{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T10:57:59Z","timestamp":1768733879039,"version":"3.49.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T00:00:00Z","timestamp":1631232000000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["MDA 577888"],"award-info":[{"award-number":["MDA 577888"]}],"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Telethon Foundation","doi-asserted-by":"publisher","award":["GGP20097"],"award-info":[{"award-number":["GGP20097"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Telethon Foundation","doi-asserted-by":"publisher","award":["GGP15140"],"award-info":[{"award-number":["GGP15140"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013465","name":"Association Fran\u00e7aise contre les Myopathies","doi-asserted-by":"publisher","award":["AFM#23000"],"award-info":[{"award-number":["AFM#23000"]}],"id":[{"id":"10.13039\/100013465","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013465","name":"Association Fran\u00e7aise contre les Myopathies","doi-asserted-by":"publisher","award":["AFM#18620"],"award-info":[{"award-number":["AFM#18620"]}],"id":[{"id":"10.13039\/100013465","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,2,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Limb-girdle muscular dystrophy R3 (LGMDR3) is caused by mutations in the SGCA gene coding for \u03b1-sarcoglycan (SG). Together with \u03b2- \u03b3- and \u03b4-SG, \u03b1-SG forms a tetramer embedded in the dystrophin associated protein complex crucial for protecting the sarcolemma from mechanical stresses elicited by muscle contraction. Most LGMDR3 cases are due to missense mutations, which result in non-properly folded, even though potentially functional \u03b1-SG. These mutants are prematurely discarded by the cell quality control. Lacking one subunit, the SG-complex is disrupted. The resulting loss of function leads to sarcolemma instability, muscle fiber damage and progressive limb muscle weakness. LGMDR3 is severely disabling and, unfortunately, still incurable. Here, we propose the use of small molecules, belonging to the class of cystic fibrosis transmembrane regulator (CFTR) correctors, for recovering mutants of \u03b1-SG defective in folding and trafficking. Specifically, CFTR corrector C17 successfully rerouted the SG-complex containing the human R98H-\u03b1-SG to the sarcolemma of hind-limb muscles of a novel LGMDR3 murine model. Notably, the muscle force of the treated model animals was fully recovered. To our knowledge, this is the first time that a compound designated for cystic fibrosis is successfully tested in a muscular dystrophy and may represent a novel paradigm of treatment for LGMDR3 as well as different other indications in which a potentially functional protein is prematurely discarded as folding-defective. Furthermore, the use of small molecules for recovering the endogenous mutated SG has an evident advantage over complex procedures such as gene or cell transfer.<\/jats:p>","DOI":"10.1093\/hmg\/ddab260","type":"journal-article","created":{"date-parts":[[2021,9,8]],"date-time":"2021-09-08T11:28:18Z","timestamp":1631100498000},"page":"499-509","source":"Crossref","is-referenced-by-count":18,"title":["CFTR corrector C17 is effective in muscular dystrophy, <i>in vivo<\/i> proof of concept in LGMDR3"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8761-1730","authenticated-orcid":false,"given":"Martina","family":"Scano","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Benetollo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonardo","family":"Nogara","sequence":"additional","affiliation":[{"name":"Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michela","family":"Bond\u00ec","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Dalla Barba","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michela","family":"Soardi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Furlan","sequence":"additional","affiliation":[{"name":"Neuroscience Institute \u2013 Italian National Research Council (CNR), Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eylem Emek","family":"Akyurek","sequence":"additional","affiliation":[{"name":"Department of Comparative Biomedicine and Food Science, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Caccin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcello","family":"Carotti","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberta","family":"Sacchetto","sequence":"additional","affiliation":[{"name":"Department of Comparative Biomedicine and Food Science, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bert","family":"Blaauw","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Padova, Italy"},{"name":"Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9908-2442","authenticated-orcid":false,"given":"Dorianna","family":"Sandon\u00e0","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,9,9]]},"reference":[{"key":"2022022310592277500_ref1","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.nmd.2018.05.007","article-title":"229th ENMC international workshop: limb girdle muscular dystrophies - nomenclature and reformed classification Naarden, the Netherlands, 17-19 march 2017","volume":"28","author":"Straub","year":"2018","journal-title":"Neuromuscul. Disord."