HUMAN GLUCOKINASE GENE - ISOLATION, CHARACTERIZATION, AND IDENTIFICATION OF 2 MISSENSE MUTATIONS LINKED TO EARLY-ONSET NON-INSULIN-DEPENDENT (TYPE-2) DIABETES-MELLITUS
HUMAN GLUCOKINASE GENE - ISOLATION, CHARACTERIZATION, AND IDENTIFICATION OF 2 MISSENSE MUTATIONS LINKED TO EARLY-ONSET NON-INSULIN-DEPENDENT (TYPE-2) DIABETES-MELLITUS
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DOI：
10.1073/pnas.89.16.7698
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发表时间：
1992-08-15
影响因子：
11.1
通讯作者：
BELL, GI
中科院分区：
文献类型：
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作者：
STOFFEL, M;FROGUEL, P;BELL, GI
葡萄糖激酶基因的DNA多态性最近被证明与几乎相当于80%的法国糖尿病患者的早发性非胰岛素依赖型糖尿病密切相关。我们之前在其中一个家族的第7外显子中发现了一个无义突变，并表明这可能是这种显性遗传疾病中葡萄糖耐受不良的原因。在这里，我们报道了人类葡萄糖激酶基因的分离和部分序列，并在第7外显子Thr-228—> Met和Gly-261—> Arg上鉴定了两个错义突变，它们与早发性非胰岛素依赖性糖尿病共分离。为了评估这两个位点的突变可能影响葡萄糖激酶活性的分子机制，我们使用相关酵母己糖激酶B的晶体结构作为人类β细胞葡萄糖激酶的简单模型。计算机辅助建模表明，Thr-228突变影响对ATP的亲和力，而Gly-261突变可能改变葡萄糖结合。葡萄糖激酶（一种在肝脏和β细胞葡萄糖代谢中起重要作用的蛋白质）突变的鉴定表明，早发性非胰岛素依赖型糖尿病可能主要是碳水化合物代谢紊乱。
DNA polymorphisms in the glucokinase gene have recently been shown to be tightly linked to early-onset non-insulin-dependent diabetes mellitus in almost-equal-to 80% of French families with this form of diabetes. We previously identified a nonsense mutation in exon 7 in one of these families and showed that it was the likely cause of glucose intolerance in this dominantly inherited disorder. Here we report the isolation and partial sequence of the human glucokinase gene and the identification of two missense mutations in exon 7, Thr-228 --> Met and Gly-261 --> Arg, that cosegregate with early-onset non-insulin-dependent diabetes mellitus. To assess the molecular mechanism by which mutations at these two sites may affect glucokinase activity, the crystal structure of the related yeast hexokinase B was used as a simple model for human beta-cell glucokinase. Computer-assisted modeling suggests that mutation of Thr-228 affects affinity for ATP and mutation of Gly-261 may alter glucose binding. The identification of mutations in glucokinase, a protein that plays an important role in hepatic and beta-cell glucose metabolism, indicates that early-onset non-insulin-dependent diabetes mellitus may be primarily a disorder of carbohydrate metabolism.