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(Circulation. 2002;106:3421.)
© 2002 American Heart Association, Inc.

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Phospholamban Missense Mutation Arg9Cys Causes Dominant Dilated Cardiomyopathy in Man and Mouse

Joachim P. Schmitt, Department of Genetics, Boston, Mass; Mitsuhiro Kamisago, Harvard Medical School, Tokyo, Japan; Michio Asahi, University of Toronto, Toronto, Canada; Guo H. Li, Ferhaan Ahmad, Harvard Medical School, Boston, Mass; David H. MacLennan, University of Toronto, Toronto, Canada; Jonathan Seidman, Harvard Medical School, Boston, Mass; Christine Seidman, Brigham and Women’s Hospital, Boston, Mass. Correspondence to Joachim P. Schmitt, Department of Genetics, Boston, MA 02115. E-mail jschmitt@genetics.med.harvard.edu

Phospholamban (PLN) inhibits the Ca2+-ATPase SERCA2 of the cardiac muscle sarcoplasmatic reticulum (SR). Here, we describe a human kindred with autosomal dominant inheritance of dilated cardiomyopathy and congestive heart failure caused by a Arg9Cys mutation in PLN (PLN-R9C; lod score 4.04;=0). To understand the underlying mechanisms, we created transgenic mice that over-express PLN-R9C. These animals precisely resemble the human phenotype and die of terminal heart failure at age 4 to 8 months. In vitro assays on Ca2+ transport revealed a 72% reduction in the ability of human PLN-R9C to inhibit Ca2+ transport by SERCA2 (P=0.004). Coexpression of PLN-wild type and PLN-R9C, mimicking the heterozygous condition, demonstrated an almost complete rescue of mutant PLN function by PLN-wild type. Furthermore, mutant PLN-R9C traps protein kinase A, thereby preventing phosphorylation of PLN-wild type. Consequently, PLN-wild type is chronically activated, which inhibits Ca2+ uptake into the SR by SERCA2. These data demonstrate that a human PLN mutation can alter Ca2+ homeostasis, trigger detrimental remodeling processes, and cause dilated cardiomyopathy. Other molecules in this pathway are likely candidate disease genes for heart failure.

Molecular Control of Progenitor Cell Migration to the Infarcted Myocardium

Daniele . . . [Full Text of this Article]