{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:47:27Z","timestamp":1790254047502,"version":"4.1.0"},"reference-count":83,"publisher":"Oxford University Press (OUP)","issue":"23","license":[{"start":{"date-parts":[[2024,9,15]],"date-time":"2024-09-15T00:00:00Z","timestamp":1726358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AR083233"],"award-info":[{"award-number":["R01AR083233"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35HL144998"],"award-info":[{"award-number":["R35HL144998"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,11,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Pathogenic variants in the titin gene (TTN) are known to cause a wide range of cardiac and musculoskeletal disorders, with skeletal myopathy mostly attributed to biallelic variants. We identified monoallelic truncating variants (TTNtv), splice site or internal deletions in TTN in probands with mild, progressive axial and proximal weakness, with dilated cardiomyopathy frequently developing with age. These variants segregated in an autosomal dominant pattern in 7 out of 8 studied families. We investigated the impact of these variants on mRNA, protein levels, and skeletal muscle structure and function. Results reveal that nonsense-mediated decay likely prevents accumulation of harmful truncated protein in skeletal muscle in patients with TTNtvs. Splice variants and an out-of-frame deletion induce aberrant exon skipping, while an in-frame deletion produces shortened titin with intact N- and C-termini, resulting in disrupted sarcomeric structure. All variant types were associated with genome-wide changes in splicing patterns, which represent a hallmark of disease progression. Lastly, RNA-seq studies revealed that GDF11, a member of the TGF-\u03b2 superfamily, is upregulated in diseased tissue, indicating that it might be a useful therapeutic target in skeletal muscle titinopathies.<\/jats:p>","DOI":"10.1093\/hmg\/ddae136","type":"journal-article","created":{"date-parts":[[2024,9,15]],"date-time":"2024-09-15T15:36:12Z","timestamp":1726414572000},"page":"2003-2023","source":"Crossref","is-referenced-by-count":9,"title":["Pathomechanisms of Monoallelic variants in <i>TTN<\/i> causing skeletal muscle disease"],"prefix":"10.1093","volume":"33","author":[{"given":"Jochen","family":"Gohlke","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of Arizona, 1656 E. Mabel St., Tucson, AZ 85724, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Lindqvist","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of Arizona, 1656 E. Mabel St., Tucson, AZ 85724, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaynab","family":"Hourani","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of Arizona, 1656 E. Mabel St., Tucson, AZ 85724, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Rich","sequence":"additional","affiliation":[{"name":"Harvard Medical School Department of Genetics - Blavatnik Institute 77 Avenue Louis Pasteur, Boston MA, 02115 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W David","family":"Arnold","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation, University of Missouri, Columbia, MO, USA; NextGen Precision Health, University of Missouri, Columbia, MO, USA; Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA; Department of Neurology, University of Missouri, Columbia, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Heintzman","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Ohio State University Wexner Medical Center, 395 W. 12th Ave, Columbus, OH 43210, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Tonino","sequence":"additional","affiliation":[{"name":"Research, Innovation and Impact Core Facilities Department, University of Arizona, 1333 N. Martin Ave, Tucson, AZ 85719, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bakri","family":"Elsheikh","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Ohio State University Wexner Medical Center, 395 W. 12th Ave, Columbus, OH 43210, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Morales","sequence":"additional","affiliation":[{"name":"Invitae Corporation, 1400 16th St., San Francisco, CA 94103, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Vatta","sequence":"additional","affiliation":[{"name":"Invitae Corporation, 1400 16th St., San Francisco, CA 94103, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Burghes","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, 370 W 9th Ave, Columbus, OH 43210, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk","family":"Granzier","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of Arizona, 1656 E. Mabel St., Tucson, AZ 85724, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6583-9996","authenticated-orcid":false,"given":"Jennifer","family":"Roggenbuck","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Ohio State University Wexner Medical Center, 395 W. 12th Ave, Columbus, OH 43210, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,9,15]]},"reference":[{"key":"2024121018015833600_ref1","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s10741-005-5251-7","article-title":"Titin: physiological function and role in cardiomyopathy and failure","volume":"10","author":"Granzier","year":"2005","journal-title":"Heart Fail Rev"},{"key":"2024121018015833600_ref2","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1161\/hh2301.100981","article-title":"The complete gene sequence of titin, expression of an 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