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

Abstract

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.

Lamr1 functional retroposon causes right ventricular dysplasia in mice

“…Alternatively, right ventricle-specific genes may be involved in the susceptibility of the right ventricle. Mice lacking the right ventricle-specific gene actinin-associated LIM-domain protein show some ARVD-like features 25 , even though the histological characteristics are considerably different from those of human ARVD. We found that one of the heterochromatin complex proteins, HP1-α, showed specific binding to LAMR1-TP1.…”

Molecular mechanisms of mechanosensing in muscle development

“…Among several candidates, PDZ-LIM domain proteins comprised of ALP and Enigma subfamilies, which contain one or three LIM domains, respectively, have been identified as ␣-actinin binding partners (Xia et al, 1997;Pomies et al, 1999;Zhou et al, 1999;Pashmforoush et al, 2001;Klaavuniemi et al, 2004). Most members of this group colocalize with ␣-actinin in the Z-disks of striated and cardiac muscles and in intercalated disks of cardiac muscles.…”

Deficiency of Actinin-Associated LIM Protein Alters Regional Right Ventricular Function and Hypertrophic Remodeling

“…Proteins such as RIL or CLP-36, which are highly homologous to ALP, may compensate for the lack of ALP by partially taking over its function, thus leading to the low penetrance. 20 In this study, mice were not selected on the basis of phenotype but on genotype, leaving the possibility that only 2-3 of the 10 ALPKO mice showed cardiomyopathy. This may explain the large variation as well as the small differences in strain.…”

“…It is expressed in the mouse heart symmetrically up to embryonic day 7.5, but is restricted to the infundibular region of the RV and parts of the septum after birth. 20 Homozygous deletion of ALP in mice results in primarily right ventricular (RV) dysmorphogenesis, a decrease in trabeculation and mild dilated cardiomyopathy (DCM), 20 resembling human arrhythmogenic RV dysplasia (ARVD). 4,9 Thus, the phenotype appears to correlate with the expression of ALP in the adult heart.…”

“…The association of ALP with plakoglobin, 20 an important anchoring protein at the intercalated disc, 5,16 which has itself been linked to ARVD, 17 suggests that ALP disruption may result in a decrease in cardiac myocyte stability and possibly impaired force transmission. This idea is further supported by the finding that ALP contains one LIM and one PDZ domain, both of which are particularly known for protein-protein interaction.…”