PMID:18832177

Citation	Le Scouarnec, S, Bhasin, N, Vieyres, C, Hund, TJ, Cunha, SR, Koval, O, Marionneau, C, Chen, B, Wu, Y, Demolombe, S, Song, LS, Le Marec, H, Probst, V, Schott, JJ, Anderson, ME and Mohler, PJ (2008) Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease. Proc. Natl. Acad. Sci. U.S.A. 105:15617-22
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.
Links	PubMed PMC2563133 Online version:10.1073/pnas.0805500105
Keywords	Adult; Animals; Ankyrins/genetics; Ankyrins/physiology; Arrhythmias, Cardiac/genetics; Arrhythmias, Cardiac/metabolism; Arrhythmias, Cardiac/physiopathology; Calcium/metabolism; Heart Conduction System/physiopathology; Humans; Ion Channels/metabolism; Membrane Transport Proteins/metabolism; Mice; Mutation; Sinoatrial Node/metabolism; Sinoatrial Node/physiopathology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:ANK2	involved_in	GO:0031647: regulation of protein stability	ECO:0000305: curator inference used in manual assertion	GO:0010628	P		Seeded From UniProt	complete
HUMAN:ANK2	involved_in	GO:0086014: atrial cardiac muscle cell action potential	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:ANK2	involved_in	GO:0086070: SA node cell to atrial cardiac muscle cell communication	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:ANK2	involved_in	GO:0098907: regulation of SA node cell action potential	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:ANK2	involved_in	GO:0060307: regulation of ventricular cardiac muscle cell membrane repolarization	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:ANK2	involved_in	GO:0002027: regulation of heart rate	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:ANK2	involved_in	GO:0003283: atrial septum development	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:ANK2	involved_in	GO:0031647: regulation of protein stability	ECO:0000305: curator inference used in manual assertion	GO:0010628	P	occurs_in:(UBERON:0002351)	Seeded From UniProt	complete
MOUSE:ANK2	involved_in	GO:0086015: SA node cell action potential	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:ANK2	involved_in	GO:0086070: SA node cell to atrial cardiac muscle cell communication	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:ANK2	located_in	GO:0005886: plasma membrane	ECO:0000315: mutant phenotype evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:ANK2	involved_in	GO:1901021: positive regulation of calcium ion transmembrane transporter activity	ECO:0000315: mutant phenotype evidence used in manual assertion		P	has_input:(UniProtKB:P70414) occurs_in:(UBERON:0002351)	Seeded From UniProt	complete
MOUSE:ANK2	involved_in	GO:0051928: positive regulation of calcium ion transport	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:ANK2	involved_in	GO:0010628: positive regulation of gene expression	ECO:0000315: mutant phenotype evidence used in manual assertion		P	occurs_in:(UBERON:0002351)	Seeded From UniProt	complete
MOUSE:ANK2	involved_in	GO:0072659: protein localization to plasma membrane	ECO:0000315: mutant phenotype evidence used in manual assertion		P	has_input:(UniProtKB:Q99246) occurs_in:(UBERON:0002351)	Seeded From UniProt	complete
MOUSE:ANK2	involved_in	GO:0002027: regulation of heart rate	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:ANK2	involved_in	GO:0006874: cellular calcium ion homeostasis	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:CAC1D	located_in	GO:0005886: plasma membrane	ECO:0000314: direct assay evidence used in manual assertion		C	part_of:(UBERON:0002351)	Seeded From UniProt	complete

References

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