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[Cardiomyopathies from the aspect of molecular cardiology]
1I. interní klinika 2. LF UK a FN, Praha-Motol.
Insights
Genetic mutations in beta-myosin heavy chain genes are specific causes of hypertrophic cardiomyopathy, affecting both familial and sporadic cases. These mutations can lead to varying clinical outcomes, including sudden cardiac death.
Area of Science:
- Molecular Cardiology
- Genetics
- Cardiovascular Diseases
Context:
- Cardiomyopathies are a group of diseases affecting the heart muscle.
- Molecular cardiology advancements have significantly improved understanding of these conditions.
- Genetic factors play a crucial role in the etiology of cardiomyopathies.
Purpose:
- To elucidate the genetic underpinnings of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM).
- To identify specific gene mutations associated with these conditions and their clinical implications.
- To explore the role of genetic mutations in the definition and classification of cardiomyopathies.
Summary:
- Multiple mutations in the beta-myosin heavy chain gene on chromosome 14 are identified as causative agents of HCM.
- These mutations lead to amino acid substitutions, altering myosin function and muscle contraction.
- Genetic mutations are responsible for approximately 20% of familial dilated cardiomyopathy cases, potentially involving genes like dystrophin and mitochondrial genes.
Impact:
- Identifies specific mutations, such as glycine to arginine substitution at position 403, linked to 100% penetrance and high sudden cardiac death risk in HCM.
- Highlights the existence of asymptomatic mutation carriers, emphasizing the need for genetic screening.
- Suggests that genetic mutations may necessitate a redefinition of cardiomyopathies, integrating molecular findings into diagnostic criteria.
Abstract:
Methods of molecular cardiology have extended our knowledge of cardiomyopathies. In hypertrophic cardiomyopathy the existence of at least nine beta-myosin heavy chain gene mutations on the arm of the 14th chromosome were detected. The latter cause substitution of amino acids in the molecule of this protein with subsequent slowing of the actin shift against myosin during muscle contractions. The presence of beta-myosin heavy chain gene mutation is strictly specific for hypertrophic cardiomyopathy, the mutations cause not only familial cases of the disease but also its sporadic incidence. There exists carriership of mutations, carriers can be quite healthy from the clinical aspect. Individual mutations differ by their penetrance and a different risk of sudden cardiac death. 100% penetrance and a high risk of sudden cardiac death are caused in particular by the mutation with substitution of glycine by arginine in position 403. In addition to possible point mutations there are also mutations with deletion of a portion of this gene and also mutations on chromosomes 1, 11 and 15; so far, however, genes with these mutations were not identified. In dilated cardiomyopathy gene mutations are the cause of familial diseases which account for cca 20% of all these diseases. Mutations can affect also the dystrophin gene on chromosome X, and genes of the mitochondrial genome which code in particular the primary structure of polypeptides participating in oxidative phosphorylation. Mutations as the cause of cardiomyopathies will probably call for a changed definition of these diseases.