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Nature 421, 634-639 (6 February 2003) | doi:10.1038/nature01335; Received 31 July 2002; Accepted 5 November 2002

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

Peter J. Mohler1,2, Jean-Jacques Schott2,3, Anthony O. Gramolini1, Keith W. Dilly4, Silvia Guatimosim4, William H. duBell5, Long-Sheng Song4, Karine Haurogné3, Florence Kyndt3, Mervat E. Ali1, Terry B. Rogers5, W. J. Lederer4, Denis Escande3, Herve Le Marec3,6 & Vann Bennett1,7

  1. Howard Hughes Medical Institute and Departments of Cell Biology, Biochemistry, and Neuroscience, Duke University Medical Center, Durham, North Carolina 27710, USA
  2. Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Moléculaires, INSERM U533, Hôtel-Dieu, Hôspital G&R Laennec, Nantes, France
  3. Département de Cardiologie, Hôspital G&R Laennec, Nantes, France
  4. Medical Biotechnology Center and Department of Physiology, University of Maryland Biotechnology Institute, Baltimore, Maryland 21021, USA
  5. Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21021, USA
  6. These authors contributed equally to this work
  7. Present address: Box 3892, Duke University Medical Center, Durham, North Carolina 27710, USA.

Correspondence to: Vann Bennett1,7 Correspondence and requests for materials should be addressed to V.B. (e-mail: Email: benne012@mc.duke.edu).

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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.

  1. Howard Hughes Medical Institute and Departments of Cell Biology, Biochemistry, and Neuroscience, Duke University Medical Center, Durham, North Carolina 27710, USA
  2. Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Moléculaires, INSERM U533, Hôtel-Dieu, Hôspital G&R Laennec, Nantes, France
  3. Département de Cardiologie, Hôspital G&R Laennec, Nantes, France
  4. Medical Biotechnology Center and Department of Physiology, University of Maryland Biotechnology Institute, Baltimore, Maryland 21021, USA
  5. Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21021, USA
  6. These authors contributed equally to this work
  7. Present address: Box 3892, Duke University Medical Center, Durham, North Carolina 27710, USA.

Correspondence to: Vann Bennett1,7 Correspondence and requests for materials should be addressed to V.B. (e-mail: Email: benne012@mc.duke.edu).