Heart failure mutation

Heart failure is a major cause of death in the developed world and a growing health-care concern. In the February 28 Science Schmitt et al. report the discovery of a mutation in patients suffering from inherited dilated cardiomyopathy with refractory congestive heart disease (Science 2003, 299:1410-1413). A dominant missense mutation (Arg→Cys) was found at residue 9 in phospholamban (PLN). Phospholamban is a 52 amino-acid transmembrane phosphoprotein that regulates the Ca²⁺ ATPase pump (SERCA2a). Schmitt et al. generated transgenic mice expressing the mutant PLN^R9C in the heart and observed biventral cardiac dilation and progressive cardiomyopathy resembling the human symptoms. Tissue culture experiments demonstrated that the PLN^R9C mutant form trapped protein kinase A (PKA), which led to inhibition of the phosphorylation of wild-type PLN^WT protein and delayed decay of Ca²⁺ transients. Manipulating Ca²⁺ handling and/or PLN activity may provide a therapeutic opportunity for treating human heart disease.