Mutations In the hepatocyte nuclear factor-4 alpha gene in maturity-onset diabetes of the young (MODY1)
Mutations In the hepatocyte nuclear factor-4 alpha gene in maturity-onset diabetes of the young (MODY1)
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DOI：
10.1038/384458a0
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发表时间：
1996-12-05
期刊：
影响因子：
64.8
通讯作者：
Bell, GI
中科院分区：
文献类型：
--
作者：
Yamagata, K;Furuta, H;Bell, GI
年轻人成熟型糖尿病（MODY）是一种遗传异质性单基因型非胰岛素依赖型（2型）糖尿病（NIDDM），其特征为发病早，通常在25岁之前，常发生在青春期或儿童期，并为常染色体显性遗传（1）。据估计，2-5%的NIDDM患者可能患有这种形式的糖尿病（2，3）。临床研究表明，糖尿病前期MODY受试者具有正常的胰岛素敏感性，但患有葡萄糖刺激的胰岛素分泌缺陷，这表明胰腺β细胞功能障碍而不是胰岛素抵抗是这种疾病的主要缺陷（4，5）。连锁研究已将MODY突变的基因定位在人类染色体20（MODY 1）（6）、7（MODY 2）（2）和12（MODY 3）（7）上，其中MODY 2和MODY 3与编码葡萄糖的基因是等位基因（2）胰岛素分泌的关键调节因子和肝细胞核因子-1 α（HNF-1 α）（8），一种参与肝脏基因的组织特异性调节的转录因子，但也在胰岛、胰岛素瘤细胞和其他组织中表达。在这里，我们表明MODY 1是编码HNF-4 α的基因（基因符号，TCF 14），是类固醇/甲状腺激素受体超家族的成员，也是HNF-1 α表达的上游调节因子-（9，11）。
THE disease maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of non-insulin-dependent (type 2) diabetes mellitus (NIDDM), characterized by early onset, usually before 25 years of age and often in adolescence or childhood, and by autosomal dominant inheritance(1). It has been estimated that 2-5% of patients with NIDDM may have this form of diabetes mellitus(2,3). Clinical studies have shown that prediabetic MODY subjects have normal insulin sensitivity but suffer from a defect in glucose-stimulated insulin secretion, suggesting that pancreatic beta-cell dysfunction rather than insulin resistance is the primary defect in this disorder(4,5). Linkage studies have localized the genes that are mutated in MODY on human chromosomes 20 (MODY1)(6), 7 (MODY2)(2) and 12 (MODY3)(7), with MODY2 and MODY3 being allelic with the genes encoding glucokinase(2), a key regulator of insulin secretion, and hepatocyte nuclear factor-1 alpha (HNF-1 alpha)(8), a transcription factor involved in tissue-specific regulation of liver genes but also expressed in pancreatic islets, insulinoma cells and other tissues. Here we show that MODY1 is the gene encoding HNF-4 alpha (gene symbol, TCF14), a member of the steroid/thyroid hormone receptor superfamily and an upstream regulator of HNF-1 alpha expressiong-(9,11).