A Failure to Adapt

Abstract

The development of serious, potentially lethal cardiac arrhythmias is determined by a complex integration of factors, including, but not limited to, common and rare genetic variants that determine the responses to gene-gene and gene-environment interactions. Even the rare “simple” channelopathies that cause long-QT syndrome (LQTS) and a host of other potentially lethal arrhythmias exhibit a complex set of phenotypes of varying severity and overlapping features. Ankyrins are a family of adapter proteins, first identified in the erythrocyte membrane, that mediate the localization of a diverse group of cellular proteins. Three genes in the mammalian genome encode ankyrins that share a similar global architecture but exhibit distinct expression patterns and functions: ANK1 encodes ankyrin-R, which exhibits a more restricted expression; ANK2 (chromosome 4q25–27) encodes the more broadly distributed ankyrin-B; and ANK3 encodes the ankyrin-G for general or global. Ankyrins bind a number of ion motive proteins essential to normal cardiac electrophysiology, including the Na+-Ca2+ exchanger; inositol 1,4,5-triphosphate receptor; Na+-K+ ATPase; and the voltage-dependent sodium channel (NaV1.5) By the very nature of the role of ankyrins in excitation and contraction in cardiac myocytes, it is understandable that variants in ankyrin-B originally described in a family with congenital LQTS1 would exhibit protean electrical phenotypes. Indeed, in the original LQTS cohort, sinus node dysfunction and atrial fibrillation have been described,1,2 and other electrophysiological abnormalities such as conduction block, idiopathic ventricular fibrillation, and catecholaminergic ventricular tachycardia have been included under the rubric of ankyrin-B syndrome.3 A mutation in the ankyrin binding domain of NaV1.5 has been associated with defective ankyrin-G binding and Brugada syndrome.4 Article p …