Syndrome of extreme insulin resistance due to decreased promoter activity of 5'-flanking region of insulin receptor gene.

我们调查了9个极端胰岛素抵抗综合征家系的遗传基础，在6个家系中发现了胰岛素受体基因的错义突变，Arg^<735>-&gt;Ser^<735>-&gt; Pro^<193>-&gt;Leu^-<193>&gt; Ala^<1048>-&gt;Asp^-<1048>&gt; Glu^<1179>-&gt;Asp^-&gt;<1179>和Trp^<1193>-&gt;Leu^-&gt;<1193>。研究了每种突变的胰岛素抵抗机制，显示如下。β<1048><1048>亚基酪氨酸激酶结构域中的Ala^ -&gt;Asp^导致酪氨酸激酶活性降低。在其他5个家系中，胰岛素结合减少是导致胰岛素抵抗的原因。在这些突变中，Arg^<735>-&gt;Ser^<735>导致胰岛素结合亲和力降低，其他突变导致细胞表面受体数量减少，即，由于合成受体的加工受损，具有这些突变的突变胰岛素受体不能转运到质膜。我们已经阐明了突变Clu^<1179>-&gt;Asp^<1179>和Trp^<1193>-&gt;Leu^中受体亲和力降低的新机制<1193>。在另一个胰岛素受体mRNA表达降低的家系中，我们对胰岛素受体基因启动子区进行了研究，发现患者和对照组胰岛素受体基因启动子区GC盒-603位点的核苷酸序列存在变异。然而，在患者的情况下，启动子活性没有降低。因此，胰岛素受体基因表达降低可能是由于其调控区存在未知的异常而引起的。

We investigated the genetic basis of nine families of syndrome of extreme insulin resistance and identified missense mutations of insulin receptor gene in six families, i.e., Arg^<735>->Ser^<735>, pro^<193>->Leu^<193>, Ala^<1048>->Asp^<1048>, Glu^<1179>->Asp^<1179> and Trp^<1193>->Leu^<1193>. The mechanisms of insulin resistance for each mutations were investigated to show as follows. Ala^<1048>->Asp^<1048> in the tyrosine kinase domain of beta subunit caused decreased tyrosine kinase activity. In other five families, decreased insulin binding was responsible for their insulin resistance. Among these mutations, Arg^<735>->Ser^<735> caused decreased insulin binding affinity and others were responsible for decreased receptor number on the cell surface, i.e., mutant insulin receptors with these mutations were not transported to the plasma membrane because of impaired processing of synthesized receptors. We have clarified a novel mechanism of decreased receptor nember in mutations Clu^<1179>->Asp^<1179> and Trp^<1193>->Leu^<1193>. When expressed in COS 7 cells, most of the mutant receptors were degraded in the biosynthetic process and only part of the receptors were able to be transported to the plasma membrane.In another family with decreased expression of insulin receptor mRNA, we studied promoter region of insulin receptor gene and observed that nucleotide sequence in GC box around position -603 was variable in the patient and control subjects. However, promoter activity was not decreased in the case of the patient. Therefore, unidentified abnormalities in regulatory region which was not studied may responsible for the decrease expression of insulin recepotor gene.