Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death by Mohler Peter J, Schott Jean-Jacques, Gramolini Anthony O, Dilly Keith W, Guatimosim Silvia, duBell William H, Song Long-Sheng, Haurogné Karine, Kyndt Florence, Ali Mervat E, Rogers Terry B, Lederer W J, Escande Denis, Le Marec Herve, Bennett Vann in Nature (2003). PubMed

Abstract

Mutations in ion channels involved in the generation and termination of action potentials constitute a family of molecular defects that underlie fatal cardiac arrhythmias in inherited long-QT syndrome. We report here that a loss-of-function (E1425G) mutation in ankyrin-B (also known as ankyrin 2), a member of a family of versatile membrane adapters, causes dominantly inherited type 4 long-QT cardiac arrhythmia in humans. Mice heterozygous for a null mutation in ankyrin-B are haploinsufficient and display arrhythmia similar to humans. Mutation of ankyrin-B results in disruption in the cellular organization of the sodium pump, the sodium/calcium exchanger, and inositol-1,4,5-trisphosphate receptors (all ankyrin-B-binding proteins), which reduces the targeting of these proteins to the transverse tubules as well as reducing overall protein level. Ankyrin-B mutation also leads to altered Ca2+ signalling in adult cardiomyocytes that results in extrasystoles, and provides a rationale for the arrhythmia. Thus, we identify a new mechanism for cardiac arrhythmia due to abnormal coordination of multiple functionally related ion channels and transporters.

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