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

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...

Full description

Saved in:
Bibliographic Details
Published in:Nature (London) 2003-02, Vol.421 (6923), p.634-639
Main Authors: Bennett, Vann, 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, Marec, Herve Le
Format: Article
Language:English
Subjects:
Action Potentials
Animals
Ankyrins - genetics
Ankyrins - physiology
Biological and medical sciences
Bradycardia - complications
Bradycardia - genetics
Bradycardia - metabolism
Bradycardia - physiopathology
Calcium Channels - metabolism
Calcium Signaling
Cardiac dysrhythmias
Cardiology. Vascular system
Cardiovascular disease
Death, Sudden, Cardiac - etiology
Electrocardiography
Female
Heart
Heart - physiopathology
Heart Rate
Heterozygote
Humans
Inositol 1,4,5-Trisphosphate Receptors
Long QT Syndrome - classification
Long QT Syndrome - genetics
Long QT Syndrome - metabolism
Long QT Syndrome - physiopathology
Male
Medical sciences
Mice
Mutation
Mutation - genetics
Myocardium - metabolism
Myocardium - pathology
Patch-Clamp Techniques
Pedigree
Phenotype
Protein Binding
Receptors, Cytoplasmic and Nuclear - metabolism
Sodium-Calcium Exchanger - metabolism
Sodium-Potassium-Exchanging ATPase - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature01335