How Do Mutations in Contractile Proteins Cause the Primary Familial Cardiomyopathies?



In this article, the available evidence about the functional effects of the contractile protein mutations that cause hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) is assessed. The molecular mechanism of the contractile apparatus of cardiac muscle and its regulation by Ca2+ and PKA phosphorylation have been extensively studied. Therefore, when a number of point mutations in the contractile protein genes were found to cause the well-defined phenotypes of HCM and DCM, it was expected that the diseases could be explained at the molecular level. However, the search for a distinctive molecular phenotype did not yield rapid results. Now that a substantial number of mutations that cause HCM or DCM have been investigated in physiologically relevant systems and with a range of experimental techniques, a pattern is emerging. In the case of HCM, the hypothesis that the major effect of mutations is to increase myofibrillar Ca2+-sensitivity seems to be well established, but the mechanisms by which an increase in myofibrillar Ca2+-sensitivity induces hypertrophy remain obscure. In contrast, DCM mutations are not correlated with a specific effect on Ca2+-sensitivity. It has recently been proposed that DCM mutations uncouple troponin I phosphorylation from Ca2+-sensitivity changes, albeit based on only a few mutations so far. A plausible link between uncoupling and DCM has been proposed via blunting of the response to α-adrenergic stimulation.


Hypertrophic cardiomyopathy Dilated cardiomyopathy Mutation Genotype–phenotype links Thin filament Myosin Contractility Ca2+-regulation 

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.NHLIImperial College LondonLondonUK

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