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

Peter J Mohler; Jean-Jacques Schott; Anthony O Gramolini; Keith W Dilly; Silvia Guatimosim; William H duBell; Long-Sheng Song; Karine Haurogné; Florence Kyndt; Mervat E Ali; Terry B Rogers; W J Lederer; Denis Escande; Herve Le Marec; Vann Bennett

doi:10.1038/nature01335

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

Journal article

Peer reviewed

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

Peter J Mohler, Jean-Jacques Schott, Anthony O Gramolini, Keith W Dilly, Silvia Guatimosim, William H duBell, Long-Sheng Song, Karine Haurogné, Florence Kyndt, Mervat E Ali, …

Nature (London), Vol.421(6923), pp.634-639

02/06/2003

DOI: 10.1038/nature01335

PMID: 12571597

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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.

Bradycardia - genetics

Calcium Channels - metabolism

Humans

Male

Death, Sudden, Cardiac - etiology

Bradycardia - complications

Long QT Syndrome - physiopathology

Action Potentials

Bradycardia - metabolism

Sodium-Calcium Exchanger - metabolism

Myocardium - metabolism

Electrocardiography

Inositol 1,4,5-Trisphosphate Receptors

Female

Calcium Signaling

Heart - physiopathology

Heart Rate

Bradycardia - physiopathology

Long QT Syndrome - classification

Myocardium - pathology

Ankyrins - physiology

Mutation - genetics

Long QT Syndrome - metabolism

Sodium-Potassium-Exchanging ATPase - metabolism

Patch-Clamp Techniques

Phenotype

Animals

Pedigree

Ankyrins - genetics

Long QT Syndrome - genetics

Protein Binding

Heterozygote

Mice

Receptors, Cytoplasmic and Nuclear - metabolism

Details

Title: Subtitle: Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death
Creators: Peter J Mohler - Howard Hughes Medical Institute and Departments of Cell Biology, Biochemistry, and Neuroscience, Duke University Medical Center, Durham, North Carolina 27710, USA
Jean-Jacques Schott
Anthony O Gramolini
Keith W Dilly
Silvia Guatimosim
William H duBell
Long-Sheng Song
Karine Haurogné
Florence Kyndt
Mervat E Ali
Terry B Rogers
W J Lederer
Denis Escande
Herve Le Marec
Vann Bennett
Resource Type: Journal article
Publication Details: Nature (London), Vol.421(6923), pp.634-639
DOI: 10.1038/nature01335
PMID: 12571597
ISSN: 0028-0836
eISSN: 1476-4687
Language: English
Date published: 02/06/2003
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984094728002771

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