Sang Yanmei, Xu Zidi, Liu Min, Yan Jie, Wu Yujun, Zhu Cheng, Ni Guichen
National Key Discipline of Pediatrics (Capital Medical University), Ministry of Education; Department of Endocrinology, genetics and metabolism, Beijing Children's Hospital Affiliated to Capital Medical University, Beijing 100045, China.
Endocr J. 2014;61(9):901-10. doi: 10.1507/endocrj.ej13-0398. Epub 2014 Jul 8.
We conducted a cohort study to elucidate the molecular spectrum of congenital hyperinsulinism (CHI) in Chinese pediatric patients. Thirty Chinese children with CHI were chosen as research subjects, 16 of whom were responsive to diazoxide and 13 of whom were not (1 patient was not given the drug for medical reasons). All exons of the adenosine triphosphate (ATP)-sensitive potassium channel (KATP channel) genes KCNJ11 and ABCC8, the hepatocyte nuclear factor 4 α (HNF4A) gene, and the Glucokinase (GCK) gene as well as exons 6 and 7 and 10-12 of the glutamate dehydrogenase 1 (GLUD1) gene were amplified from genomic DNA and directly sequenced. Mutations were identified in 14 of 30 patients (47%): 3 in GLUD1 (10%) and 11 in the KATP channel genes (37%). Six patients had paternally derived monoallelic KATP channel mutations predictive of the focal CHI form. We found a novel de novo ABCC8 mutation, p. C1000*, a novel paternally inherited ABCC8 mutation, D1505H, and a dominantly inherited ABCC8 mutation, R1217K. The GLUD1 activating mutation R269H was found in 2 patients: 1 de novo and the other paternally inherited. A de novo S445L mutation was found in 1 patient. No significant HNF4A or GCK mutations were found. CHI has complex genetic onset mechanisms. Paternally inherited monoallelic mutations of ABCC8 and KCNJ11 are likely the main causes of KATP-CHI in Chinese patients. Glutamate dehydrogenase-CHI is the second most common cause of CHI, while HNF4A and GCK are rare types of CHI in Chinese patients.
我们开展了一项队列研究，以阐明中国儿科患者先天性高胰岛素血症（CHI）的分子图谱。选取30名患有CHI的中国儿童作为研究对象，其中16名对二氮嗪有反应，13名无反应（1名患者因医疗原因未使用该药物）。从基因组DNA中扩增三磷酸腺苷（ATP）敏感性钾通道（KATP通道）基因KCNJ11和ABCC8、肝细胞核因子4α（HNF4A）基因、葡萄糖激酶（GCK）基因的所有外显子，以及谷氨酸脱氢酶1（GLUD1）基因的外显子6、7和10 - 12，并进行直接测序。30名患者中有14名（47%）检测到突变：GLUD1基因有3名（10%），KATP通道基因有11名（37%）。6名患者存在父源单等位基因KATP通道突变，提示为局灶性CHI类型。我们发现了一个新的ABCC8基因新发突变p.C1000*、一个新的父源遗传ABCC8突变D1505H以及一个显性遗传ABCC8突变R1217K。2名患者发现有GLUD1激活突变R269H：1名新发突变，另1名父源遗传。1名患者发现有新发S445L突变。未发现显著的HNF4A或GCK突变。CHI具有复杂的遗传发病机制。ABCC8和KCNJ11的父源遗传单等位基因突变可能是中国患者KATP - CHI的主要病因。谷氨酸脱氢酶 - CHI是CHI的第二大常见病因，而HNF4A和GCK在中国患者中是罕见的CHI类型。
