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

Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9137-42. doi: 10.1073/pnas.0402546101. Epub 2004 Jun 3.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Amino Acid Substitution
  • Animals
  • Ankyrins / deficiency*
  • Ankyrins / genetics
  • Ankyrins / physiology
  • Calcium Signaling
  • Electrocardiography
  • Female
  • Humans
  • Long QT Syndrome / enzymology
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / metabolism
  • Male
  • Mice
  • Middle Aged
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / ultrastructure
  • Pedigree
  • Phenotype
  • Sodium-Calcium Exchanger / metabolism
  • Sodium-Potassium-Exchanging ATPase / metabolism

Substances

  • ANK2 protein, human
  • Ank2 protein, mouse
  • Ankyrins
  • Sodium-Calcium Exchanger
  • Sodium-Potassium-Exchanging ATPase