The overall aim of this proposal is to gain insights into the relation between changes in gene expression and disease induced pathophysiological changes in the heart. Studies on humans have been frustrated so far by the difficulty of correlating the pathophysiological and structural changes occurring in various cardiomyopathies with changes at the molecular level. With the availability to us of human material obtained in the course of endocardial biopsies, preliminary studies have been carried out by my colleagues in this department on changes in one of the key contractile proteins, myosin, in cardiomyopathic heart. So far, the results of these studies indicate that the most notable changes are: an isoform of the normal ventricular light chain LC-1 is present in myopathic ventricles. This variant light chain appears to be identical to human skeletal slow muscle light chain LC-1 in terms of mobilities in two dimensional gel runs. In the proposed work we wish to use recombinant DNA technology to (1) characterize the mRNAs coding for the normal ventricular, cardiomyopathic LC-1, isoproteins and the slow skeletal LC-1 light chains; (2) to determine the nucleotide sequences of the cloned cDNA inserts for these three proteins, and use the DNA sequence information to derive their amino acid sequences. These studies will enable us to decide whether the variant LC-1 specifically found in cardiomyopathy is due to co-expression of a skeletal gene or due to expression of another gene silent in normal hearts.
