Dilated Cardiomyopathy and Heart Failure Caused by a Mutation in Phospholamban

Schmitt, Joachim P.
Kamisago, Mitsuhiro
Asahi, Michio
Li, Guo Hua
Ahmad, Ferhaan
Mende, Ulrike
Kranias, Evangelia G.
MacLennan, David H.
Seidman, J. G.
Seidman, Christine E.

¹Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115, USA. ²Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA. ³Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G1L6, Canada. ⁴Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, OH 45267, USA.

*These authors contributed equally to this work.

†To whom correspondence should be addressed. E-mail: [email protected]

Supporting Online Material: www.sciencemag.org/cgi/content/full/299/5611/1410/DC1; Materials and Methods; Figs. S1 to S3; Table S1; References

17 December 2002; accepted 27 January 2003

Science 299(5611):p 1410-1413, February 28, 2003.

Molecular etiologies of heart failure, an emerging cardiovascular epidemic affecting 4.7 million Americans and costing 17.8 billion health-care dollars annually, remain poorly understood. Here we report that an inherited human dilated cardiomyopathy with refractory congestive heart failure is caused by a dominant Arg → Cys missense mutation at residue 9 (R9C) in phospholamban (PLN), a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic reticular Ca²⁺-adenosine triphosphatase (SERCA2a) pump. Transgenic PLN^R9C mice recapitulated human heart failure with premature death. Cellular and biochemical studies revealed that, unlike wild-type PLN, PLN^R9C did not directly inhibit SERCA2a. Rather, PLN^R9C trapped protein kinase A (PKA), which blocked PKA-mediated phosphorylation of wild-type PLN and in turn delayed decay of calcium transients in myocytes. These results indicate that myocellular calcium dysregulation can initiate human heart failure-a finding that may lead to therapeutic opportunities.