Pro-arrhythmic effects of gain-of-function potassium channel mutations in the short QT syndrome.

The congenital short QT syndrome (SQTS) is a rare condition characterized by abbreviated rate-corrected QT (QTc) intervals on the electrocardiogram and by increased susceptibility to both atrial and ventricular arrhythmias and sudden death. Although mutations to multiple genes have been implicated in the SQTS, evidence of causality is particularly strong for the first three (SQT1-3) variants: these result from gain-of-function mutations in genes that encode K+ channel subunits responsible, respectively, for the IKr, IKs and IK1 cardiac potassium currents. This article reviews evidence for the impact of SQT1-3 missense potassium channel gene mutations on the electrophysiological properties of IKr, IKs and IK1 and of the links between these changes and arrhythmia susceptibility. Data from experimental and simulation studies and future directions for research in this field are considered. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8/KCNJ11 mutations.

AIMS/HYPOTHESIS: Dominantly acting loss-of-function mutations in the ABCC8/KCNJ11 genes can cause mild medically responsive hyperinsulinaemic hypoglycaemia (HH). As controversy exists over whether these mutations predispose to diabetes in adulthood we investigated the prevalence of diabetes in families with dominantly inherited ATP-sensitive potassium (K(ATP)) channel mutations causing HH in the proband. METHODS: We studied the phenotype of 30 mutation carriers (14 children and 16 adults) from nine families with dominant ABCC8/KCNJ11 mutations. Functional consequences of six novel missense mutations were examined by reconstituting the K(ATP) channel in human embryonic kidney 293 (HEK293) cells and evaluating the effect of drugs and metabolic poisoning on the channels using the (86)Rb flux assay. RESULTS: The mutant channels all showed a lack of (86)Rb efflux on exposure to the channel agonist diazoxide or metabolic inhibition. In the families, dominant ABCC8/KCNJ11 mutations were associated with increased birthweight (median + 1.56 SD score [SDS]). Fourteen children had HH and five adults were reported with HH or hypoglycaemic episodes (63%). Progression from hypoglycaemia to diabetes mellitus occurred in two individuals. Eight adults had a history of gestational diabetes in multiple pregnancies or were diabetic (diagnosed at a median age of 31 years). Within these families, none of the 19 adults who were not carriers of the ABCC8/KCNJ11 mutation was known to be diabetic. CONCLUSIONS/INTERPRETATION: The phenotype associated with dominant ABCC8/KCNJ11 mutations ranges from asymptomatic macrosomia to persistent HH in childhood. In adults, it may also be an important cause of dominantly inherited early-onset diabetes mellitus.

The role of abnormal trafficking of KCNE1 in long QT syndrome 5.

LQTS (long QT syndrome) is an important cause of cardiac sudden death. LQTS is characterized by a prolongation of the QT interval on an electrocardiogram. This prolongation predisposes the individual to torsade-de-pointes and subsequent sudden death by ventricular fibrillation. Mutations in a number of genes that encode ion channels have been implicated in LQTS. Hereditary mutations in the alpha- and beta-subunits, KCNQ1 and KCNE1 respectively, of the K(+) channel pore I(Ks) are the commonest cause of LQTS and account for LQTS types 1 and 5 respectively (LQT1 and LQT5). Recently, it has been shown that disease pathogenesis in LQT1 can be influenced by the abnormal trafficking of KCNQ1. In comparison, whether defective trafficking of KCNE1 plays a role in LQT5 is less well established.