Iwasaki N, Oda N, Ogata M, Hara M, Hinokio Y, Oda Y, Yamagata K, Kanematsu S, Ohgawara H, Omori Y, Bell G I
Diabetes Center, Tokyo Women's Medical College, Japan.
Diabetes. 1997 Sep;46(9):1504-8. doi: 10.2337/diab.46.9.1504.
Recent studies have shown that mutations in the hepatocyte nuclear factor (HNF)-1alpha gene are the cause of maturity-onset diabetes of the young type 3 (MODY3). We have screened 193 unrelated Japanese subjects with NIDDM for mutations in this gene: 83 with early-onset NIDDM (diagnosis at <30 years of age) and 110 with late-onset NIDDM (diagnosis > or = 30 years of age). All of the members of the latter group also had at least one sibling with NIDDM. The 10 exons, flanking introns, and promoter region were amplified using polymerase chain reaction and were sequenced directly. Mutations were found in 7 of the 83 (8%) unrelated subjects with early-onset NIDDM. The mutations were each different and included four missense mutations (L12H, R131Q, K205Q, and R263C) and three frameshift mutations (P379fsdelCT, T392fsdelA, and L584S585fsinsTC). One of the 110 subjects with late-onset NIDDM was heterozygous for the missense mutation G191D. This subject, who was diagnosed with NIDDM at 64 years of age, also had a brother with NIDDM (age at diagnosis, 54 years) who carried the same mutation, suggesting that this mutation contributed to the development of NIDDM in these two siblings. None of these mutations were present in 50 unrelated subjects with normal glucose tolerance (100 normal chromosomes). Mutations in the HNF-1alpha gene occur in Japanese subjects with NIDDM and appear to be an important cause of early-onset NIDDM in this population. In addition, they are present in about 1% of subjects with late-onset NIDDM.
近期研究表明，肝细胞核因子（HNF）-1α基因的突变是青年发病型3型糖尿病（MODY3）的病因。我们对193名非亲缘关系的日本2型糖尿病患者进行了该基因突变筛查：83例早发型2型糖尿病患者（30岁之前确诊）和110例晚发型2型糖尿病患者（30岁及以后确诊）。后一组的所有成员均至少有一名患2型糖尿病的兄弟姐妹。使用聚合酶链反应扩增10个外显子、侧翼内含子和启动子区域，并直接进行测序。在83例早发型2型糖尿病非亲缘关系患者中，有7例（8%）发现了突变。这些突变各不相同，包括4个错义突变（L12H、R131Q、K205Q和R263C）和3个移码突变（P379fsdelCT、T392fsdelA和L584S585fsinsTC）。110例晚发型2型糖尿病患者中有1例为错义突变G191D的杂合子。该患者64岁时被诊断为2型糖尿病，其患2型糖尿病的兄弟（诊断时年龄为54岁）也携带相同突变，提示该突变促成了这两名兄弟姐妹患2型糖尿病。50例糖耐量正常的非亲缘关系受试者（100条正常染色体）中均未出现这些突变。HNF-1α基因的突变在日本2型糖尿病患者中存在，似乎是该人群早发型2型糖尿病的一个重要病因。此外，它们在约1%的晚发型2型糖尿病患者中存在。
