Cardio-Specific Gene Expression and Genetic Analysis of Myocardial Disorders

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(A) Mechanisms of Cardio-Specific Regulation of the Genes Important to cardiac FunctionsAs for the mechanisms of cardiac hypertrophy, we showed using an in vitro stretch-model of cultured cardiac myocytes that the intracellular signaling cascades involving MAP kinase is, at least in part, mediated by myocardial angiotensin II and that myocardial renin-angiotensin system causes hypertrophy of cardiac myocytes and interstitial fibrosis. We also clarified the mechanisms regulating the expression and transcription of cardiac genes such as cytokine (IL-6), hormones (ANP,BNP,renin, angiotensin), potassium channel, and calcium pump in response to ischemia, mechanical load, calcium, and thyroid hormone. Furthermore, we isolated the human Csx gene using the murine Csx (cardio-specific homeobox) gene as a probe and found that the amino acid sequences of human and murine Csx genes are very similar, indicating that Csx gene is highly conserved among the species.(B) Analysis of the Genes Responsible for Myocardial DisordersFourteen missense mutations of the cardiac beta-myosin heavy chain gene were detected in Japanese patients with hypertrophic cardiomyopathy (HCM), and 13 out of these 14 mutations were different from those found in Caucasian patients. In 11 out of 47 affected Japanese families, there was no linkage to cardiac beta-myosin heavy chain gene, indicating the genetic heterogeneity of Japanese patients with HCM.We also identified a point mutation in tRNA-Leu gene and deletions of mitochondrial DNA in patients with mitochondrial cardiomyopathy who had cardic hypertrophy. Furthermore, we found linkage of Japanese dilated cardiomyopathy to HLA-DR locus, and Japanese long QT syndrome (Romano-Ward syndrome) to HRAS and D11S922 loci on chromosome 11p15.5.