突变体（3 个受体
甲状腺激素抵抗患者亲和力降低
T3 的功能有缺陷，但会损害 T3 的活性
正常受体，从而提供了一种机制
这种疾病的遗传方式。 （J. Clin. Invest. 1991。
87:1977-1984.) 关键词：转录调控 - erbA -
促甲状腺激素 - 甲状腺激素抵抗 * 甲状腺
激素
Thyroid hormone (T3) resistance is inherited in most cases in an
autosomal dominant manner. The disorder is characterized by
elevated free thyroid hormone levels and partial resistance to
thyroid hormone at the cellular level. Distinct single amino acid
substitutions in the ligand binding domain of the ft form of the
thyroid hormone receptor have been described in two kindreds
with this disorder. We used transient expression assays to characterize
the functional properties of these receptor mutants,
one containing a Gly to Arg change at amino acid 340 (G340R)
and the other a Pro to His change at amino acid 448 (P448H).
A nine amino acid carboxy terminal deletion (A448456), analogous
to an alteration that occurs in v-erbA, was also studied for
comparison with the mutations that occur in the T3 resistance
syndrome. None of the receptor mutants were able to mediate
thyroid hormone dependent activation (TreTKCAT) or repression
(TSHaCAT) of reporter genes when compared with the
wild type receptor. In addition, the mutants inhibited the activity
of normal a and (3 receptor isoforms when examined in coexpression
assays. This activity, referred to as dominant negative
inhibition, was manifest with respect to both the positively and
negatively regulated reporter genes. Although mutant receptor
binding to DNA was unaffected, ligand binding studies showed
that the G340R and A448456 mutants failed to bind T3,
whereas the P448H mutant bound hormone with reduced affinity
(- 10% of normal) compared to the wild type receptor. Consistent
with this finding, the P448H mutant receptor was partially
active at higher T3 concentrations. Furthermore, the dominant
negative inhibition elicited by the P448H receptor mutant
at higher T3 concentrations was reversed in the presence of high
doses of T3. These findings indicate that mutant (3 receptors in
patients with thyroid hormone resistance have reduced affinity
for T3 and are functionally deficient, but impair the activity of
normal receptors, thereby providing a mechanism for the dominant
mode of inheritance in this disorder. (J. Clin. Invest. 1991.
87:1977-1984.) Key words: transcriptional regulation - erbA -
thyroid-stimulating hormone - thyroid hormone resistance * thyroid
hormone