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Conserved cysteines in titin sustain the mechanical function of cardiomyocytes

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, View ORCID ProfileJorge Alegre-Cebollada
doi: https://doi.org/10.1101/2020.09.05.282913
Elías Herrero-Galán
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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Fernando Domínguez
2Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
3CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
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Inés Martínez-Martín
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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Cristina Sánchez-González
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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Natalia Vicente
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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Laura Lalaguna
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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Elena Bonzón-Kulichenko
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
3CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
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Enrique Calvo
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
3CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
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Esther González-López
2Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
3CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
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Marta Cobo-Marcos
2Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
3CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
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Belén Bornstein
2Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
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Ana Briceño
2Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
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Juan Pablo Ochoa
2Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
4Health in Code, A Coruña, Spain
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Jose Maria Garcia-Aznar
4Health in Code, A Coruña, Spain
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Carmen Suay-Corredera
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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Maria Rosaria Pricolo
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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Ángel Fernández-Trasancos
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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Diana Velázquez-Carreras
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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Claudio Badía Careaga
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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Belén Prados
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
3CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
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Francisco Gutiérrez-Agüera
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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Mahmoud Abdellatif
5Division of Cardiology, Medical University of Graz, Graz, Austria
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Simon Sedej
5Division of Cardiology, Medical University of Graz, Graz, Austria
6Faculty of Medicine, University of Maribor, Maribor, Slovenia
7BioTechMed Graz, Graz, Austria
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Peter P. Rainer
5Division of Cardiology, Medical University of Graz, Graz, Austria
7BioTechMed Graz, Graz, Austria
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David Giganti
8Department of Biochemistry & Molecular Pharmacology and Institute for Systems Genetics, NYU Langone Health, New York, New York, United States
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Giovanna Giovinazzo
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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Juan A. Bernal
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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Raúl Pérez-Jiménez
9CIC nanoGUNE BRTA, San Sebastian, Spain
10Ikerbasque Foundation for Science, Bibao, Spain
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Torsten Bloch Rasmussen
11Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
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Thomas Morris Hey
12Department of Cardiology, Odense University Hospital, University of Southern Denmark, Odense, Denmark
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Inmaculada Vivo-Ortega
13Department of Cardiology, Hospital Universitario de Ciudad Real, Ciudad Real, Spain
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Jesús Piqueras-Flores
13Department of Cardiology, Hospital Universitario de Ciudad Real, Ciudad Real, Spain
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Enrique Lara-Pezzi
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
3CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
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Jesús Vázquez
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
3CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
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Pablo Garcia-Pavia
2Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
3CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
14Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Spain
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  • For correspondence: pablogpavia@yahoo.es jalegre@cnic.es
Jorge Alegre-Cebollada
1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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  • ORCID record for Jorge Alegre-Cebollada
  • For correspondence: pablogpavia@yahoo.es jalegre@cnic.es
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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.

One sentence summary Mutations targeting cysteines key to the mechanoredox control of titin cause human dilated cardiomyopathy

Competing Interest Statement

The authors have declared no competing interest.

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Conserved cysteines in titin sustain the mechanical function of cardiomyocytes
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
bioRxiv 2020.09.05.282913; doi: https://doi.org/10.1101/2020.09.05.282913
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Conserved cysteines in titin sustain the mechanical function of cardiomyocytes
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
bioRxiv 2020.09.05.282913; doi: https://doi.org/10.1101/2020.09.05.282913

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