Genetics and dilated cardiomyopathy: limitations of candidate gene strategies

What is known of the genetic basis for dilated cardiomyopathy is the result of studying pedigrees with intermediate phenotypes. In these diseases the dilated hypocontractile heart is only one feature of the phenotype and other clinical manifestations allow precise definition of affection status. The first such phenotypes to be studied were Duchenne and Becker muscular dystrophies, allelic X-linked disorders, which frequently exhibit myocardial involvement resulting in dilated cardiomyopathy and are caused by mutations in the dystrophin gene. Specific dystrophin mutations may present as dilated cardiomyopathy without skeletal involvement. Usually such families can be discriminated by X-linked inheritance. Dystrophin is a major component of a large membrane-spanning glycoprotein complex, the dystrophin-associated glycoproteins. The function of this complex is unknown but it has been implicated in mechanical and signal transduction. Other members of the dystrophin-associated glycoprotein complex, in particular and sarcoglycans, also cause dilated cardiomyopathy in the context of rare recessive limb–girdle dystrophies. The Emery–Dreifuss variant of muscular dystrophy is distinguished by prominent abnormalities of atrioventricular conduction and tendon contractures. X-linked Emery–Dreifuss is caused by mutations in the nuclear lamina protein emerin. Emerin’s function is obscure but it may be involved in the higher order structure and regulation of the nucleus. The role of the nuclear membrane in conduction diseaseassociated cardiomyopathy is highlighted by the discovery of mutations in the lamin A/C gene in both an autosomal dominant variant of Emery–Dreifuss and dilated cardiomyopathy with conduction system disease. Interestingly lamin A/C mutations have also been found in a rare form of partial lipodystrophy. That such diverse phenotypes should result from defects in a single gene is intriguing and may suggest tissue-specific lamin interactions or involvement in a fundamental process, such as maintenance of differentiation, in a common mesenchymal cell lineage. Further insight will come from other muscular dystrophy loci and the systematic evaluation of disease genes in model systems.