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Alpha-tropomyosin mutations in inherited cardiomyopathies

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Abstract

The inherited cardiac diseases hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) can both be caused by missense mutations in the TPM1 gene which encodes the thin filament regulatory protein α-tropomyosin. Different mutations are responsible for either HCM or DCM, suggesting that distinct changes in tropomyosin structure and function can lead to the different diseases. Various biophysical and physiological approaches have been used to investigate the structure–function effects of the mutations, and animal models developed. The reported effects of the mutations include changes to the secondary structure of tropomyosin, its binding to actin and its position on the thin filament, and alterations to actin–myosin interactions and myofilament Ca2+ sensitivity. The latter changes have been found to be particularly consistent, with HCM mutations increasing Ca2+ sensitivity and DCM mutations in general decreasing this parameter and uncoupling the effect of troponin phosphorylation upon Ca2+ responsiveness. As well as impacting on contractility, these changes are likely to alter intracellular Ca2+ handling and signaling, and a combination of these alterations may provide the trigger for disease remodeling.

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Acknowledgments

Our work has been supported by the British Heart Foundation and the European Community’s Seventh Framework Programme Grant Agreement No. 241577 (BIG-Heart).

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  1. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, West Wing Level 6, Oxford, OX3 9DU, UK

    Charles Redwood & Paul Robinson

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  1. Charles Redwood
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  2. Paul Robinson
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Correspondence to Charles Redwood.

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Redwood, C., Robinson, P. Alpha-tropomyosin mutations in inherited cardiomyopathies. J Muscle Res Cell Motil 34, 285–294 (2013). https://doi.org/10.1007/s10974-013-9358-5

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