In vivo analysis of an essential myosin light chain mutation linked to familial hypertrophic cardiomyopathy

Mutations in cardiac motor protein genes are associated with familial hyper trophic cardiomyopathy. Mutations in both the regulatory (Glu22Lys) and ess ential light chains (Met149Val) result in an unusual pattern of hypertrophy , leading to obstruction of the midventricular cavity. When a human genomic fragment containing the Met149Val essential myosin light chain was used to generate transgenic mice, the phenotype was recapitulated. To unambiguousl y establish a causal relationship for the regulatory and essential light ch ain mutations in hypertrophic cardiomyopathy, we generated mice that expres sed either the wild-type or mutated forms, using cDNA clones encompassing o nly the coding regions of the gene loci. Expression of the proteins did not lead to a hypertrophic response, even in senescent animals. Changes did oc cur at the myofilament and cellular levels, with the myofibrils showing inc reased Ca2+ sensitivity and significant deficits in relaxation in a transge ne dose-dependent manner. Clearly, mice do not always recapitulate importan t aspects of human hypertrophy. However, because of the discordance of thes e data with data obtained in transgenic mice containing the human genomic f ragment, we believe that the concept that these paint mutations by themselv es can cause hypertrophic cardiomyopathy should be revisited.