Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease

The identification of nearly a dozen ion channel genes involved in the genesis of human atrial and ventricular arrhythmias has been critical for the diagnosis and treatment of fatal cardiovascular diseases. In contrast, very little is known about the genetic and molecular mechanisms underlying human sinus node dysfunction (SND). Here, we report a genetic and molecular mechanism for human SND. We mapped two families with highly penetrant and severe SND to the human ANK2 (ankyrin-B/AnkB) locus. Mice heterozygous for AnkB phenocopy human SND displayed severe bradycardia and rate variability. AnkB is essential for normal membrane organization of sinoatrial node cell channels and transporters, and AnkB is required for physiological cardiac pacing. Finally, dysfunction in AnkB-based trafficking pathways causes abnormal sinoatrial node (SAN) electrical activity and SND. Together, our findings associate abnormal channel targeting with human SND and highlight the critical role of local membrane organization for sinoatrial node excitability.

[1]  Carlo Napolitano,et al.  A cardiac arrhythmia syndrome caused by loss of ankyrin-B function , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[2]  H. Zhang,et al.  Connexins in the sinoatrial and atrioventricular nodes. , 2006, Advances in cardiology.

[3]  G. Lamas,et al.  The mode selection trial (MOST) in sinus node dysfunction: design, rationale, and baseline characteristics of the first 1000 patients. , 2000, American heart journal.

[4]  E Casiglia,et al.  High heart rate: a risk factor for cardiovascular death in elderly men. , 1999, Archives of internal medicine.

[5]  E. Lakatta,et al.  Membrane Potential Fluctuations Resulting From Submembrane Ca2+ Releases in Rabbit Sinoatrial Nodal Cells Impart an Exponential Phase to the Late Diastolic Depolarization That Controls Their Chronotropic State , 2006, Circulation research.

[6]  G. Breithardt,et al.  Pacemaker channel dysfunction in a patient with sinus node disease. , 2003, The Journal of clinical investigation.

[7]  Mangrum Jm,et al.  The Evaluation and Management of Bradycardia , 2000 .

[8]  E. Lakatta,et al.  Sinoatrial Nodal Cell Ryanodine Receptor and Na + -Ca 2+ Exchanger: Molecular Partners in Pacemaker Regulation , 2001, Circulation research.

[9]  H Honjo,et al.  Regional differences in the role of the Ca2+ and Na+ currents in pacemaker activity in the sinoatrial node. , 1997, The American journal of physiology.

[10]  Dan M Roden,et al.  Defining the Cellular Phenotype of “Ankyrin-B Syndrome” Variants: Human ANK2 Variants Associated With Clinical Phenotypes Display a Spectrum of Activities in Cardiomyocytes , 2007, Circulation.

[11]  Tomaso Gnecchi-Ruscone,et al.  Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. , 2006, The New England journal of medicine.

[12]  F. Collins,et al.  Hereditary spherocytosis associated with deletion of human erythrocyte ankyrin gene on chromosome 8 , 1990, Nature.

[13]  M R Boyett,et al.  Connexin45, a Major Connexin of the Rabbit Sinoatrial Node, Is Co-expressed with Connexin43 in a Restricted Zone at the Nodal-Crista Terminalis Border , 1999, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[14]  Robert H. Anderson,et al.  New insights into pacemaker activity: promoting understanding of sick sinus syndrome. , 2007, Circulation.

[15]  J. Dimarco,et al.  The evaluation and management of bradycardia. , 2000, The New England journal of medicine.

[16]  Robert H. Anderson,et al.  New insights into Sick Sinus Syndrome , 2007 .

[17]  S. Kudoh,et al.  Targeted Disruption of Na+/Ca2+ Exchanger Gene Leads to Cardiomyocyte Apoptosis and Defects in Heartbeat* , 2000, The Journal of Biological Chemistry.

[18]  Itsuo Kodama,et al.  Heterogeneous Expression of Ca2+ Handling Proteins in Rabbit Sinoatrial Node , 2002, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[19]  Michael J Ackerman,et al.  Inherited Arrhythmias: A National Heart, Lung, and Blood Institute and Office of Rare Diseases Workshop Consensus Report About the Diagnosis, Phenotyping, Molecular Mechanisms, and Therapeutic Approaches for Primary Cardiomyopathies of Gene Mutations Affecting Ion Channel Function , 2007, Circulation.

[20]  A. Baines,et al.  Spectrin and ankyrin-based pathways: metazoan inventions for integrating cells into tissues. , 2001, Physiological reviews.

[21]  Lisa J. Martin,et al.  Major Quantitative Trait Locus for Resting Heart Rate Maps to a Region on Chromosome 4 , 2004, Hypertension.

[22]  M. Printz,et al.  Reciprocal rat chromosome 2 congenic strains reveal contrasting blood pressure and heart rate QTL. , 2002, Physiological genomics.

[23]  Peter Michaely,et al.  Inositol 1,4,5-Trisphosphate Receptor Localization and Stability in Neonatal Cardiomyocytes Requires Interaction with Ankyrin-B* , 2004, Journal of Biological Chemistry.

[24]  N. Goldschlager,et al.  Medical progress : cardiac pacing , 1996 .

[25]  Jörg Striessnig,et al.  Functional role of L-type Cav1.3 Ca2+ channels in cardiac pacemaker activity , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Vann Bennett,et al.  Ankyrin-B Coordinates the Na/K ATPase, Na/Ca Exchanger, and InsP3 Receptor in a Cardiac T-Tubule/SR Microdomain , 2005, PLoS biology.

[27]  A. Gramolini,et al.  Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death , 2003, Nature.

[28]  D DiFrancesco,et al.  Pacemaker mechanisms in cardiac tissue. , 1993, Annual review of physiology.

[29]  S. Syverud,et al.  Cardiac pacing. , 1988, Emergency medicine clinics of North America.

[30]  J E Saffitz,et al.  Gap Junction Protein Phenotypes of the Human Heart and Conduction System , 1995, Journal of cardiovascular electrophysiology.

[31]  Edward G Lakatta,et al.  The emergence of a general theory of the initiation and strength of the heartbeat. , 2006, Journal of pharmacological sciences.

[32]  M. Spence,et al.  Heart Rate and Blood Pressure Quantitative Trait Loci for the Airpuff Startle Reaction , 2002, Hypertension.