[{"date_published":"2023-11-01T00:00:00Z","type":"journal_article","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"oa":1,"publication_identifier":{"issn":["1098-3600"]},"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","status":"public","file":[{"file_id":"14369","creator":"dernst","success":1,"access_level":"open_access","relation":"main_file","date_updated":"2023-09-25T08:48:54Z","content_type":"application/pdf","file_name":"2023_GeneticsMedicine_Accogli.pdf","date_created":"2023-09-25T08:48:54Z","checksum":"440f0cd8a2ffcbe03c015c1746728387","file_size":4105513}],"publication":"Genetics in Medicine","has_accepted_license":"1","month":"11","article_number":"100938","oa_version":"Published Version","language":[{"iso":"eng"}],"keyword":["Genetics (clinical)"],"date_updated":"2023-09-25T08:50:10Z","citation":{"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.","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>.","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).","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>.","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.","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>","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>"},"year":"2023","abstract":[{"lang":"eng","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."}],"doi":"10.1016/j.gim.2023.100938","day":"01","extern":"1","ddc":["570"],"volume":25,"author":[{"first_name":"Andrea","last_name":"Accogli","full_name":"Accogli, Andrea"},{"last_name":"Lin","first_name":"Sheng-Jia","full_name":"Lin, Sheng-Jia"},{"first_name":"Mariasavina","last_name":"Severino","full_name":"Severino, Mariasavina"},{"full_name":"Kim, Sung-Hoon","first_name":"Sung-Hoon","last_name":"Kim"},{"full_name":"Huang, Kevin","orcid":"0000-0002-2512-7812","last_name":"Huang","first_name":"Kevin","id":"3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3"},{"last_name":"Rocca","first_name":"Clarissa","full_name":"Rocca, Clarissa"},{"full_name":"Landsverk, Megan","last_name":"Landsverk","first_name":"Megan"},{"last_name":"Zaki","first_name":"Maha S.","full_name":"Zaki, Maha S."},{"full_name":"Al-Maawali, Almundher","last_name":"Al-Maawali","first_name":"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"},{"first_name":"G. Bradly","last_name":"Schaefer","full_name":"Schaefer, G. Bradly"},{"full_name":"Davis, Monica","last_name":"Davis","first_name":"Monica"},{"full_name":"Tonduti, Davide","last_name":"Tonduti","first_name":"Davide"},{"full_name":"Doneda, Chiara","first_name":"Chiara","last_name":"Doneda"},{"first_name":"Lara M.","last_name":"Marten","full_name":"Marten, Lara M."},{"last_name":"Mühlhausen","first_name":"Chris","full_name":"Mühlhausen, Chris"},{"full_name":"Gomez, Maria","last_name":"Gomez","first_name":"Maria"},{"full_name":"Lamantea, Eleonora","first_name":"Eleonora","last_name":"Lamantea"},{"full_name":"Mena, Rafael","first_name":"Rafael","last_name":"Mena"},{"full_name":"Nizon, Mathilde","last_name":"Nizon","first_name":"Mathilde"},{"full_name":"Procaccio, Vincent","last_name":"Procaccio","first_name":"Vincent"},{"full_name":"Begtrup, Amber","first_name":"Amber","last_name":"Begtrup"},{"full_name":"Telegrafi, Aida","first_name":"Aida","last_name":"Telegrafi"},{"full_name":"Cui, Hong","first_name":"Hong","last_name":"Cui"},{"first_name":"Heidi L.","last_name":"Schulz","full_name":"Schulz, Heidi L."