Dilated Cardiomyopathy and Heart Failure Caused by a Mutation in Phospholamban

• DOI: 10.1126/science.1081578
• Publication Date: 2003-02-27T23:26:05Z
• Authors: Joachim P. Schmitt; Mitsuhiro Kamisago; Michio Asahi; Guo Hua Li; Ferhaan Ahmad; Ulrike Mende; Evangelia G. Kranias; David H. MacLennan; J. G. Seidman; Christine E. Seidman
• Keywords: Phospholamban; Dilated Cardiomyopathy

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 inherited human dilated cardiomyopathy with refractory congestive failure is caused by a dominant Arg → Cys missense mutation at residue 9 (R9C) in phospholamban (PLN), transmembrane phosphoprotein inhibits the cardiac sarcoplasmic reticular Ca 2+ –adenosine triphosphatase (SERCA2a) pump. Transgenic PLN R9C mice recapitulated premature death. Cellular biochemical studies revealed that, unlike wild-type PLN, did not directly inhibit SERCA2a. Rather, trapped protein kinase A (PKA), which blocked PKA-mediated phosphorylation turn delayed decay calcium transients myocytes. These results indicate myocellular dysregulation can initiate failure—a finding may lead to therapeutic opportunities.