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

家族性早发性糖尿病 (MODY) 发生相关基因的鉴定

• 批准号: 08457627
• 负责人: TAKEDA Jun
• 金额: $ 4.99万
• 依托单位: GUNMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457627/
• 关键词: positional cloning; early-onset diabetes mellitus; transcription factor; insulin secretion; ポジショナルクローニング; 連鎖解析; MODY3

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.

年轻人成熟型糖尿病（MODY）是一种单基因疾病，其特征为常染色体显性遗传，发病年龄为25岁或以下。MODY基因已定位于7号染色体（MODY 2）、12号染色体（MODY 3）和20号染色体（MODY 1），临床研究表明突变与葡萄糖刺激的胰岛素分泌的异常模式相关。在本研究中，MODY 3型NIDDM在编码肝细胞核因子-1 α（HNF-1 α）的基因中存在突变。HNF-1 α是一种转录因子，有助于组织特异性调节几种肝脏基因的表达，也是大鼠胰岛素1基因的弱反式激活因子。通过聚合酶链反应和产物直接测序，扩增了MODY 3白人受试者HNF-1 α基因的10个外显子和侧翼内含子。两个移码突变在55例无关的日本IDDM患者中，有3例（5.5%）发现突变，包括两个错义突变（P291 fsinsC，P379 fsdelCT），两个错义突变（P447 L，R131 Q）和两个外显子/内含子边界突变（IVS 9 nt +1G-A，IVS 5 nt-2A-G），这些突变是两个错义突变（R272 H，R583 G）和一个移码突变（P291 fsinsC）。这些突变在100名非糖尿病受试者中均不存在。这些结果表明，HNF-1 α基因缺陷不仅可导致MODY的发展，而且也可导致IDDM的发展，暗示了将HNF-1 α缺陷型IDDM从经典类型的基于自身免疫的（1型）IDDM中细分的重要性。

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