We have updated our privacy policy. If you have any question, contact us at privacy@scicrunch.org. Dismiss and don't show again

Searching across hundreds of databases

Our searching services are busy right now. Your search will reload in five seconds.

Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

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 RIS Download

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

Research resources used in this publication

None found

Research tools detected in this publication

None found

Data used in this publication

None found

Associated grants

  • Agency: NHLBI NIH HHS, Id: HL66621
  • Agency: NHLBI NIH HHS, Id: U01 HL066621
  • Agency: NCRR NIH HHS, Id: RR18928
  • Agency: NHLBI NIH HHS, Id: R01 HL060664
  • Agency: NHLBI NIH HHS, Id: HL60664
  • Agency: NCRR NIH HHS, Id: C06 RR018928

Mouse Genome Informatics (Data, Gene Annotation)

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

We have not found any resources mentioned in this publication.