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Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death

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 syndrome1. 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 adapters2, 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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Figure 1: Loss-of-function mutation in ankyrin-B in type 4 long-QT syndrome.
Figure 2: Sinus bradycardia, heart rate variability and sudden cardiac death in AnkB+/- mice.
Figure 3: Coordinate reduction of ankyrin-B and ankyrin-B-associated proteins at Z-line/T-tubules of adult AnkB+/- cardiomyocytes.
Figure 4: Ca2+ signalling in adult AnkB+/- ventricular cardiomyocytes.

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Acknowledgements

We thank the type 4 long-QT family for participation. Research support was provided by the Howard Hughes Medical Institute, NIH, the Muscular Dystrophy Association, Canadian Institutes of Health, the Institut National de la Santé et de la Recherche Médicale (INSERM), and the programme Hospitalier de Recherche Clinique. We also thank C. Kontos and B. Knollman for discussions.

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Correspondence to Vann Bennett.

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Mohler, P., Schott, JJ., Gramolini, A. et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature 421, 634–639 (2003). https://doi.org/10.1038/nature01335

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