Adult mice deficient in actinin-associated LIM-domain protein reveal a developmental pathway for right ventricular cardiomyopathy

Although cytoskeletal mutations are known causes of genetically based forms of dilated cardiomyopathy, the pathways that link these defects with cardi omyopathy are unclear. Here we report that the alpha -actinin-associated LI M protein (ALP; Alp in mice) has an essential role in the embryonic develop ment of the right ventricular (RV) chamber during its exposure to high biom echanical workloads in utero. Disruption of the gene encoding Alp (Alp) is associated with RV chamber dilation and dysfunction, directly implicating a lpha -actinin-associated proteins in the onset of cardiomyopathy. In vitro assays showed that Alp directly enhances the capacity of a-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 co localizes at the intercalated disc with alpha -actinin and gamma -catenin, the latter being a known disease gene for human RV dysplasia. Taken togethe r, these studies point to a novel developmental pathway for RV dilated card iomyopathy via instability of alpha -actinin complexes.