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PMID:18832177

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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

Significance

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


See also

References

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