Abstract
Background: Recently, mutations of the phospholamban gene, a peculiar inhibitor of sarcoplasmic reticulum calcium ATPase (SERCA2a), have been found in patients with familial cardiomyopathy. This result suggests that mutations of SERCA2a gene also cause cardiomyopathy. In our previous study, we found one patient with hypertrophic cardiomyopathy who harbored a missense mutation in the SERCA2a gene. The mutation changed the amino acid sequence from valine (540) to alanine in the cytoplasmic region close to the ATP binding site. Objective: We examined whether the V540A mutation of SERCA2a could cause the abnormal cardiac function or not. Methods: Mouse SERCA2a cDNA was cloned and the V540A mutation was inserted into it. Transgenic mice overexpressing the V540A mutation of SERCA2a in the heart was generated. Cardiac phenotypes were observed in SERCA2a transgenic mice (TG) using in vivo echocardiography and hemodynamic analyses. Results: By Western blot analysis, we found that the expression of SERCA2a protein was increased by 1.7-fold in the ventricles of TG when compared with those of non-transgenic mice. The weight of the left ventricle was slightly, but significantly increased in TG. The maximal first derivate of left ventricular pressure in TG was significantly lower by 16%, when compared with non-transgenic mice. Conclusion: We concluded that the mutation of the SERCA2a gene resulted in the abnormal cardiac function in mice. Our results imply that the V540A mutation of the SERCA2a gene is a causal mutation in human cardiomyopathy. [J Physiol Sci. 2006;56 Suppl:S125]
