title: 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.
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, UMR 915, F-44000 Nantes, France.
authors.forename: Solena
authors.initials: S
authors.lastname: Le Scouarnec
authors.forename: Naina
authors.initials: N
authors.lastname: Bhasin
authors.forename: Claude
authors.initials: C
authors.lastname: Vieyres
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.forename: Shane R
authors.initials: SR
authors.lastname: Cunha
authors.forename: Olha
authors.initials: O
authors.lastname: Koval
authors.forename: Celine
authors.initials: C
authors.lastname: Marionneau
authors.forename: Biyi
authors.initials: B
authors.lastname: Chen
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Wu
authors.forename: Sophie
authors.initials: S
authors.lastname: Demolombe
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Song
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Marec
authors.forename: Vincent
authors.initials: V
authors.lastname: Probst
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Schott
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
mesh_terms: D000328:Adult; D000818:Animals; D017487:Ankyrins / Q000235:genetics* / Q000502:physiology*; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D006329:Heart Conduction System / Q000503:physiopathology; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D012849:Sinoatrial Node / Q000378:metabolism / Q000503:physiopathology*
chemical_list: C498994:ANK2 protein, human; D017487:Ankyrins; D007473:Ion Channels; D026901:Membrane Transport Proteins; D002118:Calcium