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Familial hypertrophic cardiomyopathy: from mutations to functional defects
G Bonne1, L Carrier, P Richard
1From the INSERM Unit 153, the Service de Biochimie B, and the IFR de Physiologie et Génétique Cardiovasculaire, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Insights
Familial hypertrophic cardiomyopathy, a genetic heart muscle disease, stems from sarcomere gene mutations. Understanding these mutations is key to unraveling disease mechanisms and developing treatments.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Diseases
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetic heart condition characterized by ventricular hypertrophy.
- It often leads to arrhythmias and sudden cardiac death.
- HCM is typically inherited as an autosomal-dominant trait.
Purpose of the Study:
- To elucidate the molecular and pathophysiological mechanisms of familial hypertrophic cardiomyopathy.
- To understand the cascade of events from genetic mutation to cardiac dysfunction.
Main Methods:
- Molecular genetics studies identifying mutations in sarcomere protein genes.
- Development of animal models for hypertrophic cardiomyopathy.
- In vitro analyses of sarcomeric and myocyte function.
Main Results:
- Identified mutations in 7 sarcomere protein genes (e.g., myosin heavy chain, troponin T).
- Demonstrated locus and allelic heterogeneity in familial HCM.
- Proposed a pathogenic cascade involving altered sarcomeric function and structure.
Conclusions:
- Familial HCM is a sarcomere disease caused by mutations leading to altered protein function.
- Mutations can result in hypocontractile or hypercontractile states, driving cardiac hypertrophy.
- Further research on animal models and mechanistic studies is crucial for understanding HCM pathogenesis.
Abstract:
Hypertrophic cardiomyopathy is characterized by left and/or right ventricular hypertrophy, which is usually asymmetric and involves the interventricular septum. Typical morphological changes include myocyte hypertrophy and disarray surrounding the areas of increased loose connective tissue. Arrhythmias and premature sudden deaths are common. Hypertrophic cardiomyopathy is familial in the majority of cases and is transmitted as an autosomal-dominant trait. The results of molecular genetics studies have shown that familial hypertrophic cardiomyopathy is a disease of the sarcomere involving mutations in 7 different genes encoding proteins of the myofibrillar apparatus: ss-myosin heavy chain, ventricular myosin essential light chain, ventricular myosin regulatory light chain, cardiac troponin T, cardiac troponin I, alpha-tropomyosin, and cardiac myosin binding protein C. In addition to this locus heterogeneity, there is a wide allelic heterogeneity, since numerous mutations have been found in all these genes. The recent development of animal models and of in vitro analyses have allowed a better understanding of the pathophysiological mechanisms associated with familial hypertrophic cardiomyopathy. One can thus tentatively draw the following cascade of events: The mutation leads to a poison polypeptide that would be incorporated into the sarcomere. This would alter the sarcomeric function that would result (1) in an altered cardiac function and then (2) in the alteration of the sarcomeric and myocyte structure. Some mutations induce functional impairment and support the pathogenesis hypothesis of a "hypocontractile" state followed by compensatory hypertrophy. Other mutations induce cardiac hyperfunction and determine a "hypercontractile" state that would directly induce cardiac hypertrophy. The development of other animal models and of other mechanistic studies linking the genetic mutation to functional defects are now key issues in understanding how alterations in the basic contractile unit of the cardiomyocyte alter the phenotype and the function of the heart.