作者
Elías Herrero-Galán, Fernando Domínguez, Inés Martínez-Martín, Cristina Sánchez-González, Natalia Vicente, Laura Lalaguna, Elena Bonzón-Kulichenko, Enrique Calvo, Esther González-López, Marta Cobo-Marcos, Belén Bornstein, Ana Briceño, Juan Pablo Ochoa, Jose Maria Garcia-Aznar, Carmen Suay-Corredera, Maria Rosaria Pricolo, Ángel Fernández-Trasancos, Diana Velázquez-Carreras, Claudio Badía Careaga, Belén Prados, Francisco Gutiérrez-Agüera, Mahmoud Abdellatif, Simon Sedej, Peter P Rainer, David Giganti, Giovanna Giovinazzo, Juan A Bernal, Raúl Pérez-Jiménez, Torsten Bloch Rasmussen, Thomas Morris Hey, Inmaculada Vivo-Ortega, Jesús Piqueras-Flores, Enrique Lara-Pezzi, Jesús Vázquez, Pablo Garcia-Pavia, Jorge Alegre-Cebollada
发表日期
2020/9/6
期刊
bioRxiv
页码范围
2020.09. 05.282913
出版商
Cold Spring Harbor Laboratory
简介
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.
One sentence summary
Mutations targeting cysteines key to the mechanoredox control of titin cause human dilated cardiomyopathy
学术搜索中的文章
E Herrero-Galán, F Domínguez, I Martínez-Martín… - bioRxiv, 2020