The Genetic Basis for Cardiomyopathy

Seidman, Jonathan G.

doi:10.1016/s0092-8674(01)00242-2

Cited by 952 publications

(236 citation statements)

References 59 publications

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“…Although etiological factors such as ischemia and diabetes can result in DCM, at least 30% of cases are genetic in origin, with mutations found in sarcomeric proteins associated with the cytoskeletal and contractile systems (3). Clinically, DCM is characterized by myocardial hypertrophy, thin-walled ventricles, and myocyte hypoplasia (2,4). Dilated hearts are hypocontractile, with systolic dysfunction leading to a reduced ejection fraction: a hallmark of a failing heart (2, 3).…”

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confidence: 99%

Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function

Schmitt

Debold²,

Ahmad³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

108

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Dilated cardiomyopathy (DCM) leads to heart failure, a leading cause of death in industrialized nations. Approximately 30% of DCM cases are genetic in origin, with some resulting from point mutations in cardiac myosin, the molecular motor of the heart. The effects of these mutations on myosin's molecular mechanics have not been determined. We have engineered two murine models characterizing the physiological, cellular, and molecular effects of DCM-causing missense mutations (S532P and F764L) in the ␣-cardiac myosin heavy chain and compared them with WT mice. Mutant mice developed morphological and functional characteristics of DCM consistent with the human phenotypes. Contractile function of isolated myocytes was depressed and preceded left ventricular dilation and reduced fractional shortening. In an in vitro motility assay, both mutant cardiac myosins exhibited a reduced ability to translocate actin (V actin) but had similar force-generating capacities. Actin-activated ATPase activities were also reduced. Single-molecule laser trap experiments revealed that the lower V actin in the S532P mutant was due to a reduced ability of the motor to generate a step displacement and an alteration of the kinetics of its chemomechanical cycle. These results suggest that the depressed molecular function in cardiac myosin may initiate the events that cause the heart to remodel and become pathologically dilated.animal models ͉ biophysics ͉ genetics ͉ single molecule ͉ laser trap D ilated cardiomyopathy (DCM) is an early step in the pathway leading to heart failure, the leading cause of human morbidity and mortality (1, 2). Although etiological factors such as ischemia and diabetes can result in DCM, at least 30% of cases are genetic in origin, with mutations found in sarcomeric proteins associated with the cytoskeletal and contractile systems (3). Clinically, DCM is characterized by myocardial hypertrophy, thin-walled ventricles, and myocyte hypoplasia (2, 4). Dilated hearts are hypocontractile, with systolic dysfunction leading to a reduced ejection fraction: a hallmark of a failing heart (2, 3). Only recently have autosomal dominant missense mutations to the ␤-cardiac myosin heavy chain (MHC) been identified that result in DCM (5, 6). Because the primary defect resides within the heart's molecular motor, we hypothesized that altered cardiac contractile function in DCM hearts might reflect changes in the mutant myosin's ability to generate force and motion as it cyclically interacts with actin during its hydrolysis of ATP.To investigate the impact of two distinct DCM-causing MHC mutations (S532P and F764L) on cardiac myosin's molecular performance, we have genetically engineered these missense mutations separately into the murine ␣-cardiac MHC gene, the human ␤-MHC homolog, to generate two separate DCM knockin mouse models. In addition to cardiac dilation and dysfunction, defects in isolated myocyte contractility were observed that are consistent with DCM. Interestingly, defects at the whole-heart and cellular levels were cor...