},{"key":"2022022310592277500_ref2","doi-asserted-by":"crossref","first-page":"744","DOI":"10.2741\/4418","article-title":"The sarcoglycan complex in skeletal muscle","volume":"21","author":"Tarakci","year":"2016","journal-title":"Front. Biosci. (Landmark Ed)"},{"key":"2022022310592277500_ref3","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1093\/hmg\/ddn029","article-title":"Mannosidase I inhibition rescues the human alpha-sarcoglycan R77C recurrent mutation","volume":"17","author":"Bartoli","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"2022022310592277500_ref4","doi-asserted-by":"crossref","first-page":"170","DOI":"10.2353\/ajpath.2008.071146","article-title":"Inhibition of proteasome activity promotes the correct localization of disease-causing alpha-sarcoglycan mutants in HEK-293 cells constitutively expressing beta-, gamma-, and delta-sarcoglycan","volume":"173","author":"Gastaldello","year":"2008","journal-title":"Am. J. Pathol."},{"key":"2022022310592277500_ref5","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1002\/humu.21659","article-title":"Rescue of sarcoglycan mutations by inhibition of endoplasmic reticulum quality control is associated with minimal structural modifications","volume":"33","author":"Soheili","year":"2012","journal-title":"Hum. Mutat."},{"key":"2022022310592277500_ref6","doi-asserted-by":"crossref","first-page":"3746","DOI":"10.1093\/hmg\/ddu088","article-title":"Unveiling the degradative route of the V247M alpha-sarcoglycan mutant responsible for LGMD-2D","volume":"23","author":"Bianchini","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"2022022310592277500_ref7","doi-asserted-by":"crossref","DOI":"10.1017\/S1462399409001203","article-title":"Sarcoglycanopathies: molecular pathogenesis and therapeutic prospects","volume":"11","author":"Sandona","year":"2009","journal-title":"Expert Rev. Mol. 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Chem."},{"key":"2022022310592277500_ref10","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1378\/chest.10-2077","article-title":"Cystic fibrosis transmembrane conductance regulator intracellular processing, trafficking, and opportunities for mutation-specific treatment","volume":"139","author":"Rogan","year":"2011","journal-title":"Chest"},{"key":"2022022310592277500_ref11","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.coph.2017.09.014","article-title":"Correcting CFTR folding defects by small-molecule correctors to cure cystic fibrosis","volume":"34","author":"Mijnders","year":"2017","journal-title":"Curr. Opin. Pharmacol."},{"key":"2022022310592277500_ref12","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.3389\/fphar.2019.01662","article-title":"CFTR modulators: the changing face of cystic fibrosis in the era of precision medicine","volume":"10","author":"Lopes-Pacheco","year":"2020","journal-title":"Front. Pharmacol."},{"key":"2022022310592277500_ref13","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1093\/hmg\/ddy013","article-title":"Repairing folding-defective alpha-sarcoglycan mutants by CFTR correctors, a potential therapy for limb-girdle muscular dystrophy 2D","volume":"27","author":"Carotti","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"2022022310592277500_ref14","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.3390\/ijms21051813","article-title":"Combined use of CFTR correctors in LGMD2D myotubes improves sarcoglycan complex recovery","volume":"21","author":"Carotti","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"2022022310592277500_ref15","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1093\/hmg\/ddn009","article-title":"A common disease-associated missense mutation in alpha-sarcoglycan fails to cause muscular dystrophy in mice","volume":"17","author":"Kobuke","year":"2008","journal-title":"Hum. Mol. 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Vaccines Ther."},{"key":"2022022310592277500_ref19","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1038\/gt.2008.104","article-title":"Construction and analysis of compact muscle-specific promoters for AAV vectors","volume":"15","author":"Wang","year":"2008","journal-title":"Gene Ther."},{"key":"2022022310592277500_ref20","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1038\/sj.gt.3301247","article-title":"Early adenovirus-mediated gene transfer effectively prevents muscular dystrophy in alpha-sarcoglycan-deficient mice","volume":"7","author":"Allamand","year":"2000","journal-title":"Gene Ther."},{"key":"2022022310592277500_ref21","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.1021\/bc2004457","article-title":"Functional fluorescently labeled bithiazole DeltaF508-CFTR corrector imaged in whole body slices in mice","volume":"22","author":"Davison","year":"2011","journal-title":"Bioconjug. 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Res."},{"key":"2022022310592277500_ref23","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1002\/mus.10566","article-title":"Specific assembly pathway of sarcoglycans is dependent on beta- and delta-sarcoglycan","volume":"29","author":"Shi","year":"2004","journal-title":"Muscle Nerve"},{"key":"2022022310592277500_ref24","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1002\/mus.20640","article-title":"The beta-delta-core of sarcoglycan is essential for deposition at the plasma membrane","volume":"34","author":"Draviam","year":"2006","journal-title":"Muscle Nerve"},{"key":"2022022310592277500_ref25","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1111\/j.1600-0854.2006.00519.x","article-title":"Processing and assembly of the dystrophin glycoprotein complex","volume":"8","author":"Allikian","year":"2007","journal-title":"Traffic"},{"key":"2022022310592277500_ref26","doi-asserted-by":"crossref","first-page":"2296","DOI":"10.1096\/fj.10-174755","article-title":"In vivo tissue engineering of functional skeletal muscle by freshly isolated satellite cells embedded in a photopolymerizable hydrogel","volume":"25","author":"Rossi","year":"2011","journal-title":"FASEB J."