Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease caused by mutations in all of the major sarcomeric proteins, including the ventricular myosin regulatory light-chain (RLC). The E22K-RLC mutation has been associated with a rare variant of cardiac hypertrophy defined by mid-left ventricular obstruction due to papillary muscle hypertrophy. This mutation was later found to cause ventricular and septal hypertrophy. We have generated transgenic (Tg) mouse lines of myc-WT (wild type) and myc-E22K mutant of human ventricular RLC and have examined the functional consequences of this FHC mutation in skinned cardiac-muscle preparations. In longitudinal sections of whole mouse hearts stained with hematoxylin and eosin, the E22K-mutant hearts of 13-month-old animals showed signs of inter-ventricular septal hypertrophy and enlarged papillary muscles with no filament disarray. Echo examination did not reveal evidence of cardiac hypertrophy in Tg-E22K mice compared to Tg-WT or Non-Tg hearts. Physiological studies utilizing skinned cardiac-muscle preparations showed an increase by ΔpCa50≥0.1 in Ca2+ sensitivity of myofibrillar ATPase activity and force development in Tg-E22K mice compared with Tg-WT or Non-Tg littermates. Our results suggest that E22K-linked FHC is mediated through Ca2+-dependent events. The FHC-mediated structural perturbations in RLC that affect Ca2+ binding properties of the mutated myocardium are responsible for triggering the abnormal function of the heart that in turn might initiate a hypertrophic process and lead to heart failure.
- Hypertrophic cardiomyopathy
- Myosin regulatory light-chain
ASJC Scopus subject areas
- Cell Biology