Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Two 
genes have been identified for the X-linked forms (dystrophin and tafazzin), 
while mutations in multiple genes cause autosomal dominant DCM. Muscle LIM 
protein (MLP) is a member of the cysteine-rich protein (CRP) family and has been 
implicated in both myogenesis and sarcomere assembly. In the latter role, it 
binds zyxin and alpha-actinin, both of which are involved in actin organization. 
An MLP-deficient mouse has been described; these mice develop dilated 
cardiomyopathy and heart failure. Based upon these data, and the recent 
descriptions of mutations in MLP in patients with DCM or hypertrophic 
cardiomyopathy, we screened patients for mutations in the MLP and 
alpha-actinin-2 genes. We identified a patient with DCM and EFE, having a 
mutation in MLP with the residue lysine 69 substituted by arginine (K69R). This 
is within a highly conserved region adjacent to the first LIM domain involved in 
alpha-actinin binding. Analysis in cell culture systems demonstrated that the 
mutation abolishes the interaction between MLP and alpha-actinin-2 and the 
cellular localization of MLP was altered. In another individual with DCM, a W4R 
mutation was identified. However, this mutation did not segregate with disease 
in this family. In another patient with DCM, a Q9R mutation was identified in 
alpha-actinin-2. This mutation also disrupted the interaction with MLP and 
appeared to inhibit alpha-actinin function in cultured cells, in respect to the 
nuclear localization of actinin and the initiation of cellular differentiation.