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Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function

Schmitt

Debold²,

Ahmad³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

108

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“…S arcomere protein gene mutations cause hypertrophic cardiomyopathy (HCM) (1,2), an autosomal dominant disorder with increased left ventricular wall thickness (LVWT; hypertrophy) and histopathologic findings of myocyte enlargement, disarray, and increased cardiac fibrosis. Clinical signs and symptoms of disease include shortness of breath, angina, palpitations, syncope, and, most importantly, sudden death.…”

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Somatic events modify hypertrophic cardiomyopathy pathology and link hypertrophy to arrhythmia

Wolf

Moskowitz

Arno

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Sarcomere protein gene mutations cause hypertrophic cardiomyopathy (HCM), a disease with distinctive histopathology and increased susceptibility to cardiac arrhythmias and risk for sudden death. Myocyte disarray (disorganized cell-cell contact) and cardiac fibrosis, the prototypic but protean features of HCM histopathology, are presumed triggers for ventricular arrhythmias that precipitate sudden death events. To assess relationships between arrhythmias and HCM pathology without confounding human variables, such as genetic heterogeneity of disease-causing mutations, background genotypes, and lifestyles, we studied cardiac electrophysiology, hypertrophy, and histopathology in mice engineered to carry an HCM mutation. Both genetically outbred and inbred HCM mice had variable susceptibility to arrhythmias, differences in ventricular hypertrophy, and variable amounts and distribution of histopathology. Among inbred HCM mice, neither the extent nor location of myocyte disarray or cardiac fibrosis correlated with ex vivo signal conduction properties or in vivo electrophysiologically stimulated arrhythmias. In contrast, the amount of ventricular hypertrophy was significantly associated with increased arrhythmia susceptibility. These data demonstrate that distinct somatic events contribute to variable HCM pathology and that cardiac hypertrophy, more than fibrosis or disarray, correlates with arrhythmic risk. We suggest that a shared pathway triggered by sarcomere gene mutations links cardiac hypertrophy and arrhythmias in HCM.fibrosis ͉ somatic modifiers ͉ disarray ͉ electrophysiology ͉ left ventrical wall thickness

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“…Recently, mutations in genes for various sarcomeric proteins were shown to cause dilated cardiomyopathy (DCM) (4). DCM is a relatively common disorder that results in heart failure and premature death (5).…”

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“…DCM is characterized by ventricular dilation and impaired systolic function. Pathological manifestation of DCM includes modest hypertrophy, myocyte degeneration, and increased interstitial fibrosis (4). Proposed causes of DCM include alcohol toxicity, ischemia, metabolic and nutritional deficiency, infectious diseases, and familial and genetic factors.…”

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Different Functional Properties of Troponin T Mutants That Cause Dilated Cardiomyopathy

Venkatraman

Harada

Gomes

et al. 2003

Journal of Biological Chemistry

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The effects of Troponin T (TnT) mutants R141W and ⌬K210, the only two currently known mutations in TnT that cause dilated cardiomyopathy(DCM) independent of familial hypertrophic cardiomyopathy (FHC), and TnT-K273E, a mutation that leads to a progression from FHC to DCM, were investigated. Studies on the Ca 2؉ sensitivity of force development in porcine cardiac fibers demonstrated that TnT-⌬K210 caused a significant decrease in Ca 2؉ sensitivity, whereas the TnT-R141W did not result in any change in Ca 2؉ sensitivity when compared with human cardiac wild-type TnT (HCWTnT). TnT-⌬K210 also caused a decrease in maximal force when compared with HCWTnT and TnT-R141W. In addition, the TnT-⌬K210 mutant decreased maximal ATPase activity in the presence of Ca 2؉ . However, the TnT-K273E mutation caused a significant increase in Ca 2؉ sensitivity but behaved similarly to HCWTnT in actomyosin activation assays. Inhibition of ATPase activity in reconstituted actin-activated myosin ATPase assays was similar for all three TnT mutants and HCWTnT. Additionally, circular dichroism studies suggest that the secondary structure of all three TnT mutants was similar to that of the HCWTnT. These results suggest that a rightward shift in Ca 2؉ sensitivity is not the only determinant for the phenotype of DCM.

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The Genetic Basis for Cardiomyopathy

Cited by 952 publications

References 59 publications

Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function

Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function

Somatic events modify hypertrophic cardiomyopathy pathology and link hypertrophy to arrhythmia

Different Functional Properties of Troponin T Mutants That Cause Dilated Cardiomyopathy

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