Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin

Christopher N. Toepfer; Hiroko Wakimoto; Amanda C. Garfinkel; Barbara McDonough; Dan Liao; Jianming Jiang; Angela C. Tai; Joshua M. Gorham; Ida G. Lunde; Mingyue Lun; Thomas L. Lynch; James W. McNamara; Sakthivel Sadayappan; Charles S. Redwood; Hugh C. Watkins; Jonathan G. Seidman; Christine E. Seidman

doi:10.1126/scitranslmed.aat1199

Research ArticleHYPERTROPHIC CARDIOMYOPATHY

Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin

View ORCID ProfileChristopher N. Toepfer ¹,²,³,*,
View ORCID ProfileHiroko Wakimoto¹,⁴,
View ORCID ProfileAmanda C. Garfinkel¹,
View ORCID ProfileBarbara McDonough⁵,
Dan Liao⁶,
View ORCID ProfileJianming Jiang⁶,
Angela C. Tai¹,
View ORCID ProfileJoshua M. Gorham¹,
View ORCID ProfileIda G. Lunde¹,⁷,
Mingyue Lun⁸,
View ORCID ProfileThomas L. Lynch IV ⁹,
View ORCID ProfileJames W. McNamara ¹⁰,
Sakthivel Sadayappan ¹⁰,
View ORCID ProfileCharles S. Redwood ²,
View ORCID ProfileHugh C. Watkins ²,³,
View ORCID ProfileJonathan G. Seidman ¹,† and
View ORCID ProfileChristine E. Seidman ¹,⁵,¹¹,*,†

¹Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
²Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DU, UK.
³Wellcome Centre for Human Genetics, University of Oxford, OX3 7BN, UK.
⁴Department of Cardiology, Children’s Hospital Boston, Boston, MA 02115, USA.
⁵Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
⁶Department of Biochemistry and Cardiovascular Research Institute (CVRI), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
⁷Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0318 Oslo, Norway.
⁸Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA.
⁹Department of Molecular Pharmacology and Therapeutics, Health Sciences Division, Loyola University Chicago, Maywood, IL 60153, USA.
¹⁰Heart, Lung and Vascular Institute, University of Cincinnati, Cincinnati, OH 45219, USA.
¹¹Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA.

↵*Corresponding author. Email: christopher_toepfer{at}hms.harvard.edu (C.N.T.); cseidman{at}genetics.med.harvard.edu (C.E.S.)

↵† Co-senior authors.

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Science Translational Medicine 23 Jan 2019:
Vol. 11, Issue 476, eaat1199
DOI: 10.1126/scitranslmed.aat1199

Christopher N. Toepfer

1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

2Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DU, UK.

3Wellcome Centre for Human Genetics, University of Oxford, OX3 7BN, UK.

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For correspondence: christopher_toepfer@hms.harvard.edu cseidman@genetics.med.harvard.edu

Hiroko Wakimoto

1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

4Department of Cardiology, Children’s Hospital Boston, Boston, MA 02115, USA.

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Amanda C. Garfinkel

1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

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Barbara McDonough

5Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

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Dan Liao

6Department of Biochemistry and Cardiovascular Research Institute (CVRI), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.

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Jianming Jiang

6Department of Biochemistry and Cardiovascular Research Institute (CVRI), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.

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Angela C. Tai

1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

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Joshua M. Gorham

1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

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Ida G. Lunde

1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

7Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0318 Oslo, Norway.

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Mingyue Lun

8Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA.

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Thomas L. Lynch IV

9Department of Molecular Pharmacology and Therapeutics, Health Sciences Division, Loyola University Chicago, Maywood, IL 60153, USA.

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James W. McNamara

10Heart, Lung and Vascular Institute, University of Cincinnati, Cincinnati, OH 45219, USA.

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Sakthivel Sadayappan

10Heart, Lung and Vascular Institute, University of Cincinnati, Cincinnati, OH 45219, USA.

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Charles S. Redwood

2Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DU, UK.

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Hugh C. Watkins

2Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DU, UK.

3Wellcome Centre for Human Genetics, University of Oxford, OX3 7BN, UK.

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Jonathan G. Seidman

1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

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Christine E. Seidman

1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

5Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

11Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA.

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For correspondence: christopher_toepfer@hms.harvard.edu cseidman@genetics.med.harvard.edu

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Manipulating myosin to curb cardiomyopathy

Hypertrophic cardiomyopathy (HCM, thickened heart muscle) is a disease typically caused by mutations in sarcomere genes. Sarcomeres are the functional and structural units in muscle that allow for contraction and relaxation. Toepfer et al. investigated how mutations in cardiac myosin-binding protein C (encoded by MYBPC3) alter cardiac muscle contraction and relaxation. Using mouse models and human muscle fibers, they showed that MYBPC3 mutations increased contractility and decreased relaxation by disrupting myosin conformations. Treating cardiomyocytes with a myosin allosteric inhibitor corrected the relaxation, contraction, and myosin conformation deficits, suggesting that the myosin inhibitor could be therapeutic for HCM.

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Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin

Manipulating myosin to curb cardiomyopathy

Science Translational Medicine

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