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A myosin missense mutation, not a null allele, causes familial hypertrophic cardiomyopathy
1Third Department of Internal Medicine, Kurume University School of Medicine, Japan.
Insights
Genetic mutations in the cardiac beta-myosin-heavy-chain (beta-MHC) gene are linked to hypertrophic cardiomyopathy (HCM). The Arg870His mutation is implicated in causing HCM, while a nonsense mutation appears benign.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Basis of Heart Disease
Background:
- Hypertrophic cardiomyopathy (HCM) is a heart muscle disease characterized by unexplained myocardial hypertrophy.
- While missense mutations in the cardiac beta-myosin-heavy-chain (beta-MHC) gene are associated with HCM, the role of gross structural abnormalities is less understood.
Purpose of the Study:
- To investigate the structural abnormalities of the cardiac beta-MHC gene in patients diagnosed with HCM.
- To determine the correlation between specific gene mutations and the development of hypertrophic cardiomyopathy.
Main Methods:
- Polymerase chain reaction-DNA conformation polymorphism analysis was employed to study the cardiac beta-MHC gene structure.
- Direct sequencing and allele-specific oligonucleotide probes were used to identify sequence variations.
- Family members were examined to trace the inheritance patterns of identified mutations.
Main Results:
- Two sequence variations, a nonsense mutation in exon 3 (codon 54) and an Arg-to-His missense mutation in exon 22 (codon 870), were identified in one HCM patient.
- The Arg870His missense mutation was found to be inherited from an affected father and present in seven individuals across two other unrelated HCM families.
- The nonsense mutation, inherited from an unaffected grandmother, did not appear to cause a dominant phenotype of heart disease.
Conclusions:
- The Arg870His mutation is strongly suggested as a causative factor for hypertrophic cardiomyopathy.
- The nonsense mutation results in a truncated cardiac beta-MHC protein, likely too short for myosin filament assembly, and does not manifest as heart disease.
- This study reports the first instance of a nonsense mutation identified in the human cardiac beta-MHC gene.
Background:
Hypertrophic cardiomyopathy (HCM) is characterized by myocardial hypertrophy of unknown etiology. Missense mutations of the cardiac beta-myosin-heavy-chain (beta-MHC) gene that may be responsible for cardiac hypertrophy have been detected in patients with HCM. On the other hand, gross structural abnormalities in the cardiac beta-MHC gene, ie, an alpha/beta hybrid gene and partial deletion of the gene, have also been reported. The direct correlation between gross abnormalities and development of HCM is not well understood.
Methods And Results:
We analyzed the structure of the cardiac beta-MHC gene from patients with HCM by using polymerase chain reaction-DNA conformation polymorphism analysis and found two sequence variations in exons 3 and 22 in one patient. These sequence variations at codon 54 (exon 3; nonsense mutation) and codon 870 (exon 22; Arg-to-His mutation) were identified by direct sequencing and dot-blot hybridization with allele-specific oligonucleotide probes. Relatives of this patient were examined for the mutations. It was revealed that the missense mutation was inherited from the affected father and the nonsense mutation from the unaffected grandmother through the unaffected mother. In addition, the missense mutation was also found in seven other patients from two other unrelated multiplex HCM families.
Conclusions:
The Arg870His mutation was suggested to cause HCM. In contrast, the gene with the nonsense mutation would encode for a cardiac beta-MHC protein of only 53 amino acid residues, which may be too short to be incorporated into the thick filament assembly of cardiac myosin chains and showed no dominant phenotype of heart disease. This is the first report of a nonsense mutation in the human cardiac beta-MHC gene.