Nature Medicine
7, 591 - 597 (2001)
doi:10.1038/87920
Adult mice deficient in actinin−associated LIM-domain protein reveal a developmental pathway for right ventricular cardiomyopathyMohammad Pashmforoush1, 5, Pascal Pomiès2, 5, Kirk L. Peterson1, Steve Kubalak4, John Ross Jr1, Andreas Hefti3, Ueli Aebi3, Mary C. Beckerle2
& Kenneth R. Chien11
UCSD-Salk Program in Molecular Medicine and the UCSD Institute of Molecular Medicine, University of California at San Diego, La Jolla, California, USA
2
Huntsman Cancer Institute and Department of Biology, University of Utah, Salt Lake City, Utah, USA
3
Biozentrum, University of Basel, Basel, Switzerland
4
Department of Cell Biology, Medical University of South Carolina, Charleston, South Carolina, USA
5
M.P. and P.P. contributed equally to this study.
Correspondence should be addressed to Kenneth R. Chien kchien@ucsd.eduAlthough 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  -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 -actinin−associated proteins in the onset of cardiomyopathy. In vitro assays showed that Alp directly enhances the capacity of -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 -actinin and  -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 -actinin complexes.
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