Molecular Genetical and Functional Analysis in Insulin Receptor Gene Mutation

非胰岛素依赖型糖尿病（NIDDM）表现为轻度至中度胰岛素抵抗，但在一些遗传综合征中也有严重胰岛素抵抗的报道。为了了解胰岛素抵抗在NIDDM中的机制，首先分析这些综合征的胰岛素抵抗机制是有用的。我们已经确定了四个胰岛素受体基因突变，并分析了这些病例中糖尿病的发展。A型Chiba在17-22外显子缺失，A型Yamanashi在14外显子缺失，A型Hokkaido-2在各自1个等位基因的第1008个氨基酸上出现Val取代Gly的点突变。Leprechaun/Asahi在一个等位基因的第15外显子上有两个碱基对缺失，在另一个等位基因上有低mRNA突变。在家谱和临床分析中，酪氨酸激酶结构域的单个突变等位基因，如a型千叶和a型北海道-2型，显性表达糖尿病，而跨膜结构域的一个突变等位基因，如a型山梨，则不显性表达糖尿病。两个等位基因的突变，如Lep/Asahi，表现出严重的胰岛素抵抗形式，如小妖精症。

Non-insulin-dependent diabetes mellitus (NIDDM) shows mild to moderate insulin resistance, but severe insulin resistance has been reported in some genetic syndromes. In order to understand the mechanism of insulin resistance in NIDDM, it is useful to first analyze this mechanism in these syndromes. We have identified four mutations in insulin receptor gene and analyzed the development of diabetes in these cases. Type A Chiba had deletion mutation in exon 17-22, Type A Yamanashi showed deletion of exon 14 and Type A Hokkaido-2 had a point mutation substituting Val for Gly in the 1008th amino acids in respective one allele. Leprechaun/Asahi showed two base pair deletion in exon 15 in one allele and low mRNA mutation in the other allele. In the pedigree and clinical analysis, a single mutant allele in the tyrosine kinase domain, such as Type A Chiba and Type A Hokkaido-2 showed dominant expression of diabetes, but the one in the transmembrane domain, such as Type A Yamanashi did not. The mutation in both alleles, such as Lep/Asahi showed severe forms of insulin resistance, such as leprechaunism.