Insulin resistance and diabetes due to different mutations in the tyrosine kinase domain of both insulin receptor gene alleles.
Insulin resistance and diabetes due to different mutations in the tyrosine kinase domain of both insulin receptor gene alleles.
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DOI：
10.1016/s0021-9258(19)67781-1
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发表时间：
1991-03
期刊：
影响因子：
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通讯作者：
Jyotirmoy KusariS;Y. Takata;E. Hatada;Gary Freidenbergs;O. Kolterman;Jerrold;Olefsky
中科院分区：
文献类型：
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作者：
Jyotirmoy KusariS;Y. Takata;E. Hatada;Gary Freidenbergs;O. Kolterman;Jerrold;Olefsky
胰岛素受体基因突变可导致体内和体外胰岛素抵抗，并可能是选定患者糖尿病的原因。我们研究了一个22岁的糖尿病妇女与A型胰岛素抵抗和黑棘皮病。胰岛素与患者红细胞、单核细胞、脂肪细胞、成纤维细胞和转化淋巴细胞的结合减少。先证者转化淋巴细胞中部分纯化的胰岛素受体对外源性底物的受体自磷酸化和酪氨酸激酶活性降低。患者胰岛素受体cDNA的核苷酸序列的测定显示，该受试者是一个复合杂合子谁继承了两个不同的突变胰岛素受体基因等位基因。父系等位基因含有错义突变，编码受体酪氨酸激酶结构域中981位的精氨酸被谷氨酰胺取代。母体等位基因含有无义突变，导致β亚基中氨基酸988后的提前终止，从而缺失大部分激酶结构域。由具有提前终止密码子的等位基因编码的mRNA可能是不稳定的，因为与另一个等位基因相比，来自该等位基因的mRNA转录物显著降低。无义突变的杂合子母亲仅表现出轻度胰岛素抵抗，而先证者严重胰岛素抵抗;这表明错义突变具有生物学意义。综上所述，（1）我们确定了一名患者及其家族，由于胰岛素受体水平的缺陷，导致胰岛素抵抗和糖尿病的遗传形式;（2）先证者是显示错义突变的复合杂合子（位置981）在一个等位基因和无义突变（3）错义突变在激酶结构域中并且编码具有受损的体外激酶活性的受体;和（4）基于体外和体内表型，981位的激酶结构域突变具有生物学意义，导致胰岛素抗性。
Mutations in the insulin receptor gene can lead to in vivo and in vitro insulin resistance and can be the cause of diabetes mellitus in selected patients. We have studied a 22-year-old diabetic woman with Type A insulin resistance and acanthosis nigricans. Insulin binding to the patient's erythrocytes, monocytes, adipocytes, fibroblasts, and transformed lymphocytes was decreased. Receptor autophosphorylation and tyrosine kinase activity toward an exogenous substrate were reduced in partially purified insulin receptors from the proband's transformed lymphocytes. Determination of the nucleotide sequence of the patient's insulin receptor cDNA revealed that the subject was a compound heterozygote who inherited two different mutant insulin receptor gene alleles. The paternal allele contains a missense mutation encoding the substitution of glutamine for arginine at position 981 in the tyrosine kinase domain of the receptor. The maternal allele contains a nonsense mutation causing premature termination after amino acid 988 in the beta-subunit, thereby deleting most of the kinase domain. The mRNA encoded by the allele with the premature stop codon is likely to be unstable, since mRNA transcripts from this allele were decreased markedly compared with the other allele. The mother, who is heterozygous for the nonsense mutation, exhibited only mild insulin resistance, whereas the proband was severely insulin-resistant; this indicates that the missense mutation is biologically significant. In summary, (1) we have identified a patient and her family with a genetic form of insulin resistance and diabetes due to a defect at the level of the insulin receptor; (2) the proband is a compound heterozygote displaying a missense mutation (position 981) in one allele and a nonsense mutation (position 988) in the other insulin receptor gene allele; (3) the missense mutation is in the kinase domain and encodes a receptor with impaired in vitro kinase activity; and (4) based on the in vitro and in vivo phenotype, the kinase domain mutation at position 981 is biologically significant leading to insulin resistance.