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Possible involvement of antisense RNA in pathogenesis of type II citrullinemia.

反义 RNA 可能参与 II 型瓜氨酸血症的发病机制。

基本信息

批准号：
62570120
负责人：
SAHEKI Takeyori
金额：
$ 1.47万
依托单位：
Kagoshima 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：
1987
资助国家：
日本
起止时间：
1987 至 1988
项目状态：
已结题

项目摘要

Deficiency of argininosuccinate synthetase (ASS), one of the urea cycle enzymes, causes citrullinemia. From the analysis of the abnormal enzymes in the liver, kidney and cultured skin fibroblasts of more than 70 cases of citrullinemia. we classified the citrullinemia into three distinct types. In type I, a low activity of the enzyme is mainly caused by abnormality in kinetic properties. In type II. the low activity is from a decrease in the enzyme protein which has normal kinetic properties. The low enzyme activity in type II citrullinemia, however, is seen only in the liver, but not in the kidney or cultured skin fibroblasts. on the other hand, no detectable enzyme activity is found in all the organ or cells tested in type III citrullinemia.In the present study. we analyzed abnormality in mRNA in type II and III citrullinemia. In two cases of type III. low levels of ASS mRNA were found in the liver and in one case, a normal content of hepatic ASS mRNA was detected. In the latter case, … More further analysis showed that the mRNA has an about 100 base-defect in the coding region near 3' end. Together with analysis of CRM, the abnormality in the genomic DNA of the patient is probably a point mutation at the exon-intron junction which causes abnormal splicing of mRNA.On the contrary, there were no abnormalities in hepatic ASS mRNA of type II citrullinemia concerning hepatic content, size and structure analyzed by SL nuclease. The results suggest that the pathogenesis of type II is suppressed translation or enhanced degradation of ASS. Possible involvement of antisense RNA in the mechanism of postulated suppressed translation of ASS were tested using sense Riboprobe of ASS mRNA for detection of antisense RNA in the liver of type II citrullinemia. As far as we tested. We could not find any evidence showing the presence of antisense RNA in the liver of control and type II citrullinemic patients. Further investigations will need to clarify the pathogenesis of type II citrullinemia. Less

尿素循环酶之一的氨基琥珀酸合成酶（ASS）缺乏会导致瓜氨酸血症。通过对70余例瓜氨酸血症患者肝、肾及培养的皮肤成纤维细胞中异常酶的分析。我们将瓜氨酸血症分为三种不同的类型。在I型中，酶的低活性主要是由动力学性质的异常引起的。第二类。低活性是由于具有正常动力学性质的酶蛋白的减少。然而，II型瓜氨酸血症的低酶活性仅见于肝脏，而非肾脏或培养的皮肤成纤维细胞。另一方面，在III型瓜氨酸血症的所有器官或细胞中均未发现可检测到的酶活性。我们分析了II型和III型瓜氨酸血症中mRNA的异常。在两种情况下，第三类。在肝脏中发现低水平的ASS mRNA，并且在一个病例中检测到肝脏ASS mRNA的正常含量。在后一种情况下， ...更多信息进一步分析表明，该mRNA在3'端编码区有约100个碱基的缺失。结合CRM分析，患者基因组DNA的异常可能是外显子-内含子连接处的点突变导致mRNA的异常剪接，而SL核酸酶分析的II型瓜氨酸血症患者肝脏ASS mRNA在肝脏含量、大小和结构方面均无异常。结果表明，II型的发病机制是抑制翻译或增强降解的ASS。使用ASS mRNA的正义核糖核酸探针检测II型瓜氨酸血症患者肝脏中的反义RNA，检测反义RNA是否参与假定的ASS翻译抑制机制。据我们测试。我们没有发现任何证据表明对照组和II型瓜氨酸血症患者的肝脏中存在反义RNA。需要进一步研究以阐明II型瓜氨酸血症的发病机制。少