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Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy
Takeharu Hayashi1, Takuro Arimura, Manatsu Itoh-Satoh
1Department of Molecular Pathogenesis, Medical Research Institute, and Laboratory of Genome Diversity, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan.
Insights
Genetic mutations in the TCAP gene are linked to cardiomyopathy. Specific TCAP gene abnormalities correlate with either hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM) based on altered protein interactions.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Z-disc Protein Interactions
Background:
- Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are leading causes of heart failure and sudden cardiac death.
- Mutations in Z-disc proteins, including titin and muscle LIM protein (MLP), are primary genetic drivers of HCM and DCM.
- The titin/Tcap/MLP complex acts as a mechanical stretch sensor, crucial for sarcomeric function.
Purpose of the Study:
- To investigate the relationship between TCAP gene abnormalities and the development of cardiomyopathy.
- To determine if specific TCAP mutations correlate with distinct cardiomyopathy phenotypes (HCM vs. DCM).
Main Methods:
- Analyzed TCAP gene in 346 HCM and 136 DCM patients.
- Utilized yeast two-hybrid and glutathione S-transferase pull-down assays to assess Tcap protein interactions.
- Examined functional changes in Tcap's binding with MLP, titin, and calsarcin-1 due to identified mutations.
Main Results:
- Identified two TCAP mutations (T137I, R153H) in HCM patients and one (E132Q) in a DCM patient.
- HCM-associated TCAP mutations enhanced Tcap's interaction with titin and calsarcin-1.
- DCM-associated TCAP mutations impaired Tcap's interaction with MLP, titin, and calsarcin-1.
Conclusions:
- Clinical phenotype differences in cardiomyopathy (HCM vs. DCM) may stem from altered binding properties among Z-disc components.
- TCAP gene mutations represent a significant factor in the pathogenesis of inherited cardiomyopathies.
- Understanding these molecular interactions provides insights into therapeutic targets for heart failure.
Objectives:
We sought to explore the relationship between a Tcap gene (TCAP) abnormality and cardiomyopathy.
Background:
Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) cause severe heart failure and sudden death. Recent genetic investigations have revealed that mutations of genes encoding Z-disc components, including titin and muscle LIM protein (MLP), are the primary cause of both HCM and DCM. The Z-disc plays a role in establishing the mechanical coupling of sarcomeric contraction and stretching, with the titin/Tcap/MLP complex serving as a mechanical stretch sensor. Tcap interacts with the calsarcin, which tethers the calcineurin to the Z-disc.
Methods:
The TCAP was analyzed in 346 patients with HCM (236 familial and 110 sporadic cases) and 136 patients with DCM (34 familial and 102 sporadic cases). Two different in vitro qualitative assays-yeast two-hybrid and glutathion S-transferase pull-down competition-were performed in order to investigate functional changes in Tcap's interaction with MLP, titin, and calsarcin-1 caused by the identified mutations and a reported DCM-associated mutation, R87Q.
Results:
Two TCAP mutations, T137I and R153H, were found in patients with HCM, and another TCAP mutation, E132Q, was identified in a patient with DCM. It was demonstrated by the qualitative assays that the HCM-associated mutations augment the ability of Tcap to interact with titin and calsarcin-1, whereas the DCM-associated mutations impair the interaction of Tcap with MLP, titin, and calsarcin-1.
Conclusions:
These observations suggest that the difference in clinical phenotype (HCM or DCM) may be correlated with the property of altered binding among the Z-disc components.
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