Novel genes for dilated cardiomyopathy: molecular basis of the disease

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The overall objective of the current SCOR and the PROPOSED RENEWAL is to elucidate the molecular basis for the long-term adaptive response of the heart to injury, both inherited and acquired, whether manifested by hypertrophy or dilatation. In this project we focus on the paradigm of dilated cardiomyopathy affecting primarily the left ventricle. Although six genetic loci are associated with the disease, none of the causative genes have been identified. We propose to identify two of these genes, mapped to1q32 and 10q23 in our families, using either a positional candidate or positional cloning approach. We will use physical mapping information available on the World Wide Web to identify YAC clones and ESTs which map to the critical regions. We will use this cloned material to identify new genetic markers to further delineate the region as well as new candidate genes to be sequenced in our families. We further propose to map a novel locus in a family we have identified that is no linked to any known FDCM locus and ultimately to identify that gene as well. Having identified a missense mutation (Il3451/Met) in the desmin gene which is responsible for DCM in a family, we will conduct in vitro studies to investigate the effect of this mutation on filament assembly and through expression in myocytes attempt to determine the reason for the cardiac restricted phenotype. In vivo studies will be conducted following expression in the transgenic mouse to ascertain the morphological changes and their temporal evolution in relationship to evolving ventricular dysfunction. Utilizing cell morphometry it will be determined whether there is a hypertrophic as well as a dilatory response as determined by the extent of myocyte thickening versus myocyte elongation. Should the phenotype be primarily ventricular dilation as expected from the phenotype in patients with FDCM, it will be of great interest despite a dilatory response to determine whether the usual growth factors (FAS, IGF-1, TGFbeta) or cytoskeletal pathways (integrin kinase, Rho-A, FAK) involved in hypertrophy are also up-regulated. These objectives address the hypothesis that identifying genetic defects and unraveling the molecular basis for familial DCM will provide insight fundamental to the understanding of ventricular dilatation and failure observed in response to a variety of other familial and acquired diseases.