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

Solena Le Scouarnec, Naina Bhasin, Claude Vieyres, Thomas J. Hund, Shane R. Cunha, Olha Koval, Celine Marionneau, Biyi Chen, Yuejin Wu, Sophie Demolombe, Long Sheng Song, Hervé Le Marec, Vincent Probst, Jean Jacques Schott, Mark Anderson, Peter J. Mohler

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)15617-15622
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number40
DOIs
StatePublished - Oct 7 2008
Externally publishedYes

    Fingerprint

Keywords

  • Arrhythmia
  • Calcium
  • Cytoskeleton
  • Trafficking

ASJC Scopus subject areas

  • General

Cite this

Le Scouarnec, S., Bhasin, N., Vieyres, C., Hund, T. J., Cunha, S. R., Koval, O., Marionneau, C., Chen, B., Wu, Y., Demolombe, S., Song, L. S., Le Marec, H., Probst, V., Schott, J. J., Anderson, M., & Mohler, P. J. (2008). Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease. Proceedings of the National Academy of Sciences of the United States of America, 105(40), 15617-15622. https://doi.org/10.1073/pnas.0805500105