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 Ca$^2+$
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.
- 1,4,5-trisphosphate
- action
- and
- animals;
- ankyrins,
- atpase,
- binding;
- bradycardia,
- calcium
- cardiac,
- channels,
- classification/genetics/metabolism/physiopathology;
- complications/genetics/metabolism/physiopathology;
- cytoplasmic
- death,
- electrocardiography;
- etiology;
- exchanger,
- female;
- genetics/physiology;
- genetics;
- heart
- heart,
- heterozygote;
- humans;
- inositol
- long
- male;
- metabolism
- metabolism/pathology;
- metabolism;
- mice;
- mutation,
- myocardium,
- nuclear,
- patch-clamp
- pedigree;
- phenotype;
- physiopathology;
- potentials;
- protein
- qt
- rate;
- receptors,
- receptors;
- signaling;
- sodium-calcium
- sodium-potassium-exchanging
- sudden,
- syndrome,
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