{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:21:28Z","timestamp":1790688088955,"version":"4.1.0"},"reference-count":92,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"855","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 GM138395"],"award-info":[{"award-number":["P30 GM138395"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ZonMW-VICI","award":["91819613"],"award-info":[{"award-number":["91819613"]}]},{"name":"Princess Beatrix Fund","award":["W.OR23-06"],"award-info":[{"award-number":["W.OR23-06"]}]},{"name":"ZonMW-VENI","award":["09150161910168"],"award-info":[{"award-number":["09150161910168"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,6,24]]},"abstract":"<jats:p>\n                    Nemaline myopathy type 6 (NEM6) is a rare neuromuscular disorder caused by pathogenic variants in the\n                    <jats:italic toggle=\"yes\">Kelch repeat and BTB domain\u2013containing 13<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">KBTBD13<\/jats:italic>\n                    ) 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\n                    <jats:italic toggle=\"yes\">Kbtbd13<\/jats:italic>\n                    :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.\n                    <jats:italic toggle=\"yes\">Kbtbd13<\/jats:italic>\n                    :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\n                    <jats:italic toggle=\"yes\">Kbtbd13<\/jats:italic>\n                    using short hairpin RNA against\n                    <jats:italic toggle=\"yes\">Kbtbd13<\/jats:italic>\n                    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\n                    <jats:italic toggle=\"yes\">Kbtbd13<\/jats:italic>\n                    knockdown might be a promising therapeutic strategy for patients with NEM6.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adx2116","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T17:58:11Z","timestamp":1782323891000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["<i>Kbtbd13<\/i>\n                    knockdown restores muscle function in a clinically relevant mouse model of nemaline myopathy type 6"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9567-972X","authenticated-orcid":true,"given":"Ricardo A.","family":"Galli","sequence":"first","affiliation":[{"name":"Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands."},{"name":"Musculoskeletal Health, Amsterdam Movement Sciences, 1081HV Amsterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3689-7318","authenticated-orcid":true,"given":"Leander A.","family":"Vonk","sequence":"additional","affiliation":[{"name":"Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3331-2985","authenticated-orcid":true,"given":"Rianne J.","family":"Baelde","sequence":"additional","affiliation":[{"name":"Department of Physiology, Amsterdam UMC, Location VUMC, 1081HV Amsterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8950-6109","authenticated-orcid":true,"given":"Anita","family":"van den Heuvel","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical 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Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2738-5399","authenticated-orcid":true,"given":"Olga","family":"Alekhina","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9516-407X","authenticated-orcid":true,"given":"Henk","family":"Granzier","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4848-3323","authenticated-orcid":true,"given":"Thomas","family":"Irving","sequence":"additional","affiliation":[{"name":"BioCAT, Department of Biology, Illinois Institute of Technology, Chicago, IL 60616, USA."},{"name":"Center for Synchrotron Radiation Research and 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Netherlands."},{"name":"Tissue Function &amp; Regeneration, Amsterdam Movement Sciences, 1081HV Amsterdam, Netherlands."},{"name":"Heart Failure &amp; Arrhythmias, Amsterdam Cardiovascular Sciences, 1081HV Amsterdam, Netherlands."},{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5837-7295","authenticated-orcid":true,"given":"Nicol","family":"Voermans","sequence":"additional","affiliation":[{"name":"Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6525EN Nijmegen, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4278-8735","authenticated-orcid":true,"given":"Josine","family":"de Winter","sequence":"additional","affiliation":[{"name":"Department of Physiology, Amsterdam UMC, Location VUMC, 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