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A causal gene and proteins related to rdw symptoms in the rdw rat with hereditary dwarfism/hypothyroidism

遗传性侏儒症/甲状腺功能减退症 rdw 大鼠中与 rdw 症状相关的致病基因和蛋白质

基本信息

批准号：
11680824
负责人：
FURUDATE Sen-ichi
金额：
$ 2.11万
依托单位：
KITASATO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

The rdw rat was initially isolated as a hereditary dwarf strain from a closed colony of Wistar-Imamichi rat. Marked hypothyroidism was subsequently noted in the rdw rat. Several recent reports have shown the presence of elevated molecular chapelone levels in the rdw thyrocytes, the endoplasmic reticulum of which was markedly dilated, suggesting a defect in intracellular protein transport. Here the studies were undertaken to identify the precise molecular defect and the usefulness for animal models in the rdw rat. First, the genetic linkage analysis revealed that the rdw locus was on rat chromosome 7 and was identical to the thyroglobulin (Tg) gene locus. Moreover, the Tg protein level was reduced in the rdw thyroid despite a similar level of the Tg gene transcripts that were indistinguishable in their size from the normal. Next, the complete sequencing of the rdw and the normal rat Tg cDNAs revealed a single nucleotide change, G6958C, resulting in a G2320R missense mutation in a highly conserved region of the Tg molecule. Finally, transient expression of the intact Tg cDNA containing the rdw mutation in the COS-7 cells showed no detectable Tg in the secreted media, indicating a severe defect in the export of the mutant Tg. Together, our observations suggest that a missense mutation, G2320R, in the Tg gene is responsible for the rdw mutation in the rdw rat. Furthermore, the usefulness as animal models was indicated in many studies on the rdw rat.

rdw大鼠最初是从封闭的Wistar-Imamichi大鼠群中分离出的遗传性侏儒品系。随后在rdw大鼠中观察到明显的甲状腺功能减退。最近的一些报道显示rdw甲状腺细胞中存在升高的Chapelone分子水平，其内质网明显扩张，提示细胞内蛋白质转运缺陷。本研究旨在确定rdw大鼠的精确分子缺陷及其作为动物模型的有效性。首先，遗传连锁分析显示，rdw基因座位于大鼠7号染色体上，与甲状腺球蛋白（Tg）基因座相同。此外，Tg蛋白水平降低，尽管在rdw甲状腺的Tg基因转录物的大小是无法区分的正常类似的水平。接下来，对rdw和正常大鼠Tg cDNA的完全测序揭示了一个单核苷酸变化，G6958 C，导致Tg分子的高度保守区域中的G2320 R错义突变。最后，在COS-7细胞中瞬时表达含有rdw突变的完整Tg cDNA，在分泌培养基中没有检测到Tg，表明突变Tg的出口存在严重缺陷。总之，我们的观察结果表明，错义突变，G2320 R，在Tg基因是负责的rdw突变的rdw大鼠。此外，在许多关于rdw大鼠的研究中表明其作为动物模型的有用性。