Dilated Cardiomyopathy (DCM) is familial in about 30 % of cases, and to date, 15 responsible genes have been identified in isolated forms and up to 25 associated with additional phenotypes including myopathy, arrythmias or more complex syndromes. No major gene for the disease has been identified, demonstrating the genetic heterogeneity of DCM. However, in a majority of families the responsible genes are still to be discovered.
The ANKRD1 gene is overexpressed in heart failure in human or animal models. The encoded protein CARP is interacting with partners such as Myopalladin or Titin, previously involved in DCM. We hypothesised that mutations in ANKRD1 could be responsible for DCM.
We have screened a DCM affected population consisting on 231 caucasian independent familial (158) and sporadic (73) cases by direct sequencing of PCR-amplified coding exons. We identified 5 missense mutations: 3 sporadic (mutations p.Glu57Gln, p.Arg66Gln and p.Leu199Arg) and 2 familial (mutations p.Thr116Met and p.Ala276Val) absent from 400 controls and affecting highly conserved residues.
Expression of the mutant CARP proteins in rat neonate cardiomyocytes indicated that at least 3 of the mutations identified (p.Glu57Gln, p.Leu199Arg, p.Ala276Val) led both to significant less repressor activity and to greater phenylephrin induced hypertrophy suggesting altered function of CARP mutant proteins.
Based on genetic and functional analysis of CARP mutations, we have identified ANKRD1 as a new gene associated with DCM, accounting for about 4 % of cases.Le texte complet de cet article est disponible en PDF.