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: PMID:15178757   (View Abstract at PubMed)
PMCID: PMC428486   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.0402546101   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
sick sinus syndrome susceptibilityIAGP 1599114 RGD 
sick sinus syndrome susceptibilityISOANK2 (Homo sapiens)1599114; 1599114 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ank2  (ankyrin 2)

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

Genes (Homo sapiens)
ANK2  (ankyrin 2)


Additional Information