{"date_updated":"2023-09-25T08:50:10Z","tmp":{"image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"article_processing_charge":"No","month":"11","day":"01","type":"journal_article","file":[{"date_updated":"2023-09-25T08:48:54Z","file_id":"14369","success":1,"date_created":"2023-09-25T08:48:54Z","file_size":4105513,"relation":"main_file","checksum":"440f0cd8a2ffcbe03c015c1746728387","content_type":"application/pdf","file_name":"2023_GeneticsMedicine_Accogli.pdf","creator":"dernst","access_level":"open_access"}],"abstract":[{"text":"Purpose: \r\nBiallelic variants in TARS2, encoding the mitochondrial threonyl-tRNA-synthetase, have been reported in a small group of individuals displaying a neurodevelopmental phenotype but with limited neuroradiological data and insufficient evidence for causality of the variants.\r\nMethods:\r\nExome or genome sequencing was carried out in 15 families. Clinical and neuroradiological evaluation was performed for all affected individuals, including review of 10 previously reported individuals. The pathogenicity of TARS2 variants was evaluated using in vitro assays and a zebrafish model.\r\nResults:\r\nWe report 18 new individuals harboring biallelic TARS2 variants. Phenotypically, these individuals show developmental delay/intellectual disability, regression, cerebellar and cerebral atrophy, basal ganglia signal alterations, hypotonia, cerebellar signs, and increased blood lactate. In vitro studies showed that variants within the TARS2301-381 region had decreased binding to Rag GTPases, likely impairing mTORC1 activity. The zebrafish model recapitulated key features of the human phenotype and unraveled dysregulation of downstream targets of mTORC1 signaling. Functional testing of the variants confirmed the pathogenicity in a zebrafish model.\r\nConclusion:\r\nWe define the clinico-radiological spectrum of TARS2-related mitochondrial disease, unveil the likely involvement of the mTORC1 signaling pathway as a distinct molecular mechanism, and establish a TARS2 zebrafish model as an important tool to study variant pathogenicity.","lang":"eng"}],"issue":"11","date_published":"2023-11-01T00:00:00Z","extern":"1","publication_status":"published","scopus_import":"1","publisher":"Elsevier","date_created":"2023-09-25T08:44:29Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","oa_version":"Published Version","oa":1,"status":"public","title":"Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder","quality_controlled":"1","publication_identifier":{"issn":["1098-3600"]},"has_accepted_license":"1","author":[{"last_name":"Accogli","first_name":"Andrea","full_name":"Accogli, Andrea"},{"last_name":"Lin","first_name":"Sheng-Jia","full_name":"Lin, Sheng-Jia"},{"full_name":"Severino, Mariasavina","first_name":"Mariasavina","last_name":"Severino"},{"full_name":"Kim, Sung-Hoon","first_name":"Sung-Hoon","last_name":"Kim"},{"first_name":"Kevin","last_name":"Huang","full_name":"Huang, Kevin","id":"3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3","orcid":"0000-0002-2512-7812"},{"full_name":"Rocca, Clarissa","first_name":"Clarissa","last_name":"Rocca"},{"full_name":"Landsverk, Megan","last_name":"Landsverk","first_name":"Megan"},{"first_name":"Maha S.","last_name":"Zaki","full_name":"Zaki, Maha S."