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.
Le Scouarnec
Solena
S
Institut National de la Sante et de la Recherche Medicale, UMR 915, F-44000 Nantes, France.
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
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*
C498994:ANK2 protein, human; D017487:Ankyrins; D007473:Ion Channels; D026901:Membrane Transport Proteins; D002118:Calcium