Abstract MP100: Scalable Functional Classification of Heart Failure-associated Genetic Variants in Cardiac Troponin T
| العنوان: | Abstract MP100: Scalable Functional Classification of Heart Failure-associated Genetic Variants in Cardiac Troponin T |
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| المؤلفون: | Nicholas Legere, Rachel Cohn, David J. Mellert, Anthony M. Pettinato, John T. Hinson, Ketan Thakar, Robert Romano, Yu-Sheng Chen, Feria A. Ladha |
| المصدر: | Circulation Research. 127 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | medicine.medical_specialty, Cardiac troponin, Physiology, business.industry, Internal medicine, Heart failure, medicine, Cardiology, Genetic variants, Cardiology and Cardiovascular Medicine, business, medicine.disease |
| الوصف: | Sarcomere gene mutations are the most common inheritable risk factor for heart failure, a disease with high morbidity and mortality, yet the pathogenicity of a large proportion of sarcomere gene variants remains unknown. The knowledge of which and how sarcomere gene variants result in heart failure would provide valuable prognostic and diagnostic information for individuals harboring sarcomere gene variants. Here, we developed a transgenic human cardiomyocyte model that enables scalable delivery of genetic variants in cardiac troponin T (cTnT; encoded by TNNT2 ), empowering high-throughput analysis of variant-specific sarcomere function. Using this model, in conjunction with CRISPR-derived isogenic standards and biomimetic cardiac tissues, we demonstrate that hypertrophic cardiomyopathy (HCM) variants in TNNT2 evoke elevated cardiac tissue contractile function, while dilated cardiomyopathy (DCM) variants produce decreased contractile function. RNA-seq revealed a transcriptional network that correlates with contractile function and identified NPPB expression as a molecular signature of contraction. Through the development of a cellular NPPB reporter, we functionally screen a panel of 51 TNNT2 variants, and provide molecular and tissue-level evidence for the functional reclassification of TNNT2 “variants of unknown significance” to pathogenic, and “pathogenic” variants to benign. Finally, adaption of this cellular reporter to assess variant calcium sensitivity, together with analysis of myofilament-localized calcium transients, demonstrates a parallel between contractile function and calcium sensitivity in human cardiomyocytes. This study establishes a new tool to study sarcomere genetic variants at scale, reclassifies the pathogenicity of previously-identified TNNT2 variants, and provides new insights into the cellular pathogenesis of human heart failure. |
| تدمد: | 1524-4571 0009-7330 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::4a973f13734b072e5195da3b2ffea153 https://doi.org/10.1161/res.127.suppl_1.mp100 |
| رقم الأكسشن: | edsair.doi...........4a973f13734b072e5195da3b2ffea153 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15244571 00097330 |
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