ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating

Martin Bienengraeber, Timothy M. Olson, Vitaliy A. Selivanov, Eva C. Kathmann, Fearghas O'Cochlain, Fan Gao, Amy B. Karger, Jeffrey D. Ballew, Denice M. Hodgson, Leonid V. Zingman, Yuan Ping Pang, Alexey E. Alekseev, Andre Terzic

Research output: Contribution to journalArticle

267 Scopus citations

Abstract

Stress tolerance of the heart requires high-fidelity metabolic sensing by ATP-sensitive potassium (KATP) channels that adjust a 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.

Original languageEnglish (US)
Pages (from-to)382-387
Number of pages6
JournalNature Genetics
Volume36
Issue number4
DOIs
StatePublished - Apr 1 2004

ASJC Scopus subject areas

  • Genetics

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    Bienengraeber, M., Olson, T. M., Selivanov, V. A., Kathmann, E. C., O'Cochlain, F., Gao, F., Karger, A. B., Ballew, J. D., Hodgson, D. M., Zingman, L. V., Pang, Y. P., Alekseev, A. E., & Terzic, A. (2004). ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating. Nature Genetics, 36(4), 382-387. https://doi.org/10.1038/ng1329