Academic Journal
Kbtbd13 knockdown restores muscle function in a clinically relevant mouse model of nemaline myopathy type 6.
| Τίτλος: | Kbtbd13 knockdown restores muscle function in a clinically relevant mouse model of nemaline myopathy type 6. |
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| Συγγραφείς: | Galli RA; Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands.; Musculoskeletal Health, Amsterdam Movement Sciences, 1081HV Amsterdam, Netherlands., Vonk LA; Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands., Baelde RJ; Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands., van den Heuvel A; Department of Human Genetics, Leiden University Medical Center, 2333ZC Leiden, Netherlands., Bogaards S; Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands., Conijn S; Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands., Siteur E; Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands., Alekhina O; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA., Granzier H; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA., Irving T; 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., Ma W; 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., Bouman K; Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6525EN Nijmegen, Netherlands., van Engelen B; Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6525EN Nijmegen, Netherlands., van der Maarel SM; Department of Human Genetics, Leiden University Medical Center, 2333ZC Leiden, Netherlands., Kirby TJ; Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands.; Tissue Function & Regeneration, Amsterdam Movement Sciences, 1081HV Amsterdam, Netherlands.; Heart Failure & Arrhythmias, Amsterdam Cardiovascular Sciences, 1081HV Amsterdam, Netherlands.; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA., Voermans N; Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6525EN Nijmegen, Netherlands., de Winter J; Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands.; Tissue Function & Regeneration, Amsterdam Movement Sciences, 1081HV Amsterdam, Netherlands., Ottenheijm CAC; Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands.; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA.; Heart Failure & Arrhythmias, Amsterdam Cardiovascular Sciences, 1081HV Amsterdam, Netherlands. |
| Πηγή: | Science translational medicine [Sci Transl Med] 2026 Jun 24; Vol. 18 (855), pp. eadx2116. Date of Electronic Publication: 2026 Jun 24. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Washington, DC : American Association for the Advancement of Science |
| Ιατρικοί όροι (MeSH): | Myopathies, Nemaline*/physiopathology , Myopathies, Nemaline*/genetics , Myopathies, Nemaline*/pathology , Myopathies, Nemaline*/therapy , Muscle, Skeletal*/physiopathology , Muscle, Skeletal*/pathology , Muscle Proteins*/metabolism , Muscle Proteins*/genetics , Gene Knockdown Techniques*, Sarcomeres/metabolism ; Animals ; Disease Models, Animal ; Humans ; Muscle Contraction ; Mice |
| Περίληψη: | 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. |
| Substance Nomenclature: | 0 (Muscle Proteins) |
| Entry Date(s): | Date Created: 20260624 Date Completed: 20260624 Latest Revision: 20260624 |
| Update Code: | 20260625 |
| DOI: | 10.1126/scitranslmed.adx2116 |
| PMID: | 42341083 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1946-6242 |
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| DOI: | 10.1126/scitranslmed.adx2116 |