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.
Tingley
Whittemore G
WG
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
Pawlikowska
Ludmila
L
Zaroff
Jonathan G
JG
Kim
Taeryn
T
Nguyen
Trieu
T
Young
Stephen G
SG
Vranizan
Karen
K
Kwok
Pui-Yan
PY
Whooley
Mary A
MA
Conklin
Bruce R
BR
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D018679:Cholinergic Agonists / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005826:Genetics, Medical; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D014630:Vagus Nerve / Q000187:drug effects
D054758:A Kinase Anchor Proteins; C484639:AKAP10 protein, human; D048868:Adaptor Proteins, Signal Transducing; C108772:Akap10 protein, mouse; D018679:Cholinergic Agonists