Department of Pediatric Endocrinology and Metabolism, Children's Medical Center, Osaka City General Hospital, 2-13-22 Miyakojima-Hondori, Miyakojima, Osaka 534-0021, Japan.
Pediatr Diabetes. 2012 Feb;13(1):26-32. doi: 10.1111/j.1399-5448.2011.00827.x. Epub 2011 Nov 8.
In Asians, mutations in the known maturity-onset diabetes of the young (MODY) genes have been identified in only <15% of patients. These results were obtained mostly through studies on adult patients.
To investigate the molecular basis of Japanese patients with pediatric-onset MODY-type diabetes.
Eighty Japanese patients with pediatric-onset MODY-type diabetes.
Mitochondrial 3243A>G mutation was first tested by the polymerase chain reaction restriction fragment length polymorphism analysis for maternally inherited families. Then, all coding exons and exon-intron boundaries of the HNF1A, HNF1B, GCK, and HNF4A genes were amplified from genomic DNA and directly sequenced. Multiplex ligation-dependent probe amplification analysis was also performed to detect whole-exon deletions.
After excluding one patient with a mitochondrial 3243A>G, mutations were identified in 38 (48.1%) patients; 18 had GCK mutations, 11 had HNF1A mutations, 3 had HNF4A mutations, and 6 had HNF1B mutations. In patients aged <8 yr, mutations were detected mostly in GCK at a higher frequency (63.6%). In patients >9 yr of age, mutations were identified less frequently (45.1%), with HNF1A mutations being the most frequent. A large fraction of mutation-negative patients showed elevated homeostasis model assessment (HOMA) insulin-resistance and normal HOMA-β indices. Most of the HNF1B mutations were large deletions, and, interestingly, renal cysts were undetectable in two patients with whole-gene deletion of HNF1B.
In Japanese patients with pediatric-onset MODY-type diabetes, mutations in known genes were identified at a much higher frequency than previously reported for adult Asians. A fraction of mutation-negative patients presented with insulin-resistance and normal insulin-secretory capacities resembling early-onset type 2 diabetes.
在亚洲人中，已知的青少年发病的成年型糖尿病（MODY）基因突变在<15%的患者中被发现。这些结果主要是通过对成年患者的研究获得的。
研究日本儿科起病 MODY 型糖尿病患者的分子基础。
80 例日本儿科起病 MODY 型糖尿病患者。
首先通过聚合酶链反应限制性片段长度多态性分析对母系遗传家系进行线粒体 3243A>G 突变检测。然后，从基因组 DNA 中扩增 HNF1A、HNF1B、GCK 和 HNF4A 基因的所有编码外显子和外显子-内含子边界，并直接测序。还进行了多重连接依赖性探针扩增分析以检测整个外显子缺失。
排除 1 例线粒体 3243A>G 患者后，在 38 例（48.1%）患者中发现了突变；18 例为 GCK 突变，11 例为 HNF1A 突变，3 例为 HNF4A 突变，6 例为 HNF1B 突变。在年龄<8 岁的患者中，GCK 突变的发生率较高（63.6%）。在年龄>9 岁的患者中，突变的发生率较低（45.1%），其中 HNF1A 突变最常见。大部分突变阴性患者表现出升高的稳态模型评估（HOMA）胰岛素抵抗和正常 HOMA-β指数。大多数 HNF1B 突变是大片段缺失，有趣的是，在两名 HNF1B 全基因缺失的患者中，肾囊肿无法检测到。
在日本儿科起病 MODY 型糖尿病患者中，已知基因的突变频率明显高于以前报道的亚洲成年患者。一部分突变阴性患者表现为胰岛素抵抗和正常的胰岛素分泌能力，类似于早发型 2 型糖尿病。
