Journal article
ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating
Nature genetics, Vol.36(4), pp.382-387
04/2004
DOI: 10.1038/ng1329
PMCID: PMC1995438
PMID: 15034580
Abstract
Stress tolerance of the heart requires high-fidelity metabolic sensing by ATP-sensitive potassium (K
ATP
) 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 K
ATP
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 K
ATP
channel phenotypes with compromised metabolic signal decoding. Defective catalysis-mediated pore regulation is thus a mechanism for channel dysfunction and susceptibility to dilated cardiomyopathy.
Details
- Title: Subtitle
- ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating
- Creators
- Martin Bienengraeber - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USATimothy M Olson - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USAVitaliy A Selivanov - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USAEva C Kathmann - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USAFearghas O’Cochlain - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USAFan Gao - Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USAAmy B Karger - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USAJeffrey D Ballew - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USADenice M Hodgson - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USALeonid V Zingman - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USAYuan-Ping Pang - Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USAAlexey E Alekseev - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USAAndre Terzic - Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USA
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.36(4), pp.382-387
- DOI
- 10.1038/ng1329
- PMID
- 15034580
- PMCID
- PMC1995438
- ISSN
- 1061-4036
- eISSN
- 1546-1718
- Language
- English
- Date published
- 04/2004
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984094560402771
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