Hypertrophic cardiomyopathy (HCM) is a frequent genetic cardiac disease and the 
most common cause of sudden cardiac death in young individuals. Most of the 
currently known HCM disease genes encode sarcomeric proteins. Previous studies 
have shown an association between CSRP3 missense mutations and either dilated 
cardiomyopathy (DCM) or HCM, but all these studies were unable to provide 
comprehensive genetic evidence for a causative role of CSRP3 mutations. We used 
linkage analysis and identified a CSRP3 missense mutation in a large German 
family affected by HCM. We confirmed CSRP3 as an HCM disease gene. Furthermore, 
CSRP3 missense mutations segregating with HCM were identified in four other 
families. We used a newly designed monoclonal antibody to show that muscle LIM 
protein (MLP), the protein encoded by CSRP3, is mainly a cytosolic component of 
cardiomyocytes and not tightly anchored to sarcomeric structures. Our functional 
data from both in vitro and in vivo analyses suggest that at least one of MLP's 
mutated forms seems to be destabilized in the heart of HCM patients harbouring a 
CSRP3 missense mutation. We also present evidence for mild skeletal muscle 
disease in affected persons. Our results support the view that HCM is not 
exclusively a sarcomeric disease and also suggest that impaired mechano-sensory 
stress signalling might be involved in the pathogenesis of HCM.