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


ABSTRACT: 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.

SUBMITTER: Le Scouarnec S 

PROVIDER: S-EPMC2563133 | biostudies-other | 2008 Oct

REPOSITORIES: biostudies-other

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

Le Scouarnec Solena S   Bhasin Naina N   Vieyres Claude C   Hund Thomas J TJ   Cunha Shane R SR   Koval Olha O   Marionneau Celine C   Chen Biyi B   Wu Yuejin Y   Demolombe Sophie S   Song Long-Sheng LS   Le Marec Hervé H   Probst Vincent V   Schott Jean-Jacques JJ   Anderson Mark E ME   Mohler Peter J PJ  

Proceedings of the National Academy of Sciences of the United States of America 20081001 40


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. Mi  ...[more]

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