AIMS: Left ventricular non-compaction (LVNC) is caused by mutations in multiple 
genes. It is still unclear whether LVNC is the primary determinant of 
cardiomyopathy or rather a secondary phenomenon with intrinsic cardiomyocyte 
dysfunction being the actual cause of the disease. Here, we describe a family 
with LVNC due to a novel missense mutation, pE96K, in the cardiac troponin T 
gene (TNNT2).
METHODS AND RESULTS: The novel mutation was identified in the index patient and 
all affected relatives, but not in 430 healthy control individuals. Mutations in 
known LVNC-associated genes were excluded. To investigate the pathophysiological 
implications of the mutation, we generated transgenic mice expressing human 
wild-type cTNT (hcTNT) or a human troponin T harbouring the pE96K mutation (mut 
cTNT). Animals were characterized by echocardiography, histology, and gene 
expression analysis. Mut cTNT mice displayed an impaired left ventricular 
function and induction of marker genes of heart failure. Remarkably, left 
ventricular non-compaction was not observed.
CONCLUSION: Familial co-segregation and the cardiomyopathy phenotype of mut cTNT 
mice strongly support a causal relationship of the pE96K mutation and disease in 
our index patient. In addition, our data suggest that a non-compaction phenotype 
is not required for the development of cardiomyopathy in this specific TNNT2 
mutation leading to LVNC.