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 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.
Mohler
Peter J
PJ
Howard Hughes Medical Institute and Departments of Cell Biology, Biochemistry, and Neuroscience, Duke University Medical Center, Durham, North Carolina 27710, USA.
Schott
Jean-Jacques
JJ
Gramolini
Anthony O
AO
Dilly
Keith W
KW
Guatimosim
Silvia
S
duBell
William H
WH
Song
Long-Sheng
LS
Haurogné
Karine
K
Kyndt
Florence
F
Ali
Mervat E
ME
Rogers
Terry B
TB
Lederer
W J
WJ
Escande
Denis
D
Le Marec
Herve
H
Bennett
Vann
V
D000200:Action Potentials; D000818:Animals; D017487:Ankyrins / Q000235:genetics* / Q000502:physiology; D001919:Bradycardia / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004562:Electrocardiography; D005260:Female; D006321:Heart / Q000503:physiopathology; D006339:Heart Rate; D006579:Heterozygote; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008133:Long QT Syndrome / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D010375:Pedigree; D010641:Phenotype; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
C498994:ANK2 protein, human; C498995:Ank2 protein, mouse; D017487:Ankyrins; D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D019831:Sodium-Calcium Exchanger; D000254:Sodium-Potassium-Exchanging ATPase