Cooper Paige E, Reutter Heiko, Woelfle Joachim, Engels Hartmut, Grange Dorothy K, van Haaften Gijs, van Bon Bregje W, Hoischen Alexander, Nichols Colin G
Department of Cell Biology and Physiology, and Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri.
Hum Mutat. 2014 Jul;35(7):809-13. doi: 10.1002/humu.22555. Epub 2014 May 6.
ATP-sensitive potassium (KATP ) channels, composed of inward-rectifying potassium channel subunits (Kir6.1 and Kir6.2, encoded by KCNJ8 and KCNJ11, respectively) and regulatory sulfonylurea receptor (SUR1 and SUR2, encoded by ABCC8 and ABCC9, respectively), couple metabolism to excitability in multiple tissues. Mutations in ABCC9 cause Cantú syndrome (CS), a distinct multiorgan disease, potentially via enhanced KATP channel activity. We screened KCNJ8 in an ABCC9 mutation-negative patient who also exhibited clinical hallmarks of CS (hypertrichosis, macrosomia, macrocephaly, coarse facial appearance, cardiomegaly, and skeletal abnormalities). We identified a de novo missense mutation encoding Kir6.1[p.Cys176Ser] in the patient. Kir6.1[p.Cys176Ser] channels exhibited markedly higher activity than wild-type channels, as a result of reduced ATP sensitivity, whether coexpressed with SUR1 or SUR2A subunits. Our results identify a novel causal gene in CS, but also demonstrate that the cardinal features of the disease result from gain of KATP channel function, not from a Kir6-independent SUR2 function.
ATP敏感性钾（KATP）通道由内向整流钾通道亚基（Kir6.1和Kir6.2，分别由KCNJ8和KCNJ11编码）和调节性磺脲类受体（SUR1和SUR2，分别由ABCC8和ABCC9编码）组成，在多个组织中将代谢与兴奋性联系起来。ABCC9突变会导致坎图综合征（CS），这是一种独特的多器官疾病，可能是通过增强KATP通道活性所致。我们在一名ABCC9突变阴性且也表现出CS临床特征（多毛症、巨大症、巨头症、面容粗糙、心脏肥大和骨骼异常）的患者中筛查了KCNJ8。我们在该患者中鉴定出一个编码Kir6.1[p.Cys176Ser]的新生错义突变。无论与SUR1还是SUR2A亚基共表达，Kir6.1[p.Cys176Ser]通道由于ATP敏感性降低而表现出比野生型通道明显更高的活性。我们的结果确定了CS中的一个新的致病基因，但也证明了该疾病的主要特征是由KATP通道功能增强导致的，而非来自不依赖Kir6的SUR2功能。
