Identification of Mutations in the Hepatocyte Nuclear Factor (HNF)-1α Gene in Japanese Subjects With IDDM
Identification of Mutations in the Hepatocyte Nuclear Factor (HNF)-1α Gene in Japanese Subjects With IDDM
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日本 IDDM 受试者肝细胞核因子 (HNF)-1α 基因突变的鉴定
DOI：
10.2337/diacare.46.10.1643
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发表时间：
1997
期刊：
影响因子：
7.7
通讯作者：
J. Takeda
中科院分区：
文献类型：
--
作者：
S. Yamada;H. Nishigori;H. Onda;T. Utsugi;T. Yanagawa;T. Maruyama;K. Onigata;K. Nagashima;R. Nagai;A. Morikawa;T. Takeuchi;J. Takeda
一种年轻人的成熟型糖尿病，MODY 3，其特征在于严重的胰岛素分泌缺陷，而MODY 2是一种葡萄糖激酶缺乏型糖尿病。最近研究表明，编码转录因子肝细胞核因子（HNF）-1α的基因突变导致MODY 3。由于MODY 3患者发展为显性糖尿病的速度很快，且需要胰岛素治疗的患病率很高，因此我们在日本IDDM受试者中筛选了HNF-1α基因突变。通过聚合酶链反应和产物直接测序来扩增这些受试者中HNF-1α基因的10个外显子和侧翼内含子。在55例无关的IDDM受试者中，有3例（5.5%）发现了突变。1例8岁时确诊为NIDDM，1年后发生IDDM的患者，HNF-1α DNA结合区存在R272 H错义突变（密码子272处Arg被His取代）。P291 fsinsC的移码突变（在密码子291附近的polyC区插入一个C作为Pro），这将产生一个340个氨基酸的突变截短蛋白，在13岁时发现高血糖症和酮尿症时开始胰岛素治疗的受试者中发现。在1例20岁时突发性IDDM患者中发现HNF-1α转录激活区R583 G错义突变（密码子583处Arg被Gly取代）。在100名非糖尿病受试者（200条正常染色体）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早发NIDDM，而且可导致IDDM的发展，这暗示了将日本人的HNF-1α缺陷型IDDM从经典的基于自身免疫的IDDM类型中细分的重要性。
One form of maturity-onset diabetes of the young, MODY3, is characterized by a severe insulin secretory defect, compared with MODY2, a glucokinase-deflcient diabetes. It has recently been shown that mutations of the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1α cause MODY3. Because of the rapid progress to overt diabetes and the high prevalence of required insulin treatment in patients with MODY3, we screened the HNF-1α gene for mutations in Japanese subjects with IDDM. Ten exons and flanking introns of the HNF-1α gene in these subjects were amplified by polymerase chain reaction and direct sequencing of the products. Mutations were identified in three (5.5%) of the 55 unrelated subjects with IDDM. A missense mutation of R272H (replacement of Arg by His in codon 272) in the DNA binding domain of HNF-1α was found in a subject who developed IDDM 1 year after diagnosis of NIDDM at 8 years of age. A frameshift mutation of P291fsinsC (insertion of a C in a polyC tract around codon 291 for Pro), which would generate a mutant truncated protein of 340 amino acids, was found in a subject who started insulin treatment when hyperglycemia and ketonuria were noticed at 13 years of age. A missense mutation of R583G (replacement of Arg by Gly in codon 583) in the transactivation domain of HNF-1α was found in a subject with sudden-onset IDDM at 20 years of age. None of these mutations were present in 100 nondiabetic subjects (200 normal chromosomes). These results indicate that the HNF-1α gene defects could lead to the development of not only early-onset NIDDM but also IDDM, implicating the importance of subclassification of HNF-1α-deficient IDDM from a classical type of autoimmune-based IDDM in Japanese.