Nature Genetics
36, 382 - 387 (2004)
Published online: 21 March 2004; | doi:10.1038/ng1329
ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gatingMartin Bienengraeber1, 2, Timothy M Olson1, 3, Vitaliy A Selivanov1, Eva C Kathmann1, 2, Fearghas O'Cochlain1, Fan Gao2, Amy B Karger1, 2, Jeffrey D Ballew1, Denice M Hodgson1, Leonid V Zingman1, 2, Yuan-Ping Pang2, Alexey E Alekseev1, 2
& Andre Terzic1, 21
Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USA. 2
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USA. 3
Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USA.
Correspondence should be addressed to Andre Terzic terzic.andre@mayo.eduStress tolerance of the heart requires high-fidelity metabolic sensing by ATP-sensitive potassium (KATP) channels that adjust membrane potential−dependent functions to match cellular energetic demand. Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac KATP channel. These missense and frameshift mutations mapped to evolutionarily conserved domains adjacent to the catalytic ATPase pocket within SUR2A. Mutant SUR2A proteins showed aberrant redistribution of conformations in the intrinsic ATP hydrolytic cycle, translating into abnormal KATP channel phenotypes with compromised metabolic signal decoding. Defective catalysis-mediated pore regulation is thus a mechanism for channel dysfunction and susceptibility to dilated cardiomyopathy.
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