Résumé
Although cytoskeletal mutations are known causes of genetically based forms of dilated cardiomyopathy, the pathways that link these defects with cardiomyopathy are unclear. Here we report that the α-actinin–associated LIM protein (ALP; Alp in mice) has an essential role in the embryonic development of the right ventricular (RV) chamber during its exposure to high biomechanical workloads
in utero
. Disruption of the gene encoding Alp (
Alp
) is associated with RV chamber dilation and dysfunction, directly implicating α-actinin–associated proteins in the onset of cardiomyopathy.
In vitro
assays showed that Alp directly enhances the capacity of α-actinin to cross-link actin filaments, indicating that the loss of Alp function contributes to destabilization of actin anchorage sites in cardiac muscle. Alp also colocalizes at the intercalated disc with α-actinin and γ-catenin, the latter being a known disease gene for human RV dysplasia. Taken together, these studies point to a novel developmental pathway for RV dilated cardiomyopathy via instability of α-actinin complexes.