Several mutations in distinct genes, all coding for sarcomeric proteins, havebeen reported in unrelated kindreds with familial hypertrophic cardiomyopathy(FHC). We have identified nine individuals from three families harboring twodistinct mutations in one copy of the β-myosin heavy chain (β-MHC) gene. In this study, the expression of the mutant β-myosin protein isoform, isolated fromslow-twitch fibers of skeletal muscle, was demonstrated by Northern and Westernblot analysis; this myosin showed a decreased in vitro motility activity andproduced a lower actin-activated ATPase activity. Isometric tension, measured in single slow-twitch fibers isolated from the affected individuals, also showed asignificant decrease. The degree of impairment of β-myosin function, as well asthe loss in isometric tension development, were strictly dependent on the amount of the isoform transcribed from the mutated allele. Interestingly, a strongcorrelation was also demonstrated between mutant β-myosin content and clinicalfeatures of FHC. On the other hand, we were unable to detect any correlationbetween mutant β-myosin expression and degree of cardiac hypertrophy, therebystrengthening the hypothesis that hypertrophy, one of the hallmarks of FHC, mightnot necessarily be related to the clinical evolution of this disease. Thesefindings lend support to the notion that additional factors rather than themutated gene may play a pathogenetic role in cardiac wall thickening, whereas theprognosis appears to be strongly related to the amount of mutant protein.

Cardiac and skeletal muscle expression of mutant β-myosin heavy chains, degree of functional impairment and phenotypic heterogeneity in hypertrophic cardiomyopathy

Casadonte R.;Ricci P.;Parrotta E.;Quaresima B.;Faniello C.;Costanzo F.;Cuda G.
2012-01-01

Abstract

Several mutations in distinct genes, all coding for sarcomeric proteins, havebeen reported in unrelated kindreds with familial hypertrophic cardiomyopathy(FHC). We have identified nine individuals from three families harboring twodistinct mutations in one copy of the β-myosin heavy chain (β-MHC) gene. In this study, the expression of the mutant β-myosin protein isoform, isolated fromslow-twitch fibers of skeletal muscle, was demonstrated by Northern and Westernblot analysis; this myosin showed a decreased in vitro motility activity andproduced a lower actin-activated ATPase activity. Isometric tension, measured in single slow-twitch fibers isolated from the affected individuals, also showed asignificant decrease. The degree of impairment of β-myosin function, as well asthe loss in isometric tension development, were strictly dependent on the amount of the isoform transcribed from the mutated allele. Interestingly, a strongcorrelation was also demonstrated between mutant β-myosin content and clinicalfeatures of FHC. On the other hand, we were unable to detect any correlationbetween mutant β-myosin expression and degree of cardiac hypertrophy, therebystrengthening the hypothesis that hypertrophy, one of the hallmarks of FHC, mightnot necessarily be related to the clinical evolution of this disease. Thesefindings lend support to the notion that additional factors rather than themutated gene may play a pathogenetic role in cardiac wall thickening, whereas theprognosis appears to be strongly related to the amount of mutant protein.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12317/7104
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