Congenital hypothyroidism with impaired thyroid response to thyrotropin (TSH) and absent circulating thyroglobulin: evidence for a new inactivating mutation of the TSH receptor gene.
Congenital hypothyroidism with impaired thyroid response to thyrotropin (TSH) and absent circulating thyroglobulin: evidence for a new inactivating mutation of the TSH receptor gene.
复制标题
先天性甲状腺功能减退症伴甲状腺对促甲状腺素 (TSH) 反应受损且循环甲状腺球蛋白缺失：TSH 受体基因新失活突变的证据。
DOI：
--
复制
发表时间：
2000
影响因子：
5.8
通讯作者：
L. Chiovato
中科院分区：
文献类型：
--
作者：
M. Tonacchera;P. Agretti;A. Pinchera;Veronica Rosellini;A. Perri;P. Collecchi;P. Vitti;L. Chiovato
由于甲状腺对 TSH 的反应受损而导致的先天性甲状腺功能减退症最初由 Stanbury 描述。如果患者患有先天性甲状腺功能减退症，甲状腺位于颈部正常位置，甲状腺大小正常或萎缩，血清TSH水平升高，TSH生物活性完整，甲状腺对TSH刺激的反应降低，则可诊断为先天性甲状腺功能减退症伴甲状腺对TSH无反应。在所有最初描述的病例中，血清甲状腺球蛋白均检测不到。我们描述了一位 22 岁的女性患者，她患有严重的甲状腺功能减退症和智力障碍。血清 T4 和 T3 浓度低于方法的灵敏度，血清 TSH 水平升高。血清甲状腺球蛋白检测不到。闪烁扫描发现位于颈部适当解剖位置的正常形状的发育不全腺体。给予牛 TSH 后，腺体在 131I 摄取、血清甲状腺激素和甲状腺球蛋白分泌方面没有反应。由于 TSH 无反应而诊断为先天性甲状腺功能减退症。产前基因分析显示 TSH 受体存在纯合失活突变，这种突变以前未曾描述过。该突变包括用异亮氨酸取代受体第一个胞外环 (T477I) 中第 477 位的高度保守的苏氨酸。父亲的兄弟、一名姐妹（无法获得其 DNA）、母亲、一名姐妹和兄弟均为 T477I 杂合子。所有杂合子均不受影响。转染COS-7细胞后，突变受体在细胞表面表现出极低的表达。与用野生型TSH受体转染的细胞不同，用突变体T477I转染的细胞没有表现出腺苷酸环化酶途径的组成型活性。在用突变型 T477I 受体转染的细胞中，观察到牛 TSH 攻击后 cAMP 积累量显着减少。突变型 TSH 受体蛋白的结构缺陷可能是导致受体难以到达细胞膜的原因。这是首次在患有严重先天性甲状腺功能减退症且因 TSH 无反应而缺乏循环甲状腺球蛋白的患者中描述 TSH 受体功能丧失突变，也是首次在第一细胞外环中描述 TSH 受体失活突变。
Congenital hypothyroidism due to impaired thyroid response to TSH was originally described by Stanbury. A diagnosis of congenital hypothyroidism with thyroid unresponsiveness to TSH is accepted if the patient has congenital hypothyroidism, the thyroid gland is in the normal position in the neck, the size of the thyroid is either normal or atrophic, the serum TSH level is increased, the bioactivity of TSH is intact, and the response of the thyroid gland to TSH stimulation is decreased. In all originally described cases serum thyroglobulin was undetectable. We describe a 22-yr-old female patient who was severely hypothyroid and mentally retarded. Serum T4 and T3 concentrations were below the sensitivity of the methods, with elevated serum TSH levels. Serum thyroglobulin was undetectable. A normally shaped hypoplastic gland located in the appropriate anatomical position in the neck was found at scintiscan. The gland did not respond after administration of bovine TSH in terms of 131I uptake, serum thyroid hormones, and thyroglobulin secretion. A diagnosis of congenital hypothyroidism due to TSH unresponsiveness was formulated. Genetic analysis in the propositus showed a homozygous inactivating mutation of the TSH receptor that had not been previously described. The mutation consisted of the substitution of an isoleucine in place of a highly conserved threonine at position 477 in the first extracellular loop of the receptor (T477I). The brother, one sister of the father (whose DNA was not available), the mother of the propositus, one sister, and the brother were heterozygous for T477I. All the heterozygous persons were unaffected. After transfection in COS-7 cells, the mutant receptor displayed an extremely low expression at cell surface. At variance with cells transfected with the wild-type TSH receptor, cells transfected with the mutant T477I did not show constitutive activity for the adenylyl cyclase pathway. A dramatic reduction in the amount of cAMP accumulation after bovine TSH challenge was observed in cells transfected with the mutant T477I receptor. A structural defect in the mutant TSH receptor protein was probably responsible for the poor routing of the receptor to the cell membrane. This is the first time that a loss of function mutation of the TSH receptor is described in a patient with severe congenital hypothyroidism and absent circulating thyroglobulin due to TSH unresponsiveness and the first time that an inactivating mutation of the TSH receptor is described in the first extracellular loop.
登录
查看更多内容
在哺乳动物细胞中过度表达的人类促甲状腺素受体之间负协同作用的证据。
DOI：
10.1210/endo.137.11.8895321
发表时间：
1996
期刊：
Endocrinology.
影响因子：
--
作者：
Chazenbalk,GD;Kakinuma,A;Jaume,JC;McLachlan,SM;Rapoport,B
通讯作者：
Rapoport,B
影响因子：
--
作者：
S. Stein;E. L. Oates;C. R. Hall;R. M. Grumbles;L. M. Fernandez;N. A. Taylor;D. Puett;S. Jin
通讯作者：
S. Stein;E. L. Oates;C. R. Hall;R. M. Grumbles;L. M. Fernandez;N. A. Taylor;D. Puett;S. Jin
牛促甲状腺素的特定生物活性是之前估计的高纯度激素的 5 至 10 倍。
影响因子：
4.8
作者：
Rapoport,B;Seto,P
通讯作者：
Seto,P
影响因子：
14.9
作者：
LOPATA, MA;CLEVELAND, DW;SOLLNERWEBB, B
通讯作者：
SOLLNERWEBB, B