Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, Lesage S, Stoffel M, Takeda J, Passa P
Centre d'Etude du Polymorphisme Humain, Paris, France.
N Engl J Med. 1993 Mar 11;328(10):697-702. doi: 10.1056/NEJM199303113281005.
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.
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 10 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.
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.
非胰岛素依赖型糖尿病（NIDDM）是一种遗传异质性疾病。青年发病的成年型糖尿病是NIDDM的一种形式，发病年龄早，呈常染色体显性遗传，可能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个患有青年发病的成年型糖尿病的法国家庭以及21个患有晚发型NIDDM的家庭，以确定葡萄糖激酶突变的频率和临床特征。采用空腹血糖浓度和口服葡萄糖耐量试验来确定代谢状态。从淋巴细胞中分离DNA，并检测葡萄糖激酶基因中的DNA多态性与糖尿病的连锁关系。通过聚合酶链反应扩增每个家庭中一名患病成员的葡萄糖激酶基因的各个外显子，并通过分析单链DNA的构象依赖性多态性和DNA测序来筛选突变。
我们发现了葡萄糖激酶基因座与青年发病的成年型糖尿病之间存在显著的连锁证据，但该基因座与晚发型NIDDM之间不存在连锁关系：在32个患有青年发病的成年型糖尿病的家庭中的18个家庭中鉴定出16种突变，但在患有晚发型NIDDM的家庭中未发现任何突变：其中包括10种导致氨基酸替代的突变、3种导致截短蛋白合成的突变以及3种影响RNA加工的突变。患有葡萄糖激酶突变的受影响受试者通常在儿童期开始出现轻度高血糖，而在非葡萄糖激酶突变导致的青年发病的成年型糖尿病受试者中，高血糖通常在青春期后出现。
葡萄糖激酶突变是相当一部分法国青年发病的成年型糖尿病患者高血糖的主要原因，并导致一种相对轻度的NIDDM形式，可在儿童期诊断。
