Journal article
Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease
Proceedings of the National Academy of Sciences - PNAS, Vol.105(40), pp.15617-15622
10/07/2008
DOI: 10.1073/pnas.0805500105
PMCID: PMC2563133
PMID: 18832177
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.
Details
- Title: Subtitle
- Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease
- Creators
- Solena Le Scouarnec - Institut National de la Sante et de la Recherche Medicale, UMR 915, F-44000 Nantes, FranceNaina Bhasin - Department of Internal Medicine, Division of Cardiovascular MedicineClaude Vieyres - Cabinet Cardiologique, Clinique St. Joseph, F-16000 Angoulême, FranceThomas J Hund - Department of Internal Medicine, Division of Cardiovascular MedicineShane R Cunha - Department of Internal Medicine, Division of Cardiovascular MedicineOlha Koval - Department of Internal Medicine, Division of Cardiovascular MedicineCeline Marionneau - Institut National de la Sante et de la Recherche Medicale, UMR 915, F-44000 Nantes, FranceBiyi Chen - Department of Internal Medicine, Division of Cardiovascular MedicineYuejin Wu - Department of Internal Medicine, Division of Cardiovascular MedicineSophie Demolombe - Institut National de la Sante et de la Recherche Medicale, UMR 915, F-44000 Nantes, FranceLong-Sheng Song - Department of Internal Medicine, Division of Cardiovascular MedicineHervé Le Marec - Institut National de la Sante et de la Recherche Medicale, UMR 915, F-44000 Nantes, FranceVincent Probst - Institut National de la Sante et de la Recherche Medicale, UMR 915, F-44000 Nantes, FranceJean-Jacques Schott - Institut National de la Sante et de la Recherche Medicale, UMR 915, F-44000 Nantes, FranceMark E Anderson - Department of Internal Medicine, Division of Cardiovascular MedicinePeter J Mohler - Department of Internal Medicine, Division of Cardiovascular Medicine
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.105(40), pp.15617-15622
- DOI
- 10.1073/pnas.0805500105
- PMID
- 18832177
- PMCID
- PMC2563133
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Language
- English
- Date published
- 10/07/2008
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984094674602771
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