A cardiac arrhythmia syndrome caused by loss of ankyrin-B function.
220-kDa ankyrin-B is required for coordinated assembly of Na/Ca exchanger, Na/K ATPase, and inositol trisphosphate (InsP(3)) receptor at transverse-tubule/sarcoplasmic reticulum sites in cardiomyocytes. A loss-of-function mutation of ankyrin-B identified in an extended kindred causes a dominantly inherited cardiac arrhythmia, initially described as type 4 long QT syndrome. Here we report the identification of eight unrelated probands harboring ankyrin-B loss-of-function mutations, including four previously undescribed mutations, whose clinical features distinguish the cardiac phenotype associated with loss of ankyrin-B activity from classic long QT syndromes. Humans with ankyrin-B mutations display varying degrees of cardiac dysfunction including bradycardia, sinus arrhythmia, idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, and risk of sudden death. However, a prolonged rate-corrected QT interval was not a consistent feature, indicating that ankyrin-B dysfunction represents a clinical entity distinct from classic long QT syndromes. The mutations are localized in the ankyrin-B regulatory domain, which distinguishes function of ankyrin-B from ankyrin-G in cardiomyocytes. All mutations abolish ability of ankyrin-B to restore abnormal Ca(2+) dynamics and abnormal localization and expression of Na/Ca exchanger, Na/K ATPase, and InsP(3)R in ankyrin-B(+/-) cardiomyocytes. This study, considered together with the first description of ankyrin-B mutation associated with cardiac dysfunction, supports a previously undescribed paradigm for human disease due to abnormal coordination of multiple functionally related ion channels and transporters, in this case the Na/K ATPase, Na/Ca exchanger, and InsP(3) receptor.
Mohler
Peter J
PJ
Howard Hughes Medical Institute and Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA. p.mohler@cellbio.duke.edu
Splawski
Igor
I
Napolitano
Carlo
C
Bottelli
Georgia
G
Sharpe
Leah
L
Timothy
Katherine
K
Priori
Silvia G
SG
Keating
Mark T
MT
Bennett
Vann
V
D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000818:Animals; D017487:Ankyrins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D020013:Calcium Signaling; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D010375:Pedigree; D010641:Phenotype; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
C498994:ANK2 protein, human; C498995:Ank2 protein, mouse; D017487:Ankyrins; D019831:Sodium-Calcium Exchanger; D000254:Sodium-Potassium-Exchanging ATPase