IDENTIFICATION OF THE GENE RESPONSIBLE FOR THE DEVELOPMENT OF FAMILIAL EARLY-ONSET DIABETES MELLITUS (MODY)

青年成熟型糖尿病(MODY)是一种单基因疾病，以常染色体显性遗传为特征，发病年龄在25岁或更早。Mody基因已定位于7号染色体(MODY2)、12号染色体(MODY3)和20号染色体(MODY1)，临床研究表明突变与葡萄糖刺激的胰岛素分泌模式异常有关。在本研究中，MODY3型NIDDM在编码肝细胞核因子-1α(HNF-1α)的基因上存在突变。HNF-1α是一种转录因子，有助于对几个肝脏基因的表达进行组织特异性调节，也是大鼠胰岛素1基因的弱反式激活因子。用聚合酶链式反应和直接测序的方法扩增了高加索人MODY3患者HNF-1α基因的10个外显子和侧翼内含子。发现两个移码突变(P291fsinsC，P379fsdelCT)，两个错义突变(P447L，R131Q)和两个外显子/内含子边界突变(IVS9nt+1G-A，IVS5nt-2A-G)。在55例无关的日本IDDM患者中，有三个突变(5.5%)，这些突变是两个错义突变(R272H，R583G)和一个移码突变(P291fsinsC)。在100名非糖尿病受试者中，这些突变均不存在。这些结果表明，HNF-1α基因缺陷不仅可导致MODY，还可导致IDDM，提示HNF-1α缺陷型IDDM与经典的基于自身免疫性(类型1)的IDDM的亚型分类的重要性。

Maturity-onset diabetes of the young (MODY), a single-gene disorder, is characterized by autosomal dominant inheritance and an age of onset of 25 years or younger. MODY genes have been localized to chromosome 7 (MODY2), 12 (MODY3) and 20 (MODY1) and clinical studies indicate that mutations are associated with abnormal patterns of glucose-stimulated insulin secretion. In this study, MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1alpha (HNF-1alpha). HNF-1alpha is a transcription factor that helps in the tissue-specific regulation of the expression of several liver genes and also functions as a weak transactivator of the rat insulin 1 gene. Ten exons and flanking introns of the HNF-1alpha gene in Caucasian subjects with MODY3 were amplified by the polymerase chain reaction and direct sequencing of the products. Two frameshift mutations (P291fsinsC,P379fsdelCT), two missense mutations (P447L,R131Q), and two mutations at exon/intron boundary (IVS9nt+1G-A,IVS5nt-2A-G) were identified.Mutations were also identified in three (5.5%) of the 55 unrelated Japanese subjects with IDDM.These mutations are two missense mutations (R272H,R583G) and a frameshift mutation (P291fsinsC). None of these mutations were present in 100 non-diabetic subjects. These results indicate that the HNF-1alpha gene defects could lead to the development of not only MODY but also IDDM,implicating the importance of subclassification of HNF-1alpha-deficient IDDM from a classical type of autoimmune-based (Type 1) IDDM.