},{"first_name":"Julia","last_name":"Mohr","full_name":"Mohr, Julia"},{"full_name":"Biskup, Saskia","first_name":"Saskia","last_name":"Biskup"},{"first_name":"Mariana Amina","last_name":"Loos","full_name":"Loos, Mariana Amina"},{"first_name":"Hilda Verónica","last_name":"Aráoz","full_name":"Aráoz, Hilda Verónica"},{"full_name":"Salpietro, Vincenzo","first_name":"Vincenzo","last_name":"Salpietro"},{"last_name":"Keppen","first_name":"Laura Davis","full_name":"Keppen, Laura Davis"},{"first_name":"Manali","last_name":"Chitre","full_name":"Chitre, Manali"},{"last_name":"Petree","first_name":"Cassidy","full_name":"Petree, Cassidy"},{"full_name":"Raymond, Lucy","last_name":"Raymond","first_name":"Lucy"},{"first_name":"Julie","last_name":"Vogt","full_name":"Vogt, Julie"},{"last_name":"Sawyer","first_name":"Lindsey B.","full_name":"Sawyer, Lindsey B."},{"first_name":"Alice A.","last_name":"Basinger","full_name":"Basinger, Alice A."},{"full_name":"Pedersen, Signe Vandal","first_name":"Signe Vandal","last_name":"Pedersen"},{"first_name":"Toni S.","last_name":"Pearson","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","last_name":"McDunnah","first_name":"Paige"},{"last_name":"Horvath","first_name":"Rita","full_name":"Horvath, Rita"},{"full_name":"Cognè, Benjamin","first_name":"Benjamin","last_name":"Cognè"},{"full_name":"Isidor, Bertrand","first_name":"Bertrand","last_name":"Isidor"},{"full_name":"Hahn, Andreas","last_name":"Hahn","first_name":"Andreas"},{"full_name":"Gripp, Karen W.","last_name":"Gripp","first_name":"Karen W."},{"full_name":"Jafarnejad, Seyed Mehdi","first_name":"Seyed Mehdi","last_name":"Jafarnejad"},{"last_name":"Østergaard","first_name":"Elsebet","full_name":"Østergaard, Elsebet"},{"first_name":"Carlos E.","last_name":"Prada","full_name":"Prada, Carlos E."},{"full_name":"Ghezzi, Daniele","first_name":"Daniele","last_name":"Ghezzi"},{"full_name":"Gowda, Vykuntaraju K.","last_name":"Gowda","first_name":"Vykuntaraju K."},{"full_name":"Taylor, Robert W.","last_name":"Taylor","first_name":"Robert W."},{"full_name":"Sonenberg, Nahum","last_name":"Sonenberg","first_name":"Nahum"},{"full_name":"Houlden, Henry","last_name":"Houlden","first_name":"Henry"},{"full_name":"Sissler, Marie","first_name":"Marie","last_name":"Sissler"},{"full_name":"Varshney, Gaurav K.","first_name":"Gaurav K.","last_name":"Varshney"},{"full_name":"Maroofian, Reza","first_name":"Reza","last_name":"Maroofian"}],"issue":"11","_id":"14368","scopus_import":"1","title":"Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder","intvolume":"        25","publication_status":"published","date_created":"2023-09-25T08:44:29Z","article_processing_charge":"No","file_date_updated":"2023-09-25T08:48:54Z","quality_controlled":"1","article_type":"original","publisher":"Elsevier"},{"date_updated":"2023-09-25T08:57:07Z","year":"2022","citation":{"ista":"Cali E, Lin S-J, Rocca C, Sahin Y, Al Shamsi A, El Chehadeh S, Chaabouni M, Mankad K, Galanaki E, Efthymiou S, Sudhakar S, Athanasiou-Fragkouli A, Celik T, Narli N, Bianca S, Murphy D, Moreira FMDC, Accogli A, Petree C, Huang K, Monastiri K, Edizadeh M, Nardello R, Ognibene M, De Marco P, Ruggieri M, Zara F, Striano P, Sahin Y, Al-Gazali L, Warde MTA, Gerard B, Zifarelli G, Beetz C, Fortuna S, Soler M, Valente EM, Varshney G, Maroofian R, Salpietro V, Houlden H, Grp SynS. 2022. A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease. Genetics in Medicine. 