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Study on the pathogenesis for syndrome of resistance to thyroid hormone using cultured human skin fibroblasts.

利用培养的人皮肤成纤维细胞研究甲状腺激素抵抗综合征的发病机制。

基本信息

批准号：
04671470
负责人：
MURATA Yoshiharu
金额：
$ 1.28万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04671470/
关键词：
Thyroid hourmone Thyroxine Hormone resistance Fibroblast

项目摘要

The syndrome of generalized resistance to thyroid hormone(GRTH)is characterized by reduced clinical and biochemical manifestations of thyroid hormone action relative to the circulating hormone levels. Several reports demonstrated abnormalities in beta isoform of T_3 receptor gene(c-erbA beta). However, a question how the mutation of c-erbA beta cause the clinical manifestation of the syndrome still remaied to be clarified. The current research aimed to uncover the pathogenesis of a syndrome of generalized resistance to thyroid hormone(GRTH)using cultured skin fibroblasts obtained from the patients. In the fitst year of investigation, we tried to clarify how the mutation in c-erbA beta affects the expression of other isoform of T_3 receptor gene(c-erbA alpha). We utilized reverse transcription-polymerase chain reaction(RT-PCR)to determine c-erbA mRNAs. We pick up two cases in family A which exibits one single nucleotide substitution in one allel of c-erbA beta gene. We also examined the exprtession of c-erbA a gene in fibroblasts from family B in which most of the coding region of c-erbA beta gene is deleted in both alleles. The result indicated that normal and mutated c-erbA beta genes are equally expressed in family A.In the case of family B, no c-erbA beta mRNA was detected. In both famity A and B, c-erbA alpha was expressed like in fibroblasts from normal subjects. From these results indicated hat the mutation does not affect the expression of normal c-erbA gene. Thus, we conculuded the pathogenesis of GRTH is unlikeky due to the abnormal expression of a normal allele of c-erbA beta and of c-erbA alpha. We next examined whether the type of mutation is related to the responsiveness to T_3 when the expressions of mRNAs for T_3 responsive genes are used as a marker of T_3 action. At first, we used the collagenase and the fibronetin as a marker, however, we gofound that these mRNA expression were altered by other factors than T<@2

甲状腺激素抵抗综合征（GRTH）的特征是甲状腺激素作用相对于循环激素水平的临床和生化表现减少。有报道表明T_3受体基因β亚型（c-erbA β）存在异常。然而，c-erbA β基因突变如何导致该综合征的临床表现仍有待进一步研究。目前的研究旨在揭示甲状腺激素抵抗综合征（GRTH）的发病机制，使用培养的皮肤成纤维细胞从患者中获得。在第一年的研究中，我们试图阐明c-erbA β突变如何影响T_3受体基因的其它亚型（c-erbA α）的表达。我们利用逆转录-聚合酶链反应（RT-PCR），以确定c-erbA mRNA。我们在家族A中挑选了两例c-erbA β基因的一个外显子上有一个单核苷酸替换的病例。我们还检测了来自家族B的成纤维细胞中c-erbA β基因的表达，其中两个等位基因中c-erbA β基因的大部分编码区均缺失。结果表明，正常和突变的c-erbA β基因在A家族中表达相同，在B家族中未检测到c-erbA β mRNA。在家系A和B中，c-erbA α表达与正常受试者的成纤维细胞相似。结果表明，该突变不影响正常c-erbA基因的表达。因此，我们认为GRTH的发病机制是不一样的，由于异常表达的正常等位基因的c-erbA β和c-erbA α。我们接下来研究了当T_3反应基因的mRNA表达被用作T_3作用的标志时，突变类型是否与T_3反应性有关。本研究首先以胶原酶和槲皮素作为标记物，发现这些mRNA的表达受T<@2以外的其他因素影响，