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Isolation and Kv Channel Recordings in Murine Atrial and Ventricular Cardiomyocytes
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Published on: March 12, 2013

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

Martin Bienengraeber1, Timothy M Olson, Vitaliy A Selivanov

  • 1Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, Minnesota 55905, USA.

Nature Genetics
|March 23, 2004
PubMed

Insights

Mutations in the ABCC9 gene disrupt cardiac ATP-sensitive potassium (K(ATP)) channels, impairing heart function and leading to dilated cardiomyopathy. This study reveals a novel mechanism of channel dysfunction in heart failure.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Channelopathies

Background:

  • Cardiac ATP-sensitive potassium (K(ATP)) channels are crucial for heart stress tolerance.
  • These channels regulate membrane potential to match cellular energy demand.

Purpose of the Study:

  • To investigate the genetic basis of heart failure and rhythm disturbances in idiopathic dilated cardiomyopathy.
  • To identify mutations in the ABCC9 gene and their impact on cardiac K(ATP) channel function.

Main Methods:

  • Genomic DNA scanning of patients with heart failure and rhythm disturbances.
  • Analysis of mutations in the ABCC9 gene, encoding the SUR2A subunit.
  • Biochemical and biophysical characterization of mutant SUR2A proteins and K(ATP) channel phenotypes.

Main Results:

  • Two mutations (missense and frameshift) were identified in the ABCC9 gene.
  • Mutations affected evolutionarily conserved domains of the SUR2A subunit, near the ATPase pocket.
  • Mutant SUR2A proteins exhibited altered conformations and impaired K(ATP) channel function, compromising metabolic signal decoding.

Conclusions:

  • Defective catalysis-mediated pore regulation by mutant SUR2A is a mechanism for cardiac K(ATP) channel dysfunction.
  • This dysfunction contributes to susceptibility to idiopathic dilated cardiomyopathy.
  • ABCC9 mutations represent a novel genetic cause of heart failure and rhythm disturbances.

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