Familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disorder, is caused by mutations in cardiac muscle filament proteins. One FHC variant, which is characterized by mid-left ventricular obstruction due to papillary muscle hypertrophy, is caused by an E22K mutation in the ventricular myosin regulatory light chain (RLC). To investigate the functional consequences of this mutation, Danuta Szczesna-Cordary and co-workers have generated transgenic mice overexpressing the E22K mutant of human ventricular RLC (see ). Histologically, the hearts of these animals resemble those of human patients although, surprisingly, the mice have apparently normal echocardiograms. Physiological studies reveal an increased calcium sensitivity of ATPase activity and force development in the cardiac muscles from transgenic E22K-RLC mice when compared with muscles from mice carrying wild-type human RLC. These and results from other model systems indicate that the E22K mutation causes structural perturbations in RLC that affect the myocardium's calcium binding properties and trigger abnormal heart function. This, the authors suggest, may initiate a hypertrophic process and lead to heart failure.
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