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Desmin mutation responsible for idiopathic dilated cardiomyopathy
1Section of Cardiology, Molecular Biology Computational Resource, Baylor College of Medicine, Houston, TX, USA.
Insights
A novel desmin gene mutation, Ile451Met, causes familial dilated cardiomyopathy (FDCM) without skeletal issues. This finding highlights the desmin tail
Area of Science:
- Genetics and Molecular Biology
- Cardiology
- Biochemistry
Background:
- Familial dilated cardiomyopathy (FDCM) accounts for 20% of idiopathic dilated cardiomyopathy cases, leading to heart failure and transplantation needs.
- Previous research mapped six autosomal dominant FDCM loci, but causative genes remained elusive until actin was identified.
- Desmin, a muscle-specific intermediate filament, is implicated in cardiac growth and development, making it a candidate gene for FDCM.
Purpose of the Study:
- To investigate whether desmin gene defects cause familial dilated cardiomyopathy (FDCM).
- To identify the specific genetic mutation responsible for FDCM in affected families.
Main Methods:
- Clinical evaluation and DNA analysis of 44 probands with FDCM.
- Echocardiography used to diagnose dilated cardiomyopathy based on ventricular dimensions and ejection fraction.
- Sequencing of desmin gene exons after polymerase chain reaction amplification.
Main Results:
- A novel missense desmin mutation, Ile451Met, was identified in a 4-generation family with FDCM.
- This mutation cosegregated with FDCM and did not present with clinically evident skeletal muscle abnormalities.
- The Ile451Met mutation was absent in 460 unrelated healthy individuals, confirming its association with FDCM.
Conclusions:
- The novel desmin mutation Ile451Met is the genetic cause of idiopathic dilated cardiomyopathy in the studied family.
- This is the first mutation found in the desmin tail domain, suggesting its critical role in cardiac function.
- The restricted cardiac phenotype associated with this mutation implies the desmin tail is crucial for heart tissue function.
Background:
Idiopathic dilated cardiomyopathy, of which approximately 20% of cases are familial (FDCM), is a primary myocardial disorder characterized by ventricular dilatation and impaired systolic function. It is a common cause of heart failure and the need for cardiac transplantation. Although 6 chromosomal loci responsible for autosomal dominant FDCM have been mapped by linkage analysis, none of these genes have been identified. By use of the candidate-gene approach, actin was identified recently as being responsible for dilated cardiomyopathy. Considerable evidence suggests desmin, a muscle-specific intermediate filament, plays a significant role in cardiac growth and development.
Methods And Results:
To determine whether a defect of desmin induces dilated cardiomyopathy, 44 probands with FDCM underwent clinical evaluation and DNA analysis. Diagnostic criteria, detected by echocardiography, consisted of ventricular dimension of >/=2.7 cm/m(2) with an ejection fraction
Conclusions:
A novel missense mutation of desmin, Ile451Met, was identified as the genetic cause of idiopathic dilated cardiomyopathy. This finding is of particular significance because this is the first mutation detected in the desmin tail domain, and the function of the desmin tail remains unknown. Because this mutation leads to a restricted cardiac phenotype in the family studied in the present report, it suggests that the tail of desmin plays an important functional role in cardiac tissue.
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