},{"last_name":"Al-Maawali","first_name":"Almundher","full_name":"Al-Maawali, Almundher"},{"full_name":"Srinivasan, Varunvenkat M.","first_name":"Varunvenkat M.","last_name":"Srinivasan"},{"full_name":"Al-Thihli, Khalid","last_name":"Al-Thihli","first_name":"Khalid"},{"full_name":"Schaefer, G. Bradly","last_name":"Schaefer","first_name":"G. Bradly"},{"last_name":"Davis","first_name":"Monica","full_name":"Davis, Monica"},{"last_name":"Tonduti","first_name":"Davide","full_name":"Tonduti, Davide"},{"last_name":"Doneda","first_name":"Chiara","full_name":"Doneda, Chiara"},{"first_name":"Lara M.","last_name":"Marten","full_name":"Marten, Lara M."},{"full_name":"Mühlhausen, Chris","last_name":"Mühlhausen","first_name":"Chris"},{"last_name":"Gomez","first_name":"Maria","full_name":"Gomez, Maria"},{"last_name":"Lamantea","first_name":"Eleonora","full_name":"Lamantea, Eleonora"},{"first_name":"Rafael","last_name":"Mena","full_name":"Mena, Rafael"},{"full_name":"Nizon, Mathilde","last_name":"Nizon","first_name":"Mathilde"},{"last_name":"Procaccio","first_name":"Vincent","full_name":"Procaccio, Vincent"},{"full_name":"Begtrup, Amber","last_name":"Begtrup","first_name":"Amber"},{"last_name":"Telegrafi","first_name":"Aida","full_name":"Telegrafi, Aida"},{"first_name":"Hong","last_name":"Cui","full_name":"Cui, Hong"},{"full_name":"Schulz, Heidi L.","last_name":"Schulz","first_name":"Heidi L."},{"full_name":"Mohr, Julia","first_name":"Julia","last_name":"Mohr"},{"first_name":"Saskia","last_name":"Biskup","full_name":"Biskup, Saskia"},{"first_name":"Mariana Amina","last_name":"Loos","full_name":"Loos, Mariana Amina"},{"last_name":"Aráoz","first_name":"Hilda Verónica","full_name":"Aráoz, Hilda Verónica"},{"full_name":"Salpietro, Vincenzo","last_name":"Salpietro","first_name":"Vincenzo"},{"last_name":"Keppen","first_name":"Laura Davis","full_name":"Keppen, Laura Davis"},{"last_name":"Chitre","first_name":"Manali","full_name":"Chitre, Manali"},{"full_name":"Petree, Cassidy","first_name":"Cassidy","last_name":"Petree"},{"full_name":"Raymond, Lucy","last_name":"Raymond","first_name":"Lucy"},{"last_name":"Vogt","first_name":"Julie","full_name":"Vogt, Julie"},{"full_name":"Sawyer, Lindsey B.","first_name":"Lindsey B.","last_name":"Sawyer"},{"first_name":"Alice A.","last_name":"Basinger","full_name":"Basinger, Alice A."},{"full_name":"Pedersen, Signe Vandal","first_name":"Signe Vandal","last_name":"Pedersen"},{"last_name":"Pearson","first_name":"Toni S.","full_name":"Pearson, Toni S."},{"full_name":"Grange, Dorothy K.","first_name":"Dorothy K.","last_name":"Grange"},{"last_name":"Lingappa","first_name":"Lokesh","full_name":"Lingappa, Lokesh"},{"full_name":"McDunnah, Paige","first_name":"Paige","last_name":"McDunnah"},{"first_name":"Rita","last_name":"Horvath","full_name":"Horvath, Rita"},{"last_name":"Cognè","first_name":"Benjamin","full_name":"Cognè, Benjamin"},{"full_name":"Isidor, Bertrand","first_name":"Bertrand","last_name":"Isidor"},{"first_name":"Andreas","last_name":"Hahn","full_name":"Hahn, Andreas"},{"first_name":"Karen W.","last_name":"Gripp","full_name":"Gripp, Karen W."},{"first_name":"Seyed Mehdi","last_name":"Jafarnejad","full_name":"Jafarnejad, Seyed Mehdi"},{"full_name":"Østergaard, Elsebet","first_name":"Elsebet","last_name":"Østergaard"},{"first_name":"Carlos E.","last_name":"Prada","full_name":"Prada, Carlos E."},{"full_name":"Ghezzi, Daniele","last_name":"Ghezzi","first_name":"Daniele"},{"full_name":"Gowda, Vykuntaraju K.","last_name":"Gowda","first_name":"Vykuntaraju K."},{"full_name":"Taylor, Robert W.","first_name":"Robert W.","last_name":"Taylor"},{"last_name":"Sonenberg","first_name":"Nahum","full_name":"Sonenberg, Nahum"},{"last_name":"Houlden","first_name":"Henry","full_name":"Houlden, Henry"},{"last_name":"Sissler","first_name":"Marie","full_name":"Sissler, Marie"},{"full_name":"Varshney, Gaurav K.","last_name":"Varshney","first_name":"Gaurav K."