Mutations in the Hepatocyte Nuclear Factor-1α/MODY3 Gene in Japanese Subjects With Early- and Late-Onset NIDDM
Mutations in the Hepatocyte Nuclear Factor-1α/MODY3 Gene in Japanese Subjects With Early- and Late-Onset NIDDM
复制标题
日本早发型和晚发型 NIDDM 受试者肝细胞核因子 1α/MODY3 基因突变
作者：
N. Iwasaki;N. Oda;M. Ogata;M. Hara;Y. Hinokio;Y. Oda;K. Yamagata;S. Kanematsu;H. Ohgawara;Y. Omori;G. Bell
最近的研究表明，肝细胞核因子(HNF)-1α基因突变是导致年轻3型糖尿病（MODY3）的原因。我们筛选了193名与NIDDM无关的日本受试者进行该基因突变：83名早发性NIDDM（诊断年龄小于30岁），110名晚发性NIDDM（诊断年龄小于30岁）。后一组的所有成员也至少有一个兄弟姐妹患有NIDDM。利用聚合酶链反应扩增10个外显子、侧翼内含子和启动子区，并直接测序。83例无血缘关系的早发性NIDDM患者中有7例（8%）发生突变。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例迟发性NIDDM患者中有1例为杂合型错义突变G191D。该受试者在64岁时被诊断为NIDDM，其兄弟也患有NIDDM（诊断时年龄54岁），携带相同的突变，表明该突变导致了这两个兄弟姐妹的NIDDM的发展。这些突变在50名无血缘关系且葡萄糖耐量正常的受试者（100条正常染色体）中均不存在。HNF-1α基因突变发生在日本NIDDM患者中，似乎是该人群早发性NIDDM的重要原因。此外，约1%的迟发性NIDDM患者存在这些症状。
Recent studies have shown that mutations in the hepatocyte nuclear factor (HNF)-1α 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 >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-1α 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.