Takahashi Y, Kadowaki H, Momomura K, Fukushima Y, Orban T, Okai T, Taketani Y, Akanuma Y, Yazaki Y, Kadowaki T
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Diabetologia. 1997 Apr;40(4):412-20. doi: 10.1007/s001250050695.
We report a homozygous missense mutation at position 1092 (substitution of glutamine for arginine) in the tyrosine kinase domain of the insulin receptor in a patient with leprechaunism associated with severe insulin resistance and intrauterine growth retardation. Site-directed mutagenesis as well as analyses of the patient's lymphocytes revealed that this mutation causes a marked decrease in tyrosine kinase activity of the insulin receptor without any defect in insulin binding, which causes severe defects in insulin-stimulated glucose transport, glycogen synthesis and DNA synthesis. Thus, this is the first homozygous mutation resulting in a selective-kinase defect of the insulin receptor. Interestingly, the parents who are cousins and are heterozygous for the mutation have type A insulin resistance syndrome. This correlation between genotype and phenotype in a single pedigree suggests that the severity of the mutation will determine the phenotype. Based upon this assumption, we have been successful in prenatal diagnosis of the fifth child. Furthermore, we have demonstrated the effectiveness of clinical administration of insulin-like growth factor-I (IGF-I) in this patient and in vitro analysis of the patient's skin fibroblasts, suggesting that IGF-I can compensate for insulin action via the IGF-I receptor in a patient almost lacking functional insulin receptors.
我们报告了一名患有妖精貌综合征（伴有严重胰岛素抵抗和宫内生长迟缓）的患者，其胰岛素受体酪氨酸激酶结构域第1092位存在纯合错义突变（精氨酸被谷氨酰胺取代）。定点诱变以及对患者淋巴细胞的分析表明，该突变导致胰岛素受体酪氨酸激酶活性显著降低，而胰岛素结合无任何缺陷，这导致胰岛素刺激的葡萄糖转运、糖原合成和DNA合成出现严重缺陷。因此，这是首个导致胰岛素受体选择性激酶缺陷的纯合突变。有趣的是，身为近亲且为该突变杂合子的父母患有A型胰岛素抵抗综合征。单个家系中这种基因型与表型的相关性表明，突变的严重程度将决定表型。基于这一假设，我们成功地对第五个孩子进行了产前诊断。此外，我们已证明胰岛素样生长因子-I（IGF-I）临床给药对该患者有效，并对患者皮肤成纤维细胞进行了体外分析，表明在几乎缺乏功能性胰岛素受体的患者中，IGF-I可通过IGF-I受体补偿胰岛素作用。
