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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Mohler, PJ; Schott, J-J; Gramolini, AO; Dilly, KW; Guatimosim, S; duBell, WH; Song, L-S; Haurogné, K; Kyndt, F; Ali, ME; Rogers, TB; Lederer, WJ; Escande, D; Le Marec, H; Bennett, V

Published Date

  • February 6, 2003

Published In

Volume / Issue

  • 421 / 6923

Start / End Page

  • 634 - 639

PubMed ID

  • 12571597

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature01335


  • eng

Conference Location

  • England