},{"first_name":"Reza","last_name":"Maroofian","full_name":"Maroofian, Reza"}],"publication":"Genetics in Medicine","doi":"10.1016/j.gim.2023.100938","_id":"14368","article_number":"100938","language":[{"iso":"eng"}],"article_type":"original","citation":{"ama":"Accogli A, Lin S-J, Severino M, et al. Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder. <i>Genetics in Medicine</i>. 2023;25(11). doi:<a href=\"https://doi.org/10.1016/j.gim.2023.100938\">10.1016/j.gim.2023.100938</a>","chicago":"Accogli, Andrea, Sheng-Jia Lin, Mariasavina Severino, Sung-Hoon Kim, Kevin Huang, Clarissa Rocca, Megan Landsverk, et al. “Clinical, Neuroradiological, and Molecular Characterization of Mitochondrial Threonyl-TRNA-Synthetase (TARS2)-Related Disorder.” <i>Genetics in Medicine</i>. Elsevier, 2023. <a href=\"https://doi.org/10.1016/j.gim.2023.100938\">https://doi.org/10.1016/j.gim.2023.100938</a>.","ista":"Accogli A, Lin S-J, Severino M, Kim S-H, Huang K, Rocca C, Landsverk M, Zaki MS, Al-Maawali A, Srinivasan VM, Al-Thihli K, Schaefer GB, Davis M, Tonduti D, Doneda C, Marten LM, Mühlhausen C, Gomez M, Lamantea E, Mena R, Nizon M, Procaccio V, Begtrup A, Telegrafi A, Cui H, Schulz HL, Mohr J, Biskup S, Loos MA, Aráoz HV, Salpietro V, Keppen LD, Chitre M, Petree C, Raymond L, Vogt J, Sawyer LB, Basinger AA, Pedersen SV, Pearson TS, Grange DK, Lingappa L, McDunnah P, Horvath R, Cognè B, Isidor B, Hahn A, Gripp KW, Jafarnejad SM, Østergaard E, Prada CE, Ghezzi D, Gowda VK, Taylor RW, Sonenberg N, Houlden H, Sissler M, Varshney GK, Maroofian R. 2023. Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder. Genetics in Medicine. 25(11), 100938.","apa":"Accogli, A., Lin, S.-J., Severino, M., Kim, S.-H., Huang, K., Rocca, C., … Maroofian, R. (2023). Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder. <i>Genetics in Medicine</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.gim.2023.100938\">https://doi.org/10.1016/j.gim.2023.100938</a>","short":"A. Accogli, S.-J. Lin, M. Severino, S.-H. Kim, K. Huang, C. Rocca, M. Landsverk, M.S. Zaki, A. Al-Maawali, V.M. Srinivasan, K. Al-Thihli, G.B. Schaefer, M. Davis, D. Tonduti, C. Doneda, L.M. Marten, C. Mühlhausen, M. Gomez, E. Lamantea, R. Mena, M. Nizon, V. Procaccio, A. Begtrup, A. Telegrafi, H. Cui, H.L. Schulz, J. Mohr, S. Biskup, M.A. Loos, H.V. Aráoz, V. Salpietro, L.D. Keppen, M. Chitre, C. Petree, L. Raymond, J. Vogt, L.B. Sawyer, A.A. Basinger, S.V. Pedersen, T.S. Pearson, D.K. Grange, L. Lingappa, P. McDunnah, R. Horvath, B. Cognè, B. Isidor, A. Hahn, K.W. Gripp, S.M. Jafarnejad, E. Østergaard, C.E. Prada, D. Ghezzi, V.K. Gowda, R.W. Taylor, N. Sonenberg, H. Houlden, M. Sissler, G.K. Varshney, R. Maroofian, Genetics in Medicine 25 (2023).","mla":"Accogli, Andrea, et al. “Clinical, Neuroradiological, and Molecular Characterization of Mitochondrial Threonyl-TRNA-Synthetase (TARS2)-Related Disorder.” <i>Genetics in Medicine</i>, vol. 25, no. 11, 100938, Elsevier, 2023, doi:<a href=\"https://doi.org/10.1016/j.gim.2023.100938\">10.1016/j.gim.2023.100938</a>.","ieee":"A. Accogli <i>et al.</i>, “Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder,” <i>Genetics in Medicine</i>, vol. 25, no. 11. Elsevier, 2023."},"year":"2023","volume":25,"intvolume":"        25","ddc":["570"],"keyword":["Genetics (clinical)"],"file_date_updated":"2023-09-25T08:48:54Z"}