Related Experiment Video
Updated: May 5, 2026
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy
M Kamisago1, S D Sharma, S R DePalma
1Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School and Howard Hughes Medical Institute, Boston, MA, USA.
Insights
Genetic mutations in sarcomere proteins are a significant cause of familial dilated cardiomyopathy, particularly in early-onset cases. These mutations lead to ventricular dysfunction and heart failure, distinct from hypertrophic cardiomyopathy.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Heart Failure Pathophysiology
Background:
- Idiopathic dilated cardiomyopathy (DCM) is a myocardial disorder with unknown molecular basis, leading to reduced contractile function.
- Familial DCM cases linked to cardiac cytoskeletal protein mutations suggest impaired contractile-force transmission.
- Investigating genetic causes is crucial for understanding this heart failure etiology.
Purpose of the Study:
- To elucidate genetic causes of familial dilated cardiomyopathy (DCM).
- To identify mutations in sarcomere protein genes associated with DCM.
- To understand the link between sarcomere protein defects and heart remodeling.
Main Methods:
- Clinical evaluations of 21 kindreds with familial DCM.
- Genome-wide linkage studies to identify genetic loci.
- Screening of genes encoding beta-myosin heavy chain, troponin T, troponin I, and alpha-tropomyosin for mutations.
Main Results:
- Identified a genetic locus for DCM mutations at chromosome 14q11.2-13, encoding cardiac beta-myosin heavy chain.
- Discovered disease-causing dominant mutations in sarcomere protein genes in four kindreds.
- Specific mutations (Ser532Pro, Phe764Leu in beta-myosin heavy chain; deltaLys210 in troponin T) caused early-onset ventricular dilatation, dysfunction, and heart failure without prior hypertrophy.
Conclusions:
- Sarcomere protein gene mutations account for ~10% of familial DCM, especially with early-onset ventricular dilatation.
- Distinct sarcomere protein mutations can cause either DCM or hypertrophic cardiomyopathy.
- Mutant sarcomere proteins trigger different molecular events leading to distinct heart remodeling pathways.
Background:
The molecular basis of idiopathic dilated cardiomyopathy, a primary myocardial disorder that results in reduced contractile function, is largely unknown. Some cases of familial dilated cardiomyopathy are caused by mutations in cardiac cytoskeletal proteins; this finding implicates defects in contractile-force transmission as one mechanism underlying this disorder. To elucidate this important cause of heart failure, we investigated other genetic causes of dilated cardiomyopathy.
Methods:
Clinical evaluations were performed in 21 kindreds with familial dilated cardiomyopathy. A genome-wide linkage study prompted a search of the genes encoding beta-myosin heavy chain, troponin T, troponin I, and alpha-tropomyosin for disease-causing mutations.
Results:
A genetic locus for mutations associated with dilated cardiomyopathy was identified at chromosome 14q11.2-13 (maximal lod score, 5.11; theta=0), where the gene for cardiac beta-myosin heavy chain is encoded. Analyses of this and other genes for sarcomere proteins identified disease-causing dominant mutations in four kindreds. Cardiac beta-myosin heavy-chain missense mutations (Ser532Pro and Phe764Leu) and a deletion in cardiac troponin T (deltaLys210) caused early-onset ventricular dilatation (average age at diagnosis, 24 years) and diminished contractile function and frequently resulted in heart failure. Affected persons had neither antecedent cardiac hypertrophy (average maximal left-ventricular-wall thickness, 8.5 mm) nor histopathological findings characteristic of hypertrophy.
Conclusion:
Mutations in sarcomere protein genes account for approximately 10 percent of cases of familial dilated cardiomyopathy and are particularly prevalent in families with early-onset ventricular dilatation and dysfunction. Because distinct mutations in sarcomere proteins cause either dilated or hypertrophic cardiomyopathy, the effects of mutant sarcomere proteins on muscle mechanics must trigger two different series of events that remodel the heart.
Related Concept Videos
01:21Satellite Stem Cells and Muscular Dystrophy
01:25Cardiomyopathy I: Introduction and Classification
01:30Cardiomyopathy II: Dilated Cardiomyopathy
01:29Cardiomyopathy III: Hypertrophic Cardiomyopathy
01:29Cardiomyopathy IV: Restrictive Cardiomyopathy
01:29Cardiomyopathy V: Interprofessional Care