Abstract
Inherited human cardiomyopathies often lead to heart failure. A common
feature of these conditions is that affected individuals can express
the disease causing mutations for many years without showing clinical
signs of the disease. Previous studies have demonstrated that sarcomere
protein gene mutations can cause either dilated cardiomyopathy or
hypertrophic cardiomyopathy. Here we demonstrate that the Arg442His
missense mutation in beta-cardiac myosin heavy chain (betaMHC) causes
dilated cardiomyopathy, endocardial fibroelastosis and heart failure
at a very early age. Using standard genetic engineering tools we
and others have made murine models by introducing human disease causing
mutations into mice. The central hypothesis of these studies has
been that by identifying the pathophysiological pathways activated
by these mutations we can define enzymatic activities that are modified
during the disease process and which may be involved in pathways
that involve more common forms of cardiac disease. Murine models
bearing different mutant myosins are being used to address whether
each disease causing mutant betaMHC activates the same or different
cellular pathways. Dissecting the molecular pathways modulated by
mutations in sarcomere protein genes as well as other genes has already
demonstrated that there are multiple pathways leading to cardiac
remodelling and heart failure. Defining the mechanisms by which mutations
in the same genes activate different cellular pathways remains an
important question.
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