| Autor: |
Simon Sedej, Torsten Bloch Rasmussen, Fernando Domínguez, Jose Maria Garcia-Aznar, Jesús Vázquez, Ana Briceño, Jesús Piqueras-Flores, Jorge Alegre-Cebollada, Giovanna Giovinazzo, Elías Herrero-Galán, Enrique Calvo, Carmen Suay-Corredera, David Giganti, Mahmoud Abdellatif, Juan A. Bernal, Inmaculada Vivo-Ortega, Francisco Gutiérrez-Agüera, Natalia Vicente, Belén Bornstein, Esther Gonzalez-Lopez, Thomas Morris Hey, Enrique Lara-Pezzi, Diana Velázquez-Carreras, Peter P. Rainer, Ángel Fernández-Trasancos, Laura Lalaguna, Belén Prados, Inés Martínez-Martín, Raul Perez-Jimenez, Pablo García-Pavía, Juan Pablo Ochoa, Claudio Badía Careaga, Maria Rosaria Pricolo, Elena Bonzón-Kulichenko, Marta Cobo-Marcos, Cristina Sánchez-González |
| Rok vydání: |
2020 |
| Předmět: |
|
| DOI: |
10.1101/2020.09.05.282913 |
| Popis: |
The protein titin determines cardiomyocyte contraction and truncating variants in the titin gene (TTN) are the most common cause of dilated cardiomyopathy (DCM). Different to truncations, missense variants inTTNare currently classified as variants of uncertain significance due to their high frequency in the population and the absence of functional annotation. Here, we report the regulatory role of conserved, mechanically active titin cysteines, which, contrary to current views, we uncover to be reversibly oxidized in basal conditions leading to isoform- and force-dependent modulation of titin stiffness and dynamics. Building on our functional studies, we demonstrate that missense mutations targeting a conserved titin cysteine alter myocyte contractile function and cause DCM in humans. Our findings have a direct impact on genetic counselling in clinical practice.One sentence summaryMutations targeting cysteines key to the mechanoredox control of titin cause human dilated cardiomyopathy |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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