Novel Adult-Onset Systolic Cardiomyopathy Due to MYH7 E848G Mutation in Patient-Derived Induced Pluripotent Stem Cells
| Autor: | Hans Reinecke, Deok Ho Kim, Lil Pabon, Joy Xu, Kai Chun Yang, Akiko Futakuchi-Tsuchida, Michael Regnier, Maria V. Razumova, Peter Hofsteen, Charles E. Murry, J. Carter Ralphe, Cody Schopf, Alex Jiao, Astrid Breitbart, Robert J. Boucek, Willem J. de Lange |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
genetic cardiomyopathy lcsh:Diseases of the circulatory (Cardiovascular) system HCM hypertrophic cardiomyopathy induced pluripotent stem cells Cardiomyopathy Disease Biology medicine.disease_cause Ad-GFP green fluorescent protein–encoding adenovirus iPSC-CM induced pluripotent stem cell–derived cardiomyocyte 03 medical and health sciences PRECLINICAL RESEARCH cMyBP-C cardiac myosin-binding protein C medicine In patient disease-modeling Allele Induced pluripotent stem cell DCM dilated cardiomyopathy MOI multiplicity of infections Mutation KO knockout hiPSC-CM human induced pluripotent stem cell–derived cardiomyocyte Binding protein MYH myosin heavy chain medicine.disease FCM familial cardiomyopathy EHT engineered heart tissue WT wild-type 3. Good health Cell biology 030104 developmental biology lcsh:RC666-701 engineered heart tissue MYH7 Cardiology and Cardiovascular Medicine |
| Zdroj: | JACC: Basic to Translational Science JACC: Basic to Translational Science, Vol 3, Iss 6, Pp 728-740 (2018) |
| ISSN: | 2452-302X |
| Popis: | Visual Abstract Highlights • 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. Summary 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. |
| Databáze: | OpenAIRE |
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