Key result
Mutations in ankyrin-B and ankyrin-G cause cardiac arrhythmias, including a new syndrome associated with sinus node dysfunction and Brugada syndrome, by disrupting ion channel localization.
Ankyrin mutations disrupt cellular targeting of ion channels, representing a new mechanism for cardiac arrhythmias such as Brugada syndrome and sinus node dysfunction.
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May prompt genetic evaluation in select arrhythmia patients; leaves open targeted therapy development.
PURPOSE OF REVIEW: This review addresses a new mechanism for arrhythmia due to abnormal cellular localization of membrane ion channels and transporters. The focus is on ankyrins, a family of proteins that localize diverse membrane ion channels and transporters, and recent evidence that mutations affecting functions of ankyrins result in cardiac arrhythmia. RECENT FINDINGS: A loss-of-function mutation of ankyrin-B in humans and a null mutation in mice result in a dominantly-inherited fatal cardiac arrhythmia initially classified as type 4 long QT syndrome. Characterization of additional probands suggests ankyrin-B mutations cause a new cardiac arrhythmia syndrome associated with sinus node dysfunction that is distinct from long QT syndrome. Ankyrin-B mutation results in elevated calcium transients in cardiomyocytes accompanied by loss of cellular targeting of Na/K ATPase, Na/Ca exchanger, and InsP3 receptor (all ankyrin-binding proteins) to cardiomyocyte membrane domains. The principal voltage-gated Na channel in heart, Nav1.5, is directly associated with ankyrin-G, which is encoded by a distinct gene from ankyrin-B. Mutation of Nav1.5 causing loss of binding to ankyrin-G results in Brugada syndrome and loss of targeting of Nav1.5 to the cell surface of cardiomyocytes. SUMMARY: Ankyrin-B and ankyrin-G are recently recognized constituents of the heart that target diverse ion channels/pumps/transporters to physiologic sites of action in cardiomyocytes. Mutations of ankyrin-B cause a newly defined cardiac arrhythmia syndrome associated with abnormal calcium homeostasis in a mouse model. Ankyrin-G associates with the principal voltage-gated Na channel in the heart, and loss of this interaction due to mutation of Nav1.5 results in Brugada syndrome.
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Mohler et al. (2005) conducted a review in Cardiac arrhythmias. Ankyrin-B and ankyrin-G mutations was evaluated. Mutations in ankyrin-B and ankyrin-G cause cardiac arrhythmias, including a new syndrome associated with sinus node dysfunction and Brugada syndrome, by disrupting ion channel localization.
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