RGD Reference Report - A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. - Rat Genome Database

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

Authors: Mohler, PJ  Splawski, I  Napolitano, C  Bottelli, G  Sharpe, L  Timothy, K  Priori, SG  Keating, MT  Bennett, V 
Citation: Mohler PJ, etal., Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9137-42. Epub 2004 Jun 3.
RGD ID: 1599114
Pubmed: (View Article at PubMed) PMID:15178757
DOI: Full-text: DOI:10.1073/pnas.0402546101

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.

Annotation

Disease Annotations    
sick sinus syndrome  (IAGP,ISO)

Objects Annotated

Genes (Rattus norvegicus)
Ank2  (ankyrin 2)

Genes (Mus musculus)
Ank2  (ankyrin 2, brain)

Genes (Homo sapiens)
ANK2  (ankyrin 2)


Additional Information