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Analysis of protein regulating expression of insulin receptor gene.

胰岛素受体基因的蛋白调节表达分析。

基本信息

批准号：
02671099
负责人：
KAWAMORI Ryuzo
金额：
$ 1.47万
依托单位：
Osaka 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：
1990
资助国家：
日本
起止时间：
1990 至 1991
项目状态：
已结题

项目摘要

Mutations have been identified in the insulin-receptor gene in insulin-resistant patients. We studied two patients with acanthosis nigricans and insulin resistance caused by a decrease in the number of -cell surface insulin receptors. Patient 1 was an 11-yr-old boy with a fasting insulin level of 2130 PM ; patient 2 was a 14-yr-old girl with hyperandrogenism and a fasting insulin level of 580-740 pM. Based on Southern-blotting studies, the structure of both alleles of the insulin-receptor gene in both patients appeared to be grossly normal. There wag no evidence of insertions, deletions, or major rearrangements. Moreover, the nucleotide sequences of all 22 exons of the gene were normal in both patients. Thus, the predieted amino acid sequences of both patients' insulin receptors were normal. In Epstein-Barr virus-transformed lymphoblasts from patient 1, insulin-receptor mRNA levels were so low they could not be detected with an RNase A protection assay, whereas mRNA levels from patient … More 2 were in the lower half of the normal range. By use of a more sensitive assay based on the polymerase chain reaction, insulin-receptor mRNA could be detected in Epstein-Barr virus-transformed lymphoblasts from both patients. Moreover, because of the existence of silent polymorphisms in the nucleotide sequences, it was possible to differentiate the two allele the two alleles of the insulin-receptor gene in both patients. In patient 2, the two alleles were expressed asymmetrically, with 90% of the mRNA molecules having been transcribed from one allele but only 10% transcribed from the second allele. This suggeststhat there is an unidentified mutation in the underexpressed allele that acts in cis-dominant fashion to decrease insulin-receptor mRNA levels. However, in patient 1, both alleles were expressed symmetrically in similarly low levels. Although not proven, it seems likely that the mutations that decrease insulin-receptor mRNA levels in patient 1 also map to the insulin-receptor locus. Less

在胰岛素抵抗患者的胰岛素受体基因中已经发现了突变。我们研究了两名患者黑棘皮病和胰岛素抵抗引起的细胞表面胰岛素受体的数量减少。患者1是一名11岁男孩，空腹胰岛素水平为2130 pM ;患者2是一名14岁女孩，患有高雄激素血症，空腹胰岛素水平为580-740 pM。基于Southern印迹研究，两名患者的胰岛素受体基因的两个等位基因的结构似乎是大体正常的。没有证据表明有插入、缺失或大的重排。此外，该基因的所有22个外显子的核苷酸序列在两名患者中均正常。因此，这两个病人的胰岛素受体的预定氨基酸序列是正常的。在来自患者1的EB病毒转化的淋巴母细胞中，胰岛素受体mRNA水平如此之低，以至于不能用RNA酶A保护测定法检测到，而来自患者1的mRNA水平则非常低。 ...更多信息 2例在正常范围的下半部分。通过使用一个更敏感的检测聚合酶链反应的基础上，胰岛素受体mRNA可以检测到EB病毒转化的淋巴母细胞从这两个病人。此外，由于核苷酸序列中存在沉默多态性，因此有可能区分两个患者中胰岛素受体基因的两个等位基因。在患者2中，两个等位基因不对称表达，90%的mRNA分子从一个等位基因转录，但只有10%从第二个等位基因转录。这表明在低表达的等位基因中存在一个未知的突变，该突变以顺式显性的方式降低胰岛素受体mRNA水平。然而，在患者1中，两个等位基因以相似的低水平对称表达。尽管尚未证实，但似乎1号患者中降低胰岛素受体mRNA水平的突变也可能映射到胰岛素受体基因座。少