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Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death.
- Source :
-
Nature [Nature] 2003 Feb 06; Vol. 421 (6923), pp. 634-9. - Publication Year :
- 2003
-
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.
- Subjects :
- Action Potentials
Animals
Ankyrins physiology
Bradycardia complications
Bradycardia genetics
Bradycardia metabolism
Bradycardia physiopathology
Calcium Channels metabolism
Calcium Signaling
Electrocardiography
Female
Heart physiopathology
Heart Rate
Heterozygote
Humans
Inositol 1,4,5-Trisphosphate Receptors
Long QT Syndrome classification
Long QT Syndrome metabolism
Long QT Syndrome physiopathology
Male
Mice
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
Ankyrins genetics
Death, Sudden, Cardiac etiology
Long QT Syndrome genetics
Mutation genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0028-0836
- Volume :
- 421
- Issue :
- 6923
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 12571597
- Full Text :
- https://doi.org/10.1038/nature01335