Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy
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G Bonne1, L Carrier, J Bercovici
1INSERM UR153, Groupe Hospitalier Pitié-Salpétrière, Paris, France.
Insights
Mutations in the cardiac myosin binding protein-C gene are linked to hypertrophic cardiomyopathy. This finding supports the role of contractile protein gene mutations in causing this heart condition.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant condition causing ventricular hypertrophy and is a leading cause of sudden cardiac death in young individuals.
- Three genes (beta-myosin heavy chain, cardiac troponin T, alpha-tropomyosin) are known to cause FHC.
- The cardiac myosin binding protein-C (MyBP-C) gene on chromosome 11p11.2 is a candidate for the fourth FHC locus (CMH4).
Purpose of the Study:
- To investigate the role of the MyBP-C gene in chromosome 11-linked hypertrophic cardiomyopathy.
- To identify mutations in the MyBP-C gene in families with FHC.
Main Methods:
- Genetic analysis of two unrelated French families linked to the CMH4 locus.
- Mutation screening of the MyBP-C gene, focusing on splice sites.
Main Results:
- A splice acceptor site mutation was identified in the MyBP-C gene in affected individuals from both families.
- This mutation leads to exon skipping and the potential production of truncated MyBP-C proteins.
Conclusions:
- Mutations in the cardiac MyBP-C gene are a likely cause of chromosome 11-linked hypertrophic cardiomyopathy.
- This reinforces the hypothesis that FHC results from mutations in genes encoding sarcomeric contractile proteins.
Abstract:
Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease characterized by a ventricular hypertrophy predominantly affecting the interventricular septum and associated with a large extent of myocardial and myofibrillar disarray. It is the most common cause of sudden death in the young. In the four disease loci found, three genes have been identified which code for beta-myosin heavy chain, cardiac troponin T and alpha-tropomyosin. Recently the human cardiac myosin binding protein-C (MyBP-C) gene was mapped to chromosome 11p11.2 (ref. 8), making this gene a good candidate for the fourth locus, CMH4 (ref. 5). Indeed, MyBP-C is a substantial component of the myofibrils that interacts with several proteins of the thick filament of the sarcomere. In two unrelated French families linked to CMH4, we found a mutation in a splice acceptor site of the MyBP-C gene, which causes the skipping of the associated exon and could produce truncated cardiac MyBP-Cs. Mutations in the cardiac MyBP-C gene likely cause chromosome 11-linked hypertrophic cardiomyopathy, further supporting the hypothesis that hypertrophic cardiomyopathy results from mutations in genes encoding contractile proteins.