Hepatic function in a family with a nonsense mutation (R154X) in the hepatocyte nuclear factor-4 alpha 1/MODY1 gene
Hepatic function in a family with a nonsense mutation (R154X) in the hepatocyte nuclear factor-4 alpha 1/MODY1 gene
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DOI：
10.1172/jci119660
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发表时间：
1997-09-15
影响因子：
15.9
通讯作者：
Bell, GI
中科院分区：
文献类型：
--
作者：
Lindner, T;Gragnoli, C;Bell, GI
青少年发病型糖尿病 (MODY) 是一种遗传异质性单基因疾病，其特征为常染色体显性遗传，通常在 25 岁之前发病，并且胰腺 β 细胞功能异常。肝细胞核因子 (HNF)-4 α/MODY1、葡萄糖激酶/MODY2 和 HNF-1 α/MODY3 基因的突变可导致这种形式的糖尿病。与葡萄糖激酶和 HNF-1 α 基因相比，HNF-4 α 基因突变是 MODY 相对不常见的原因，我们对 MODY1 形式糖尿病的了解仅基于对单一家族（R-W 谱系）的研究。在此，我们报告了 MODY1 的第二个家族的鉴定，以及第一个家族的肝功能的详细表征。该家族的受影响成员 Dresden-II 继承了 HNF-4 α 基因中的无义突变 R154X，预计该转录因子在其表达的组织（包括胰岛、肝脏、肾脏和肠道）中的水平会降低。具有 R154X 突变的受试者表现出对口服葡萄糖的胰岛素分泌反应减弱。 HNF-4 α 在肝脏基因表达的组织特异性调节中发挥核心作用，包括控制参与胆固醇和脂蛋白代谢以及凝血级联的蛋白质的合成。然而，具有 R154X 突变的受试者除了血清脂蛋白 (a) 水平矛盾地增加 3.3 倍外，没有表现出脂质代谢或凝血异常，也没有任何肾功能障碍的证据。结果表明 MODY1 主要是一种 β 细胞功能紊乱。
Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic disorder characterized by autosomal dominant inheritance, onset usually before 25 yr of age, and abnormal pancreatic beta-cell function. Mutations in the hepatocyte nuclear factor(HNF)-4 alpha/MODY1, glucokinase/MODY2, and HNF-1 alpha/MODY3 genes can cause this form of diabetes. In contrast to the glucokinase and HNF-1 alpha genes, mutations in the HNF-4 alpha gene are a relatively uncommon cause of MODY, and our understanding of the MODY1 form of diabetes is based on studies of only a single family, the R-W pedigree. Here we report the identification of a second family with MODY1 and the first in which there has been a detailed characterization of hepatic function. The affected members of this family, Dresden-ll, have inherited a nonsense mutation, R154X, in the HNF-4 alpha gene, and are predicted to have reduced levels of this transcription factor in the tissues in which it is expressed, including pancreatic islets, liver, kidney, and intestine. Subjects with the R154X mutation exhibited a diminished insulin secretory response to oral glucose. HNF-4 alpha plays a central role in tissue-specific regulation of gene expression in the liver, including the control of synthesis of proteins involved in cholesterol and lipoprotein metabolism and the coagulation cascade. Subjects with the R154X mutation, however, showed no abnormalities in lipid metabolism or coagulation except for a paradoxical 3.3-fold increase in serum lipoprotein(a) levels, nor was there any evidence of renal dysfunction in these subjects. The results suggest that MODY1 is primarily a disorder of beta-cell function.