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 </=50% in the absence of other potential causes. After amplification by polymerase chain reaction, the exons of the desmin gene were sequenced. A missense desmin mutation, Ile451Met, which cosegregates with FDCM without clinically evident skeletal muscle abnormalities, was identified in a 4-generation family but was not detected in 460 unrelated healthy individuals.
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.