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- Title
Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death.
- Authors
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
- 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.
- Publication
Nature, 2003, Vol 421, Issue 6923, p634
- ISSN
0028-0836
- Publication type
Journal Article
- DOI
10.1038/nature01335