Kbtbd13 knockdown restores muscle function in a clinically relevant mouse model of nemaline myopathy type 6
Science Translational Medicine, vol. 18, pp. eadx2116
Abstract
Nemaline myopathy type 6 (NEM6) is a rare neuromuscular disorder caused by pathogenic variants in the Kelch repeat and BTB domain–containing 13 ( KBTBD13 ) gene. Patients experience muscle weakness, excessive fatigue, and impaired muscle relaxation that affect their daily activities related to abnormal protein aggregation in muscle cells and a predominance of slow-twitch myofibers, and no specific therapies are available. Here, we studied a clinically relevant Kbtbd13 :p.Arg408Cys knockin mouse model to elucidate the molecular changes driving disease pathogenesis through measurements of muscle contractility, single myofiber assays, super-resolution microscopy, and x-ray diffraction. Kbtbd13 :p.Arg408Cys knockin mice closely phenocopied human NEM6 pathology at the morphological, functional, and transcriptional levels, with the p.Arg408Cys variant causing mislocalization of KBTBD13 in the muscle sarcomere, associated with disease onset between 1 and 3 months of age, plateauing by 9 months, and with little progression at 18 months. As a potential therapeutic approach, we knocked down Kbtbd13 using short hairpin RNA against Kbtbd13 delivered intramuscularly via an adeno-associated virus 9 vector at either the prephenotype (1-month-old) or peak-phenotype (3- or 7-month-old) stages. A single treatment at the prephenotype stage prevented the development of impaired relaxation kinetics, nemaline rod aggregation, and slow-twitch myofiber predominance at 3 months of age. A single treatment at 3 months of age, after onset of disease, restored muscle morphology, contractility, and muscle-relaxation kinetics over 6 months. These data provide insights into NEM6 pathogenesis and suggest that Kbtbd13 knockdown might be a promising therapeutic strategy for patients with NEM6.
Authors 18
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R. Galli corresponding
Amsterdam Movement Sciences · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands
Musculoskeletal Health, Amsterdam Movement Sciences, 1081HV Amsterdam, Netherlands
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Leander A. Vonk corresponding
Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands
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R. Baelde corresponding
Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, 2333ZC Leiden, Netherlands
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Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands
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Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands
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Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands
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Affiliation as printed
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA
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Affiliation as printed
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA
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Illinois Institute of Technology
Affiliation as printed
BioCAT, Department of Biology, Illinois Institute of Technology, Chicago, IL 60616, USA
Center for Synchrotron Radiation Research and Instrumentation, Illinois Institute of Technology, Chicago, IL 60616, USA
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Illinois Institute of Technology · Pritzker Institute of Biomedical Science and Engineering
Affiliation as printed
BioCAT, Department of Biology, Illinois Institute of Technology, Chicago, IL 60616, USA
Center for Synchrotron Radiation Research and Instrumentation, Illinois Institute of Technology, Chicago, IL 60616, USA
Pritzker Institute of Biomedical Science and Engineering, Illinois Institute of Technology, Chicago, IL 60616, USA
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Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6525EN Nijmegen, Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6525EN Nijmegen, Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, 2333ZC Leiden, Netherlands
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University of Kentucky · Amsterdam Movement Sciences · Amsterdam Cardiovascular Sciences · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA
Heart Failure & Arrhythmias, Amsterdam Cardiovascular Sciences, 1081HV Amsterdam, Netherlands
Tissue Function & Regeneration, Amsterdam Movement Sciences, 1081HV Amsterdam, Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour
Affiliation as printed
Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6525EN Nijmegen, Netherlands
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Amsterdam Movement Sciences · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands
Tissue Function & Regeneration, Amsterdam Movement Sciences, 1081HV Amsterdam, Netherlands
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Coen A. C. Ottenheijm corresponding
University of Arizona · Amsterdam Cardiovascular Sciences · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA
Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands
Heart Failure & Arrhythmias, Amsterdam Cardiovascular Sciences, 1081HV Amsterdam, Netherlands
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