BACKGROUND: Dilated cardiomyopathy (DCM) is characterized by idiopathic 
dilatation and systolic contractile dysfunction of the ventricle(s) leading to 
an impaired systolic function. The origin of DCM is heterogeneous, but genetic 
transmission of the disease accounts for up to 50% of the cases. Mutations in 
alpha-tropomyosin (TPM1), a thin filament protein involved in structural and 
regulatory roles in muscle cells, are associated with hypertrophic 
cardiomyopathy (HCM) and very rarely with DCM.
METHODS AND RESULTS: Here we present a large four-generation family in which DCM 
is inherited as an autosomal dominant trait. Six family members have a 
cardiomyopathy with the age of diagnosis ranging from 5 months to 52 years. The 
youngest affected was diagnosed with dilated and non-compaction cardiomyopathy 
(NCCM) and died at the age of five. Three additional children died young of 
suspected heart problems. We mapped the phenotype to chromosome 15 and 
subsequently identified a missense mutation in TPM1, resulting in a p.D84N amino 
acid substitution. In addition we sequenced 23 HCM/DCM genes using next 
generation sequencing. The TPM1 p.D84N was the only mutation identified. The 
mutation co-segregates with all clinically affected family members and 
significantly weakens the binding of tropomyosin to actin by 25%.
CONCLUSIONS: We show that a mutation in TPM1 is associated with DCM and a 
lethal, early onset form of NCCM, probably as a result of diminished actin 
binding caused by weakened charge-charge interactions. Consequently, the 
screening of TPM1 in patients and families with DCM and/or (severe, early onset 
forms of) NCCM is warranted. This article is part of a Special Issue entitled: 
Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and 
Contraction.