},{"key":"2022022310592277500_ref27","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1152\/japplphysiol.00803.2009","article-title":"Eccentric contractions lead to myofibrillar dysfunction in muscular dystrophy","volume":"108","author":"Blaauw","year":"2010","journal-title":"J. Appl. Physiol."},{"key":"2022022310592277500_ref28","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.cbpa.2013.04.020","article-title":"Correctors of the basic trafficking defect of the mutant F508del-CFTR that causes cystic fibrosis","volume":"17","author":"Birault","year":"2013","journal-title":"Curr. Opin. Chem. Biol."},{"key":"2022022310592277500_ref29","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1750-1172-8-11","article-title":"Compounds that correct F508del-CFTR trafficking can also correct other protein trafficking diseases: an in vitro study using cell lines","volume":"8","author":"Sampson","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"2022022310592277500_ref30","doi-asserted-by":"crossref","first-page":"19743","DOI":"10.1074\/jbc.M115.647685","article-title":"Rescuing trafficking mutants of the ATP-binding cassette protein, ABCA4, with small molecule correctors as a treatment for stargardt eye disease","volume":"290","author":"Sabirzhanova","year":"2015","journal-title":"J. Biol. Chem."},{"key":"2022022310592277500_ref31","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1016\/j.jhep.2016.02.001","article-title":"Rescue of defective ATP8B1 trafficking by CFTR correctors as a therapeutic strategy for familial intrahepatic cholestasis","volume":"64","author":"Woerd","year":"2016","journal-title":"J. Hepatol."},{"key":"2022022310592277500_ref32","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1083\/jcb.142.6.1461","article-title":"Progressive muscular dystrophy in alpha-sarcoglycan-deficient mice","volume":"142","author":"Duclos","year":"1998","journal-title":"J. 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Mutat."},{"key":"2022022310592277500_ref39","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1080\/21678707.2016.1256769","article-title":"Pathogenesis, clinical features and diagnosis of sarcoglycanopathies","volume":"4","author":"Angelini","year":"2016","journal-title":"Expert Opin. Orphan Drugs"},{"key":"2022022310592277500_ref40","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1212\/WNL.0b013e3181a1885e","article-title":"Frequency of LGMD gene mutations in Italian patients with distinct clinical phenotypes","volume":"72","author":"Fanin","year":"2009","journal-title":"Neurology"},{"key":"2022022310592277500_ref41","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1007\/s004150070151","article-title":"Sarcoglycanopathies in Dutch patients with autosomal recessive limb girdle muscular dystrophy","volume":"247","author":"Ginjaar","year":"2000","journal-title":"J. Neurol."},{"key":"2022022310592277500_ref42","first-page":"1907","article-title":"Limb-girdle muscular dystrophy subtypes: first-reported cohort from northeastern China","volume":"8","author":"Mahmood","year":"2013","journal-title":"Neural Regen. Res."},{"key":"2022022310592277500_ref43","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/B978-0-08-045031-5.00003-7","article-title":"Sarcoglycanopathies","volume":"101","author":"Kirschner","year":"2011","journal-title":"Handb. Clin. Neurol."},{"key":"2022022310592277500_ref44","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aay8416","article-title":"Rebalancing expression of HMGB1 redox isoforms to counteract muscular dystrophy","volume":"13","author":"Careccia","year":"2021","journal-title":"Sci. Transl. 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J."},{"key":"2022022310592277500_ref46","year":"2016","journal-title":"The International Encyclopedia of Adverse Drug Reactions and Interactions"},{"key":"2022022310592277500_ref47","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1002\/mus.21624","article-title":"Muscle weakness and atrophy are associated with decreased regenerative capacity and changes in mTOR signaling in skeletal muscles of venerable (18-24-month-old) dystrophic mdx mice","volume":"41","author":"Mouisel","year":"2010","journal-title":"Muscle Nerve"},{"key":"2022022310592277500_ref48","doi-asserted-by":"crossref","first-page":"937","DOI":"10.3389\/fmicb.2018.00937","article-title":"Application of real-time quantitative PCR to detect mink circovirus in naturally and experimentally infected minks","volume":"9","author":"Cui","year":"2018","journal-title":"Front. Microbiol."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddab260\/41068540\/ddab260.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/4\/499\/42579500\/ddab260.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/31\/4\/499\/42579500\/ddab260.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T12:43:26Z","timestamp":1645620206000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/31\/4\/499\/6367978"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,9]]},"references-count":48,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,9,9]]},"published-print":{"date-parts":[[2022,2,21]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddab260","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,2,15]]},"published":{"date-parts":[[2021,9,9]]}}}