Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function

Joachim P Schmitt; Edward P Debold; Ferhaan Ahmad; Amy Armstrong; Andrea Frederico; David A Conner; Ulrike Mende; Martin J Lohse; David Warshaw; Christine E Seidman; J G Seidman

doi:10.1073/pnas.0606383103

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Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function

Journal article

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Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function

Joachim P Schmitt, Edward P Debold, Ferhaan Ahmad, Amy Armstrong, Andrea Frederico, David A Conner, Ulrike Mende, Martin J Lohse, David Warshaw, Christine E Seidman, …

Proceedings of the National Academy of Sciences - PNAS, Vol.103(39), pp.14525-14530

09/26/2006

DOI: 10.1073/pnas.0606383103

PMCID: PMC1599993

PMID: 16983074

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Abstract

Dilated cardiomyopathy (DCM) leads to heart failure, a leading cause of death in industrialized nations. Approximately 30% of DCM cases are genetic in origin, with some resulting from point mutations in cardiac myosin, the molecular motor of the heart. The effects of these mutations on myosin's molecular mechanics have not been determined. We have engineered two murine models characterizing the physiological, cellular, and molecular effects of DCM-causing missense mutations (S532P and F764L) in the alpha-cardiac myosin heavy chain and compared them with WT mice. Mutant mice developed morphological and functional characteristics of DCM consistent with the human phenotypes. Contractile function of isolated myocytes was depressed and preceded left ventricular dilation and reduced fractional shortening. In an in vitro motility assay, both mutant cardiac myosins exhibited a reduced ability to translocate actin (V(actin)) but had similar force-generating capacities. Actin-activated ATPase activities were also reduced. Single-molecule laser trap experiments revealed that the lower V(actin) in the S532P mutant was due to a reduced ability of the motor to generate a step displacement and an alteration of the kinetics of its chemomechanical cycle. These results suggest that the depressed molecular function in cardiac myosin may initiate the events that cause the heart to remodel and become pathologically dilated.

Echocardiography

Myocytes, Cardiac - cytology

Protein Structure, Secondary

Cardiac Myosins - genetics

Actins - metabolism

Mutant Proteins - metabolism

Myocardium - pathology

Cardiomyopathy, Dilated - metabolism

Mutation, Missense - genetics

Myocardium - cytology

Homozygote

Biomechanical Phenomena

Cardiomyopathy, Dilated - diagnostic imaging

Animals

Heterozygote

Molecular Motor Proteins - metabolism

Mice

Cardiac Myosins - chemistry

Disease Models, Animal

Details

Title: Subtitle: Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function
Creators: Joachim P Schmitt - Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA
Edward P Debold
Ferhaan Ahmad
Amy Armstrong
Andrea Frederico
David A Conner
Ulrike Mende
Martin J Lohse
David Warshaw
Christine E Seidman
J G Seidman
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.103(39), pp.14525-14530
DOI: 10.1073/pnas.0606383103
PMID: 16983074
PMCID: PMC1599993
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences; United States
Language: English
Date published: 09/26/2006
Academic Unit: Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984025406502771

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