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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

甲状腺激素广泛抵抗综合征（GRTH）的特点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。一些报告表明 T_3 受体基因 (c-erbA beta) 的 β 亚型存在异常。然而，c-erbAβ突变如何导致该综合征的临床表现仍有待阐明。目前的研究旨在利用从患者身上获得的培养皮肤成纤维细胞来揭示甲状腺激素广泛抵抗综合征（GRTH）的发病机制。在研究的第一年，我们试图阐明c-erbA beta的突变如何影响T_3受体基因的其他亚型（c-erbA alpha）的表达。我们利用逆转录聚合酶链反应（RT-PCR）来测定c-erbA mRNA。我们在 A 家族中选取了两个病例，该病例在 c-erbA beta 基因的一个等位基因中存在一个单核苷酸取代。我们还检测了 B 家族成纤维细胞中 c-erbA 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被删除。结果表明，正常和突变的c-erbA beta基因在A家族中表达相同。在B家族中，没有检测到c-erbA beta mRNA。在 A 族和 B 族中，c-erbA α 的表达与正常受试者的成纤维细胞相似。这些结果表明该突变不影响正常c-erbA基因的表达。因此，我们得出结论，GRTH 的发病机制不太可能是由于 c-erbA β 和 c-erbA α 正常等位基因的异常表达所致。接下来，我们检查了当 T_3 反应基因的 mRNA 表达用作 T_3 作用的标记时，突变类型是否与对 T_3 的反应性相关。起初，我们使用胶原酶和纤连蛋白作为标记，然而，我们发现这些 mRNA 表达受到除 T<@2 之外的其他因素的影响