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Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban

Joachim P Schmitt1, Mitsuhiro Kamisago, Michio Asahi

  • 1Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115, USA.

Science (New York, N.Y.)
|March 1, 2003
PubMed

Insights

An inherited heart failure mutation in phospholamban (PLN) disrupts calcium handling in heart muscle cells. This discovery in dilated cardiomyopathy may lead to new treatments for heart failure.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Genetics

Background:

  • Heart failure is a growing epidemic with poorly understood molecular causes.
  • Dilated cardiomyopathy is a significant form of heart failure.

Purpose of the Study:

  • To identify the molecular cause of an inherited dilated cardiomyopathy.
  • To understand the mechanism by which a phospholamban mutation leads to heart failure.

Main Methods:

  • Genetic sequencing to identify mutations.
  • Creation of transgenic mouse models expressing the mutated phospholamban.
  • Cellular and biochemical assays to study protein function and calcium handling.

Main Results:

  • A dominant Arg --> Cys missense mutation at residue 9 (R9C) in phospholamban (PLN) was identified as the cause of inherited dilated cardiomyopathy.
  • Transgenic mice with PLN(R9C) exhibited heart failure and premature death.
  • The mutated PLN(R9C) protein trapped protein kinase A (PKA), preventing phosphorylation of wild-type PLN and altering myocyte calcium transients.

Conclusions:

  • Myocellular calcium dysregulation, initiated by the PLN(R9C) mutation, can cause human heart failure.
  • This finding opens potential therapeutic avenues for heart failure by targeting calcium handling mechanisms.

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