Familial Dilated Cardiomyopathy Caused by an Alpha-Tropomyosin Mutation: The Distinctive Natural History of Sarcomeric DCM

Background: Dilated cardiomyopathy (DCM) is an important cause of heart failure (HF) and leading indication for heart transplantation. Genetic etiologies of DCM remain incompletely defined, but include mutations in several sarcomere genes. Methods and Results: Clinical evaluations of two large unrelated families revealed autosomal dominant inheritance of DCM that was not accompanied by conduction system or skeletal muscle disease. Sequencing of sarcomere genes was performed and a missense mutation was identified in TPM1 (D230N), the gene encoding alpha-tropomyosin, a key regulatory sarcomere protein. The mutation occurred at an evolutionarily conserved residue, was absent in a control population and demonstrated cosegregation with disease in 16 affected individuals. No affected patients had features of hypertrophic cardiomyopathy. Onset of clinical manifestations ranged from presentation in infancy with severe HF or sudden death, to asymptomatic left ventricular dysfunction in the 6th decade. Remarkably, infants surviving an index presentation of severe HF exhibited dramatic recovery.

In common with other DCM mutations in thin filament proteins, recombinant D230N mutant-tropomyosin was found to significantly reduce Ca2+ affinity compared to wild type when incorporated into reconstituted thin filaments in vitro. Conclusion: These family studies demonstrate that mutations in TPM1 can cause DCM; possibly initiated by diminshed thin filament Ca2+ affinity. The diverse age of presentation is consistent with previously reported sarcomere-associated DCM but distinct from other genetic causes of DCM where infantile/early childhood onset or clinical recovery does not typically occur.