Otonkoski Timo, Jiao Hong, Kaminen-Ahola Nina, Tapia-Paez Isabel, Ullah Mohammed S, Parton Laura E, Schuit Frans, Quintens Roel, Sipilä Ilkka, Mayatepek Ertan, Meissner Thomas, Halestrap Andrew P, Rutter Guy A, Kere Juha
Hospital for Children and Adolescents and Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Am J Hum Genet. 2007 Sep;81(3):467-74. doi: 10.1086/520960. Epub 2007 Jul 26.
Exercise-induced hyperinsulinism (EIHI) is a dominantly inherited hypoglycemic disorder characterized by inappropriate insulin secretion during anaerobic exercise or on pyruvate load. We aimed to identify the molecular basis of this novel disorder of beta -cell regulation. EIHI mapped to chromosome 1 (LOD score 3.6) in a genome scan performed for two families with 10 EIHI-affected patients. Mutational analysis of the promoter of the SLC16A1 gene, which encodes monocarboxylate transporter 1 (MCT1), located under the linkage peak, revealed changes in all 13 identified patients with EIHI. Patient fibroblasts displayed abnormally high SLC16A1 transcript levels, although monocarboxylate transport activities were not changed in these cells, reflecting additional posttranscriptional control of MCT1 levels in extrapancreatic tissues. By contrast, when examined in beta cells, either of two SLC16A1 mutations identified in separate pedigrees resulted in increased protein binding to the corresponding promoter elements and marked (3- or 10-fold) transcriptional stimulation of SLC16A1 promoter-reporter constructs. These studies show that promoter-activating mutations in EIHI induce SLC16A1 expression in beta cells, where this gene is not usually transcribed, permitting pyruvate uptake and pyruvate-stimulated insulin release despite ensuing hypoglycemia. These findings describe a novel disease mechanism based on the failure of cell-specific transcriptional silencing of a gene that is highly expressed in other tissues.
运动诱导的高胰岛素血症（EIHI）是一种常染色体显性遗传的低血糖症，其特征是在无氧运动期间或丙酮酸负荷时胰岛素分泌异常。我们旨在确定这种新型β细胞调节紊乱的分子基础。在对两个家族中10名受EIHI影响的患者进行的全基因组扫描中，EIHI被定位到1号染色体（LOD评分3.6）。对位于连锁峰下的编码单羧酸转运体1（MCT1）的SLC16A1基因启动子进行突变分析，结果显示在所有13名确诊的EIHI患者中均存在变化。患者成纤维细胞显示出异常高的SLC16A1转录水平，尽管这些细胞中的单羧酸转运活性没有改变，这反映了胰腺外组织中MCT1水平的额外转录后调控。相比之下，在β细胞中检测时，在不同家系中鉴定出的两个SLC16A1突变中的任何一个都会导致与相应启动子元件的蛋白质结合增加，并显著（3倍或10倍）刺激SLC16A1启动子报告构建体的转录。这些研究表明，EIHI中的启动子激活突变会在β细胞中诱导SLC16A1表达，而该基因通常不在β细胞中转录，从而尽管会出现低血糖，但仍允许丙酮酸摄取和丙酮酸刺激的胰岛素释放。这些发现描述了一种基于细胞特异性转录沉默失败的新型疾病机制，该基因在其他组织中高度表达。
