Desmin mutation responsible for idiopathic dilated cardiomyopathy

Background-Idiopathic dilated cardiomyopathy, of which approximate to 20% o f cases are familial (FDCM), is a primary myocardial disorder characterized by ventricular dilatation and impaired systolic function. it is a common c ause of heart failure and the need for cardiac transplantation. Although 6 chromosomal loci responsible for autosomal dominant FDCM have been mapped b y linkage analysis, none of these genes have been identified. By use of the candidate-gene approach, actin was identified recently as being responsibl e for dilated cardiomyopathy. Considerable evidence suggests desmin, a musc le-specific intermediate filament, plays a significant role in cardiac grow th and development. Methods and Results-To determine whether a defect of desmin induces dilated cardiomyopathy, 44 probands with FDCM underwent clinical evaluation and DN A analysis. Diagnostic criteria, detected by echocardiography, consisted of ventricular dimension of greater than or equal to 2.7 cm/m(2) with an ejec tion fraction less than or equal to 50% in the absence of other potential c auses. After amplification by polymerase chain reaction, the exons of the d esmin gene were sequenced. A missense desmin mutation, Ile451Met, which cos egregates with FDCM without clinically evident skeletal muscle abnormalitie s, was identified in a 4-generation family but was not detected in 460 unre lated 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 t he desmin tail domain, and the function of the desmin tail remains unknown. Because this mutation leads to a restricted cardiac phenotype in the famil y studied in the present report, it suggests that the tail of desmin plays an important functional role in cardiac tissue.