An FDA-approved drug structurally and phenotypically corrects the K210del mutation in genetic cardiomyopathy models

Dilated cardiomyopathy (DCM) due to genetic disorders results in decreased myocardial contractility, leading to high morbidity and mortality rates. There are several therapeutic challenges in treating DCM, including poor understanding of the underlying mechanism of impaired myocardial contractility and the difficulty of developing targeted therapies to reverse mutation-specific pathologies. In this report, we focused on K210del, a DCM-causing mutation, due to 3-nucleotide deletion of sarcomeric troponin T (TnnT), resulting in loss of Lysine210. We resolved the crystal structure of the troponin complex carrying the K210del mutation. K210del induced an allosteric shift in the troponin complex resulting in distortion of activation Ca2+-binding domain of troponin C (TnnC) at S69, resulting in calcium discoordination. Next, we adopted a structure-based drug repurposing approach to identify bisphosphonate risedronate as a potential structural corrector for the mutant troponin complex. Cocrystallization of risedronate with the mutant troponin complex restored the normal configuration of S69 and calcium coordination. Risedronate normalized force generation in K210del patient-induced pluripotent stem cell-derived (iPSC-derived) cardiomyocytes and improved calcium sensitivity in skinned papillary muscles isolated from K210del mice. Systemic administration of risedronate to K210del mice normalized left ventricular ejection fraction. Collectively, these results identify the structural basis for decreased calcium sensitivity in K210del and highlight structural and phenotypic correction as a potential therapeutic strategy in genetic cardiomyopathies.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-02-16
DOI
https://doi.org/10.1172/jci174081
Citations
1
Primary Topic
Cardiomyopathy and Myosin Studies
Type
article
Field-Weighted Citation Impact
1.39

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article

An FDA-approved drug structurally and phenotypically corrects the K210del mutation in genetic cardiomyopathy models

David A. Elliott, Hayley L. Pointer, Ivan Menendez-Montes, Ping Wang et al.
1 citations
Journal of Clinical Investigation
Cardiomyopathy and Myosin Studies
1.39
article

An FDA-approved drug structurally and phenotypically corrects the K210del mutation in genetic cardiomyopathy models

David A. Elliott, Hayley L. Pointer, Ivan Menendez-Montes, Ping Wang, Janaka Wansapura, Ngoc Uyen Nhi Nguyen, Tara C. Tassin, Rui Zhao, Kevin I. Watt, Waleed M. Elhelaly, James W. McNamara, Nan Ma, Sakthivel Sadayappan, Nicholas T. Lam, Enzo R. Porrello, Hesham A. Sadek, Eric Crossley, Mahmoud Ahmed, Alisson C. Cardoso, Ching‐Cheng Hsu, Ayman Farag, Suwannee Thet, Noelle Sevilir Williams, Tiejun Zhang, Rohit Singh, Sachio Morimoto
article en
1 citations

Abstract

Dilated cardiomyopathy (DCM) due to genetic disorders results in decreased myocardial contractility, leading to high morbidity and mortality rates. There are several therapeutic challenges in treating DCM, including poor understanding of the underlying mechanism of impaired myocardial contractility and the difficulty of developing targeted therapies to reverse mutation-specific pathologies. In this report, we focused on K210del, a DCM-causing mutation, due to 3-nucleotide deletion of sarcomeric troponin T (TnnT), resulting in loss of Lysine210. We resolved the crystal structure of the troponin complex carrying the K210del mutation. K210del induced an allosteric shift in the troponin complex resulting in distortion of activation Ca2+-binding domain of troponin C (TnnC) at S69, resulting in calcium discoordination. Next, we adopted a structure-based drug repurposing approach to identify bisphosphonate risedronate as a potential structural corrector for the mutant troponin complex. Cocrystallization of risedronate with the mutant troponin complex restored the normal configuration of S69 and calcium coordination. Risedronate normalized force generation in K210del patient-induced pluripotent stem cell-derived (iPSC-derived) cardiomyocytes and improved calcium sensitivity in skinned papillary muscles isolated from K210del mice. Systemic administration of risedronate to K210del mice normalized left ventricular ejection fraction. Collectively, these results identify the structural basis for decreased calcium sensitivity in K210del and highlight structural and phenotypic correction as a potential therapeutic strategy in genetic cardiomyopathies.

Journal of Clinical InvestigationVol. 135(4)
Texas Tech University (US), Royal Children's Hospital (AU), University of Arizona (US), The University of Melbourne (AU), Cardiovascular Institute of the South (US), Spanish National Centre for Cardiovascular Research (ES), Fukuoka International University (JP), Advanced Imaging Research (United States) (US), Brazilian Biosciences National Laboratory (BR), University of Cincinnati (US), International University of Health and Welfare (JP), The University of Texas Southwestern Medical Center (US), Texas Tech University Health Sciences Center (US), Stanford University (US)
University of Texas Southwestern Medical Center, NHLBI Division of Intramural Research
Good health and well-being
Openalex Percentile: Top 23%
Cardiomyopathy and Myosin Studies
1.39
DOIOpen Access PDFOpenAlex
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