Pharmacological rescue of mutant ion channels

See article by Valdivia et al. [1] (pages 279–289) in this issue. The congenital Long QT (LQT) syndrome [1] is a disorder that probably affects 1 per 5000 to 10 000 individuals. The disorder presents clinically with syncope, seizures and a torsade de pointes ventricular tachycardia. It is a repolarization abnormality caused by a decrease in net outward current during the repolarization phase of the cardiac action potential, thereby prolonging action potential duration. Six genes have thus far been linked to the disorder. Mutations in the potassium channel subunits KCNQ1 (LQT1) and KCNE1 (LQT5) affect the slowly activating component of the delayed rectifier current (IKs), while mutations in the potassium channel subunits KCNH2 (LQT2) and KCNE2 (LQT6) affect the rapidly activating component of this current (IKr). Mutations in SCN5A (the gene that encodes the cardiac sodium [Na+] channel) are associated with one of the least common forms of LQT syndrome, type 3, affecting 5–10% of Long QT patients. LQT-associated SCN5A mutations typically lead to the delayed repolarization phenotype by a ‘gain-of-function’ mechanism, through a sustained non-inactivating (depolarizing) Na+ current during the plateau phase of the action potential. A variant of the LQT syndrome is the Jervell–Lange–Nielsen syndrome, wherein homozygous mutations in KCNQ1 or KCNE1 not only result in QT-prolongation but also in sensorineural deafness. Another variant, with mutations in the KCNJ2 gene that encodes the inward rectifier channel Kir2.1, presents with periodic paralysis and dysmorphic features [2].