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Gene-trapped mouse embryonic stem cell-derived cardiac myocytes and human genetics implicate AKAP10 in heart rhythm regulation.

Sudden cardiac death due to abnormal heart rhythm kills 400,000-460,000 Americans each year. To identify genes that regulate heart rhythm, we are developing a screen that uses mouse embryonic stem cells (mESCs) with gene disruptions that can be differentiated into cardiac cells for phenotyping. Here, we show that the heterozygous disruption of the Akap10 (D-AKAP2) gene that disrupts the final 51 aa increases the contractile response of cultured cardiac cells to cholinergic signals. In both heterozygous and homozygous mutant mice derived from these mESCs, the same Akap10 disruption increases the cardiac response to cholinergic signals, suggesting a dominant interfering effect of the Akap10 mutant allele. The mutant mice have cardiac arrhythmias and die prematurely. We also found that a common variant of AKAP10 in humans (646V, 40% of alleles) was associated with increased basal heart rate and decreased heart rate variability (markers of low cholinergic/vagus nerve sensitivity). These markers predict an increased risk of sudden cardiac death. Although the molecular mechanism remains unknown, our findings in mutant mESCs, mice, and a common human AKAP10 SNP all suggest a role for AKAP10 in heart rhythm control. Our stem cell-based screen may provide a means of identifying other genes that control heart rhythm.

Pubmed ID: 17485678

Authors

  • Tingley WG
  • Pawlikowska L
  • Zaroff JG
  • Kim T
  • Nguyen T
  • Young SG
  • Vranizan K
  • Kwok PY
  • Whooley MA
  • Conklin BR

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

May 15, 2007

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL60664
  • Agency: NHLBI NIH HHS, Id: HL66621
  • Agency: NCRR NIH HHS, Id: RR18928

Mesh Terms

  • A Kinase Anchor Proteins
  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • Cells, Cultured
  • Cholinergic Agonists
  • Embryonic Stem Cells
  • Female
  • Genetics, Medical
  • Genotype
  • Heart Rate
  • Humans
  • Male
  • Mice
  • Mice, Mutant Strains
  • Middle Aged
  • Molecular Sequence Data
  • Mutation
  • Myocytes, Cardiac
  • Polymorphism, Single Nucleotide
  • Signal Transduction
  • Survival Analysis
  • Vagus Nerve