24(10), 2194–2203.","mla":"Cali, Elisa, et al. “A Homozygous MED11 C-Terminal Variant Causes a Lethal Neurodegenerative Disease.” <i>Genetics in Medicine</i>, vol. 24, no. 10, Elsevier, 2022, pp. 2194–203, doi:<a href=\"https://doi.org/10.1016/j.gim.2022.07.013\">10.1016/j.gim.2022.07.013</a>.","short":"E. Cali, S.-J. Lin, C. Rocca, Y. Sahin, A. Al Shamsi, S. El Chehadeh, M. Chaabouni, K. Mankad, E. Galanaki, S. Efthymiou, S. Sudhakar, A. Athanasiou-Fragkouli, T. Celik, N. Narli, S. Bianca, D. Murphy, F.M.D.C. Moreira, A. Accogli, C. Petree, K. Huang, K. Monastiri, M. Edizadeh, R. Nardello, M. Ognibene, P. De Marco, M. Ruggieri, F. Zara, P. Striano, Y. Sahin, L. Al-Gazali, M.T.A. Warde, B. Gerard, G. Zifarelli, C. Beetz, S. Fortuna, M. Soler, E.M. Valente, G. Varshney, R. Maroofian, V. Salpietro, H. Houlden, Syn.S. Grp, Genetics in Medicine 24 (2022) 2194–2203.","ieee":"E. Cali <i>et al.</i>, “A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease,” <i>Genetics in Medicine</i>, vol. 24, no. 10. Elsevier, pp. 2194–2203, 2022.","chicago":"Cali, Elisa, Sheng-Jia Lin, Clarissa Rocca, Yavuz Sahin, Aisha Al Shamsi, Salima El Chehadeh, Myriam Chaabouni, et al. “A Homozygous MED11 C-Terminal Variant Causes a Lethal Neurodegenerative Disease.” <i>Genetics in Medicine</i>. Elsevier, 2022. <a href=\"https://doi.org/10.1016/j.gim.2022.07.013\">https://doi.org/10.1016/j.gim.2022.07.013</a>.","apa":"Cali, E., Lin, S.-J., Rocca, C., Sahin, Y., Al Shamsi, A., El Chehadeh, S., … Grp, Syn. S. (2022). A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease. <i>Genetics in Medicine</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.gim.2022.07.013\">https://doi.org/10.1016/j.gim.2022.07.013</a>","ama":"Cali E, Lin S-J, Rocca C, et al. A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease. <i>Genetics in Medicine</i>. 2022;24(10):2194-2203. doi:<a href=\"https://doi.org/10.1016/j.gim.2022.07.013\">10.1016/j.gim.2022.07.013</a>"},"abstract":[{"lang":"eng","text":"Purpose: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. Methods: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. Results: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. Conclusion: Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics."}],"doi":"10.1016/j.gim.2022.07.013","day":"01","extern":"1","ddc":["570"],"volume":24,"author":[{"last_name":"Cali","first_name":"Elisa","full_name":"Cali, Elisa"},{"first_name":"Sheng-Jia","last_name":"Lin","full_name":"Lin, Sheng-Jia"},{"last_name":"Rocca","first_name":"Clarissa","full_name":"Rocca, Clarissa"},{"last_name":"Sahin","first_name":"Yavuz","full_name":"Sahin, Yavuz"},{"first_name":"Aisha","last_name":"Al Shamsi","full_name":"Al Shamsi, Aisha"},{"first_name":"Salima","last_name":"El Chehadeh","full_name":"El Chehadeh, Salima"},{"first_name":"Myriam","last_name":"Chaabouni","full_name":"Chaabouni, Myriam"},{"full_name":"Mankad, Kshitij","last_name":"Mankad","first_name":"Kshitij"},{"full_name":"Galanaki, Evangelia","last_name":"Galanaki","first_name":"Evangelia"},{"full_name":"Efthymiou, Stephanie","last_name":"Efthymiou","first_name":"Stephanie"},{"last_name":"Sudhakar","first_name":"Sniya","full_name":"Sudhakar, Sniya"},{"full_name":"Athanasiou-Fragkouli, Alkyoni","first_name":"Alkyoni","last_name":"Athanasiou-Fragkouli"},{"full_name":"Celik, Tamer","first_name":"Tamer","last_name":"Celik"},{"last_name":"Narli","first_name":"Nejat","full_name":"Narli, Nejat"},{"full_name":"Bianca, Sebastiano","first_name":"Sebastiano","last_name":"Bianca"},{"first_name":"David","last_name":"Murphy","full_name":"Murphy, David"},{"full_name":"Moreira, Francisco