To further define the role of sarcomere mutations in DCM and associated clinical phenotypes.
Mutations in several contractile proteins contribute to DCM, but definitive evidence for the roles of most sarcomere genes remains limited by the lack of robust genetic support.
Direct sequencing of 6 sarcomere genes was performed on 334 probands with DCM. A novel D230N missense mutation in the gene encoding α-tropomyosin (TPM1) was identified. Functional assessment was performed using an in vitro reconstituted sarcomere complex to evaluate ATPase regulation and Ca2+ affinity as correlates of contractility.
TPM1 D230N segregated with DCM in two large unrelated families. This mutation altered an evolutionarily conserved residue and was absent in >1000 control chromosomes. In vitro studies demonstrated major inhibitory effects on sarcomere function with reduced Ca2+-sensitivity, maximum activation, and Ca2+ affinity compared to wildtype TPM1. Clinical manifestations ranged from decompensated heart failure or sudden death in those presenting early in life, to asymptomatic left ventricular dysfunction in those diagnosed during adulthood. Notably, several affected infants had remarkable improvement.
Genetic segregation in 2 unrelated families and functional analyses conclusively establish a pathogenic role for TPM1 mutations in DCM. In vitro results demonstrate contrasting effects of DCM and HCM mutations in TPM1, suggesting that specific functional consequences shape cardiac remodeling. Along with prior reports, our data support a distinctive, age-dependent phenotype with sarcomere-associated DCM where presentation early in life is associated with severe, sometimes lethal, disease. These observations have implications for the management of familial DCM.