{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T19:13:57Z","timestamp":1789413237288,"version":"build-2803163510"},"reference-count":46,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,23]],"date-time":"2021-05-23T00:00:00Z","timestamp":1621728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health (NIH)","award":["R01-HL081753"],"award-info":[{"award-number":["R01-HL081753"]}]},{"name":"National Institutes of Health (NIH)","award":["R01-HL107304"],"award-info":[{"award-number":["R01-HL107304"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A de novo missense variant in Rag GTPase protein C (RagCS75Y) was recently identified in a syndromic dilated cardiomyopathy (DCM) patient. However, its pathogenicity and the related therapeutic strategy remain unclear. We generated a zebrafish RragcS56Y (corresponding to human RagCS75Y) knock-in (KI) line via TALEN technology. The KI fish manifested cardiomyopathy-like phenotypes and poor survival. Overexpression of RagCS75Y via adenovirus infection also led to increased cell size and fetal gene reprogramming in neonatal rat ventricle cardiomyocytes (NRVCMs), indicating a conserved mechanism. Further characterization identified aberrant mammalian target of rapamycin complex 1 (mTORC1) and transcription factor EB (TFEB) signaling, as well as metabolic abnormalities including dysregulated autophagy. However, mTOR inhibition failed to ameliorate cardiac phenotypes in the RagCS75Y cardiomyopathy models, concomitant with a failure to promote TFEB nuclear translocation. This observation was at least partially explained by increased and mTOR-independent physical interaction between RagCS75Y and TFEB in the cytosol. Importantly, TFEB overexpression resulted in more nuclear TFEB and rescued cardiomyopathy phenotypes. These findings suggest that S75Y is a pathogenic gain-of-function mutation in RagC that leads to cardiomyopathy. A primary pathological step of RagCS75Y cardiomyopathy is defective mTOR\u2013TFEB signaling, which can be corrected by TFEB overexpression, but not mTOR inhibition.<\/jats:p>","DOI":"10.3390\/ijms22115494","type":"journal-article","created":{"date-parts":[[2021,5,23]],"date-time":"2021-05-23T23:58:05Z","timestamp":1621814285000},"page":"5494","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["TFEB Overexpression, Not mTOR Inhibition, Ameliorates RagCS75Y Cardiomyopathy"],"prefix":"10.3390","volume":"22","author":[{"given":"Maengjo","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55901, USA"},{"name":"Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linghui","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55901, USA"},{"name":"Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55901, USA"},{"name":"School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey V.","family":"Dvornikov","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55901, USA"},{"name":"Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55901, USA"},{"name":"Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55901, USA"},{"name":"Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghe","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55901, USA"},{"name":"Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55901, USA"},{"name":"Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy M.","family":"Olson","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55901, USA"},{"name":"Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN 55901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueying","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55901, USA"},{"name":"Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55901, USA"},{"name":"Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/s41572-019-0084-1","article-title":"Dilated cardiomyopathy","volume":"5","author":"Schultheiss","year":"2019","journal-title":"Nat. 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