FAMILIAL HYPERGLYCEMIA DUE TO MUTATIONS IN GLUCOKINASE - DEFINITION OF A SUBTYPE OF DIABETES-MELLITUS
FAMILIAL HYPERGLYCEMIA DUE TO MUTATIONS IN GLUCOKINASE - DEFINITION OF A SUBTYPE OF DIABETES-MELLITUS
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DOI：
10.1056/nejm199303113281005
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发表时间：
1993-03-11
影响因子：
158.5
通讯作者：
COHEN, D
中科院分区：
文献类型：
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作者：
FROGUEL, P;ZOUALI, H;COHEN, D
研究背景与方法。非胰岛素依赖型糖尿病（NIDDM）是一种遗传异质性疾病。年轻人的成熟型糖尿病是NIDDM的一种形式，发病年龄早，常染色体显性遗传，可由葡萄糖激酶突变引起，葡萄糖激酶是β细胞和肝脏中葡萄糖代谢的关键酶。我们研究了32个法国青年成熟型糖尿病家庭和21个迟发性NIDDM家庭，以确定葡萄糖激酶突变的频率和临床特征。空腹血浆葡萄糖浓度和口服葡萄糖耐量试验用于测定代谢状态。从淋巴细胞中分离DNA，并检测葡萄糖激酶基因的DNA多态性与糖尿病的联系。通过聚合酶链反应扩增每个家族中一个受影响成员的葡萄糖激酶基因的单个外显子，并通过单链DNA构象依赖性多态性分析和DNA测序筛选突变。我们发现了大量的证据表明葡萄糖激酶位点与年轻人的成熟型糖尿病之间存在联系，但与迟发性NIDDM之间没有联系。在32个青年成熟型糖尿病家族中，18个家族中发现了16个突变，但在迟发性NIDDM家族中未发现突变。它们包括10个导致氨基酸替代的突变，3个导致截断蛋白质的合成，3个影响RNA加工。葡萄糖激酶突变的糖尿病患者通常在儿童期开始出现轻度高血糖，而非由于葡萄糖激酶突变引起的青年期成熟型糖尿病患者，高血糖通常在青春期后出现。葡萄糖激酶突变是法国相当一部分年轻的成熟型糖尿病患者高血糖的主要原因，并导致一种相对轻微的NIDDM，可在儿童时期诊断出来。
Background and Methods. Non-insulin-dependent diabetes mellitus (NIDDM) is a genetically heterogeneous disorder. Maturity-onset diabetes of the young, a form of NIDDM with an early age of onset and autosomal dominant inheritance, can result from mutations in glucokinase, a key enzyme of glucose metabolism in beta cells and the liver. We studied 32 French families with maturity-onset diabetes of the young as well as 21 families with late-onset NIDDM to determine the frequency and clinical features of mutations of glucokinase. Fasting plasma glucose concentrations and oral glucose-tolerance tests were used to determine metabolic status. DNA was isolated from lymphocytes, and DNA polymorphisms in the glucokinase gene were tested for linkage with diabetes. Individual exons of the glucokinase gene from one affected member in each family were amplified by the polymerase chain reaction and screened for mutations by analysis of the conformation-dependent polymorphisms of single-stranded DNA and by DNA sequencing.Results. We found substantial evidence of linkage between the glucokinase locus and maturity-onset diabetes of the young but not between this locus and late-onset NIDDM. Sixteen mutations were identified in 18 of the 32 families with maturity-onset diabetes of the young, but none were found in families with late-onset NIDDM. They included 1 0 mutations that resulted in an amino acid substitution, 3 that resulted in the synthesis of a truncated protein, and 3 that affected RNA processing. The affected subjects with glucokinase mutations usually had mild hyperglycemia that began during childhood, whereas in subjects with maturity-onset diabetes of the young not due to glucokinase mutations, hyperglycemia usually appeared after puberty.Conclusions. Mutations in glucokinase are the primary cause of hyperglycemia in a substantial fraction of French patients with maturity-onset diabetes of the young and result in a relatively mild form of NIDDM that can be diagnosed in childhood.