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 cardiomyopathy are unclear. Here we report that the alpha-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 alpha-actinin-associated proteins in the onset of cardiomyopathy. In vitro assays showed that Alp directly enhances the capacity of alpha-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 alpha-actinin and gamma-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 alpha-actinin complexes.
Pashmforoush
M
M
UCSD-Salk Program in Molecular Medicine and the UCSD Institute of Molecular Medicine, University of California at San Diego, La Jolla, California, USA.
Pomiès
P
P
Peterson
K L
KL
Kubalak
S
S
Ross
J
J
Hefti
A
A
Aebi
U
U
Beckerle
M C
MC
Chien
K R
KR
D000185:Actinin / Q000235:genetics*; D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology* / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000378:metabolism; D051180:Desmoplakins; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D051185:gamma Catenin
D003598:Cytoskeletal Proteins; D051180:Desmoplakins; D018398:Homeodomain Proteins; C495293:Jup protein, mouse; D051185:gamma Catenin; D000185:Actinin