Mutations in the ANKRD1 gene encoding CARP are responsible for human dilated cardiomyopathy.

AIMS: Dilated cardiomyopathy (DCM) is familial in approximately 30% of cases, and mutations have been identified in several genes. However, in a majority of familial cases, the responsible genes are still to be discovered. The ANKRD1 gene is over-expressed in heart failure in human and animal models. The encoded protein CARP interacts with partners such as myopalladin or titin, previously shown to be involved in DCM. We hypothesized that mutations in ANKRD1 could be responsible for DCM.

METHODS AND RESULTS: We sequenced the coding region of ANKRD1 from 231 independent DCM cases. We identified five missense mutations (three sporadic and two familial) absent from 400 controls and affecting highly conserved residues. Expression of the mutant CARP proteins after transfection in rat neonate cardiomyocytes indicated that most of them led to both significantly less repressor activity measured in a reporter gene assay and greater phenylephrin-induced hypertrophy, suggesting altered function of CARP mutant proteins.

CONCLUSION: On the basis of genetic and functional analysis of CARP mutations, we have identified ANKRD1 as a new gene associated with DCM, accounting for approximately 2% of cases.