Novel inactivating missense mutations in the thyrotropin receptor gene in Japanese children with resistance to thyrotropin
Novel inactivating missense mutations in the thyrotropin receptor gene in Japanese children with resistance to thyrotropin
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DOI：
10.1089/105072501750302859
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发表时间：
2001-06-01
期刊：
影响因子：
6.6
通讯作者：
Morikawa, A
中科院分区：
文献类型：
--
作者：
Nagashima, T;Murakami, M;Morikawa, A
我们描述了对促甲状腺素（TSH）具有抗性的日本兄弟姐妹，他们是 TSH 受体基因中两个新突变的复合杂合子。受影响的兄弟姐妹血清 TSH 升高，血清甲状腺激素正常，甲状腺位置正常但略有发育不全。突变的父本等位基因在 TSH 受体密码子 450 (R450H) 处用 His (CAC) 取代 Arg (CGC)。突变的母体等位基因在 TSH 受体的密码子 498 (G498S) 处用 Ser (AGT) 取代 Gly (GGT)。转染 R450H 突变体的 COS-7 细胞表现出 TSH 结合略有下降，并且对 TSH 的环磷酸腺苷 (cAMP) 反应略有下降，而用 C498S 突变体转染的细胞则表现出明显降低的 TSH 结合和对 TSH 的 cAMP 反应。流式免疫细胞荧光分析表明，尽管细胞内合成正常，但与野生型受体和R450H突变体相比，G498S突变体导致细胞表面的表达极低。目前的病例是日本第一例 TSH 耐药患者，其中 TSH 受体基因发生突变。这些新的突变可能有助于理解 TSH 受体的结构-功能关系。
We describe Japanese siblings with resistance to thyrotropin (TSH) who are compound heterozygotes for two novel mutations in the TSH receptor gene. The affected siblings had increased serum TSH, normal serum thyroid hormones, and normal positioned but slightly hypoplastic thyroid glands. The mutated paternal allele has the substitution of His (CAC) in place of Arg (CGC) at codon 450 (R450H) of the TSH receptor. The mutated maternal allele has the substitution of Ser (AGT) in place of Gly (GGT) at codon 498 (G498S) of the TSH receptor. COS-7 cells transfected with the R450H mutant exhibited a slightly decreased TSH binding and a slightly decreased cyclic adenosine monophosphate (cAMP) response to TSH, whereas cells transfected with the C498S mutant exhibited a markedly decreased TSH binding and a markedly decreased cAMP response to TSH. Flow immunocytofluorometry analysis demonstrated that the G498S mutant resulted in extremely low expression at the cell surface as compared with the wild type receptor and the R450H mutant, in spite of a normal intracellular synthesis. The present cases are the first Japanese patients with TSH resistance in whom mutations in the TSH receptor gene have been identified. These novel mutations may contribute to understanding of the structure-function relationship of the TSH receptor.