Martins De Carvalho","last_name":"Moreira","first_name":"Francisco Martins De Carvalho"},{"full_name":"Accogli, Andrea","first_name":"Andrea","last_name":"Accogli"},{"full_name":"Petree, Cassidy","first_name":"Cassidy","last_name":"Petree"},{"full_name":"Huang, Kevin","orcid":"0000-0002-2512-7812","last_name":"Huang","first_name":"Kevin","id":"3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3"},{"full_name":"Monastiri, Kamel","last_name":"Monastiri","first_name":"Kamel"},{"full_name":"Edizadeh, Masoud","first_name":"Masoud","last_name":"Edizadeh"},{"last_name":"Nardello","first_name":"Rosaria","full_name":"Nardello, Rosaria"},{"full_name":"Ognibene, Marzia","first_name":"Marzia","last_name":"Ognibene"},{"last_name":"De Marco","first_name":"Patrizia","full_name":"De Marco, Patrizia"},{"last_name":"Ruggieri","first_name":"Martino","full_name":"Ruggieri, Martino"},{"first_name":"Federico","last_name":"Zara","full_name":"Zara, Federico"},{"full_name":"Striano, Pasquale","first_name":"Pasquale","last_name":"Striano"},{"full_name":"Sahin, Yavuz","last_name":"Sahin","first_name":"Yavuz"},{"full_name":"Al-Gazali, Lihadh","last_name":"Al-Gazali","first_name":"Lihadh"},{"first_name":"Marie Therese Abi","last_name":"Warde","full_name":"Warde, Marie Therese Abi"},{"last_name":"Gerard","first_name":"Benedicte","full_name":"Gerard, Benedicte"},{"full_name":"Zifarelli, Giovanni","last_name":"Zifarelli","first_name":"Giovanni"},{"full_name":"Beetz, Christian","first_name":"Christian","last_name":"Beetz"},{"first_name":"Sara","last_name":"Fortuna","full_name":"Fortuna, Sara"},{"full_name":"Soler, Miguel","first_name":"Miguel","last_name":"Soler"},{"last_name":"Valente","first_name":"Enza Maria","full_name":"Valente, Enza Maria"},{"last_name":"Varshney","first_name":"Gaurav","full_name":"Varshney, Gaurav"},{"last_name":"Maroofian","first_name":"Reza","full_name":"Maroofian, Reza"},{"full_name":"Salpietro, Vincenzo","last_name":"Salpietro","first_name":"Vincenzo"},{"full_name":"Houlden, Henry","first_name":"Henry","last_name":"Houlden"},{"first_name":"SYNaPS Study","last_name":"Grp","full_name":"Grp, SYNaPS Study"}],"issue":"10","_id":"14355","scopus_import":"1","title":"A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease","intvolume":"        24","publication_status":"published","article_processing_charge":"No","department":[{"_id":"GradSch"}],"date_created":"2023-09-20T20:57:18Z","file_date_updated":"2023-09-25T08:56:06Z","page":"2194-2203","quality_controlled":"1","article_type":"original","publisher":"Elsevier","date_published":"2022-10-01T00:00:00Z","type":"journal_article","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"oa":1,"publication_identifier":{"issn":["1098-3600"]},"status":"public","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","file":[{"date_updated":"2023-09-25T08:56:06Z","content_type":"application/pdf","file_name":"2022_GeneticsMedicine_Calin.pdf","date_created":"2023-09-25T08:56:06Z","checksum":"8117175a89129eb5022d81ffe7625f9f","file_size":1434037,"file_id":"14371","creator":"dernst","access_level":"open_access","success":1,"relation":"main_file"}],"publication":"Genetics in Medicine","has_accepted_license":"1","month":"10","oa_version":"Published Version","language":[{"iso":"eng"}],"keyword":["Human mediator complex","MED11","MEDopathies"]}]