Biagiotti Laura, Proverbio Maria Carla, Bosio Laura, Gervasi Fabio, Rovida Ermanna, Cerioni Valeria, Bove Maddalena, Valin Paola Sogno, Albarello Luca, Zamproni Ilaria, Grassi Stefano, Doglioni Claudio, Mora Stefano, Chiumello Giuseppe, Biunno Ida
Department of Sciences and Biomedical Technologies, University of Milan, Italy.
Exp Mol Pathol. 2007 Aug;83(1):59-64. doi: 10.1016/j.yexmp.2006.11.006. Epub 2007 Jan 17.
Congenital Hyperinsulinism of Infancy (CHI) is a genetically heterogeneous disorder characterized by profound hypoglycemia related to inappropriate insulin secretion. Two histopathologically and genetically distinct groups are recognized among patients with CHI due to ATP-sensitive potassium channel (KATP) defects: a diffuse type (Di-CHI), which involves the whole pancreas, and a focal form (Fo-CHI), which shows adenomatous islet-cell hyperplasia of a particular area within the normal pancreas. The beta-cell KATP channel consists of two essential subunits: Kir6.2 encoded by the KCNJ11 gene which is the pore-forming unit and belongs to the inwardly rectifying potassium channel family, and SUR1 (sulfonylurea receptor 1) encoded by the ABCC8 gene, which belongs to the ATP-binding cassette (ABC) transporter family. The KATP channel is an octameric complex of four Kir6.2 and four SUR1 subunits. More than one hundred mutations have been found in KATP channel genes ABCC8 and KCNJ11, but to date only twenty mutations have been identified in KCNJ11, most of them are missense mutations and only one is a single base deletion. The Fo-CHI has been demonstrated to arise in individuals who have a germline mutation in the paternal allele of ABCC8 or KCNJ11 in addition to a somatic loss of the maternally derived chromosome region 11p15 in adenomatous pancreatic beta-cells, while Di-CHI predominantly arises from the autosomal recessive inheritance of KATP channel gene mutations. Here we describe the molecular findings in nine children who presented, in the neonatal period, with signs and symptoms of hypoglycemia and diagnosed affected by CHI according to international diagnostic criteria. Direct sequencing of the complete coding exon and promoter region of KCNJ11 gene showed, in two Italian patients, two new heterozygous mutations which result in the appearance of premature translation termination codons resulting in the premature end of Kir6.2. Interestingly most of the CHI mutations detected in other population studies are situated in the ABCC8 gene.
婴儿先天性高胰岛素血症（CHI）是一种基因异质性疾病，其特征为与不适当胰岛素分泌相关的严重低血糖。由于ATP敏感性钾通道（KATP）缺陷，在CHI患者中可识别出两种组织病理学和遗传学上不同的类型：弥漫型（Di-CHI），累及整个胰腺；局灶型（Fo-CHI），表现为正常胰腺内特定区域的腺瘤样胰岛细胞增生。β细胞KATP通道由两个必需亚基组成：由KCNJ11基因编码的Kir6.2，它是形成孔的单位，属于内向整流钾通道家族；以及由ABCC8基因编码的SUR1（磺脲类受体1），它属于ATP结合盒（ABC）转运蛋白家族。KATP通道是由四个Kir6.2和四个SUR1亚基组成的八聚体复合物。在KATP通道基因ABCC8和KCNJ11中已发现一百多种突变，但迄今为止在KCNJ11中仅鉴定出20种突变，其中大多数是错义突变，只有一种是单碱基缺失。已证明Fo-CHI发生于ABCC8或KCNJ11父本等位基因存在种系突变，且腺瘤样胰腺β细胞中母源11p15染色体区域发生体细胞丢失的个体，而Di-CHI主要源于KATP通道基因突变的常染色体隐性遗传。在此，我们描述了9名新生儿期出现低血糖体征和症状并根据国际诊断标准被诊断为CHI的儿童的分子学发现。对KCNJ11基因完整编码外显子和启动子区域进行直接测序发现，两名意大利患者存在两个新的杂合突变，这些突变导致出现过早的翻译终止密码子，从而导致Kir6.2提前终止。有趣的是，在其他人群研究中检测到的大多数CHI突变位于ABCC8基因中。
