Author + information
- Received June 20, 2018
- Revision received August 16, 2018
- Accepted August 21, 2018
- Published online December 31, 2018.
- Kai-Chun Yang, MDa,b,c,d,∗,
- Astrid Breitbart, MDb,c,d,∗,
- Willem J. De Lange, PhDe,
- Peter Hofsteen, PhDb,c,d,
- Akiko Futakuchi-Tsuchida, BSb,c,d,
- Joy Xu, MSEb,d,f,
- Cody Schopf, BSb,c,d,
- Maria V. Razumova, PhDb,d,f,
- Alex Jiao, PhDb,d,f,
- Robert Boucek, MDg,
- Lil Pabon, PhDb,c,d,
- Hans Reinecke, PhDb,c,d,
- Deok-Ho Kim, PhDb,d,f,
- J. Carter Ralphe, MDe,
- Michael Regnier, PhDb,d,f and
- Charles E. Murry, MD, PhDa,b,c,d,f,∗ ()
- aDepartment of Medicine/Cardiology, University of Washington, Seattle, Washington
- bCenter for Cardiovascular Biology, University of Washington, Seattle, Washington
- cDepartment of Pathology, University of Washington, Seattle, Washington
- dInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington
- eDepartment of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- fDepartment of Bioengineering, University of Washington, Seattle, Washington
- gDepartment of Pediatrics, Seattle’s Children’s Hospital and the University of Washington, Seattle, Washington
- ↵∗Address for correspondence:
Dr. Charles E. Murry, Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Room 453, Brotman Building, Seattle, Washington 98109.
• Many cardiomyopathy families have genetic variants whose significance is unknown. We studied a novel (E848G) mutation in MYH7, a sarcomeric protein.
• Patient-specific induced pluripotent stem cell–derived cardiomyocytes and engineered heart tissues recapitulated the contractile dysfunction.
• Overexpression of the E848G allele in MYH7-null induced pluripotent stem cell–derived cardiomyocytes confirms the causality of the E848G variant.
• The E848G allele disrupts the protein–protein interaction between MYH7 and cardiac myosin binding protein C, presenting a potential mechanism of action.
• Assessing the pathogenicity of new MYH7 variants by overexpressing them in a null background should accelerate their screening for disease causality.
A novel myosin heavy chain 7 mutation (E848G) identified in a familial cardiomyopathy was studied in patient-specific induced pluripotent stem cell–derived cardiomyocytes. The cardiomyopathic human induced pluripotent stem cell–derived cardiomyocytes exhibited reduced contractile function as single cells and engineered heart tissues, and genome-edited isogenic cells confirmed the pathogenic nature of the E848G mutation. Reduced contractility may result from impaired interaction between myosin heavy chain 7 and cardiac myosin binding protein C.
↵∗ Drs. Yang and Breitbart contributed equally to this work and are joint first authors.
This work was supported by grants from the Robert B. McMillen Foundation, from the Fondation Leducq Transatlantic Networks of Excellence, and National Institutes of Health grants P01 HL094374, R01HL128362, R01 HL084642, P01 GM081619, and U01 HL100405 (to Dr. Murry). This work was also supported by National Institutes of Health grants R01HL135143 to Drs. Kim and Murry and R01 HL111197 and R01 HL128368 to Dr. Regnier. Dr. Yang was supported by grant T32HL007828 from the National Heart, Lung, and Blood Institute and a Bruce-Laughlin Research Fellowship. Dr. Kim is a co-founder and scientific advisor of NanoSurface. Dr. Murry is the scientific founder of and equity holder in Cytocardia. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received June 20, 2018.
- Revision received August 16, 2018.
- Accepted August 21, 2018.
- 2018 The Authors