Elias Blacksmith-Galan, Fernando Dominguez, Ines Martinez-Martin, Cristina Sanchez-Gonzalez, Natalia Vicente, Laura Lalaguna, Elena Bonzon-Kulichenko, Enrique Calvo, Esther Gonzalez-Lopez, Martha Cobo-Marcos, Belen Bornstein, Ana Briceno, Juan Pablo Ochoa, Jose Maria Garcia-Aznar, Carmen Suay-Corredera, Maria Rosaria pricolo, Angel Fernandez-Trasancos, Diana Velazquez-Carreras, Claudio Careaga Bay, Belen Meadows, Francisco Gutierrez-Aguera, Mahmoud Abdellatif, Simon Sit down, Peter P Rainer, David Giants, Giovanna Giovinazzo, Juan A. Bernal, Raul Perez-Jimenez, Torsten Bloch Rasmussen, Thomas Morris Hey, Immaculate Live-Ortega, Jesus Piqueras-Flowers, Enrique Lara-Pezzi, Jesus Vazquez, Pablo Garcia-Pavia, Jorge Perky-Onion

Abstract: 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 in TTN are 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.

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