A cardiac arrhythmia syndrome caused by loss of ankyrin-B function

Peter J. Mohler, Igor Splawski, Carlo Napolitano, Georgia Bottelli, Leah Sharpe, Katherine Timothy, Silvia G. Priori, Mark T. Keating, Vann Bennett

Research output: Contribution to journalArticle

Abstract

220-kDa ankyrin-B is required for coordinated assembly of Na/Ca exchanger, Na/K ATPase, and inositol trisphosphate (InsP3) 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 Ca2+ dynamics and abnormal localization and expression of Na/Ca exchanger, Na/K ATPase, and InsP3R 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 InsP3 receptor.

Original languageEnglish
Pages (from-to)9137-9142
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number24
DOIs
Publication statusPublished - Jun 15 2004

ASJC Scopus subject areas

  • Genetics
  • General

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