--- _id: '14368' 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." article_number: '100938' article_processing_charge: No article_type: original author: - first_name: Andrea full_name: Accogli, Andrea last_name: Accogli - first_name: Sheng-Jia full_name: Lin, Sheng-Jia last_name: Lin - first_name: Mariasavina full_name: Severino, Mariasavina last_name: Severino - first_name: Sung-Hoon full_name: Kim, Sung-Hoon last_name: Kim - first_name: Kevin full_name: Huang, Kevin id: 3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3 last_name: Huang orcid: 0000-0002-2512-7812 - first_name: Clarissa full_name: Rocca, Clarissa last_name: Rocca - first_name: Megan full_name: Landsverk, Megan last_name: Landsverk - first_name: Maha S. full_name: Zaki, Maha S. last_name: Zaki - first_name: Almundher full_name: Al-Maawali, Almundher last_name: Al-Maawali - first_name: Varunvenkat M. full_name: Srinivasan, Varunvenkat M. last_name: Srinivasan - first_name: Khalid full_name: Al-Thihli, Khalid last_name: Al-Thihli - first_name: G. Bradly full_name: Schaefer, G. Bradly last_name: Schaefer - first_name: Monica full_name: Davis, Monica last_name: Davis - first_name: Davide full_name: Tonduti, Davide last_name: Tonduti - first_name: Chiara full_name: Doneda, Chiara last_name: Doneda - first_name: Lara M. full_name: Marten, Lara M. last_name: Marten - first_name: Chris full_name: Mühlhausen, Chris last_name: Mühlhausen - first_name: Maria full_name: Gomez, Maria last_name: Gomez - first_name: Eleonora full_name: Lamantea, Eleonora last_name: Lamantea - first_name: Rafael full_name: Mena, Rafael last_name: Mena - first_name: Mathilde full_name: Nizon, Mathilde last_name: Nizon - first_name: Vincent full_name: Procaccio, Vincent last_name: Procaccio - first_name: Amber full_name: Begtrup, Amber last_name: Begtrup - first_name: Aida full_name: Telegrafi, Aida last_name: Telegrafi - first_name: Hong full_name: Cui, Hong last_name: Cui - first_name: Heidi L. full_name: Schulz, Heidi L. last_name: Schulz - first_name: Julia full_name: Mohr, Julia last_name: Mohr - first_name: Saskia full_name: Biskup, Saskia last_name: Biskup - first_name: Mariana Amina full_name: Loos, Mariana Amina last_name: Loos - first_name: Hilda Verónica full_name: Aráoz, Hilda Verónica last_name: Aráoz - first_name: Vincenzo full_name: Salpietro, Vincenzo last_name: Salpietro - first_name: Laura Davis full_name: Keppen, Laura Davis last_name: Keppen - first_name: Manali full_name: Chitre, Manali last_name: Chitre - first_name: Cassidy full_name: Petree, Cassidy last_name: Petree - first_name: Lucy full_name: Raymond, Lucy last_name: Raymond - first_name: Julie full_name: Vogt, Julie last_name: Vogt - first_name: Lindsey B. full_name: Sawyer, Lindsey B. last_name: Sawyer - first_name: Alice A. full_name: Basinger, Alice A. last_name: Basinger - first_name: Signe Vandal full_name: Pedersen, Signe Vandal last_name: Pedersen - first_name: Toni S. full_name: Pearson, Toni S. last_name: Pearson - first_name: Dorothy K. full_name: Grange, Dorothy K. last_name: Grange - first_name: Lokesh full_name: Lingappa, Lokesh last_name: Lingappa - first_name: Paige full_name: McDunnah, Paige last_name: McDunnah - first_name: Rita full_name: Horvath, Rita last_name: Horvath - first_name: Benjamin full_name: Cognè, Benjamin last_name: Cognè - first_name: Bertrand full_name: Isidor, Bertrand last_name: Isidor - first_name: Andreas full_name: Hahn, Andreas last_name: Hahn - first_name: Karen W. full_name: Gripp, Karen W. last_name: Gripp - first_name: Seyed Mehdi full_name: Jafarnejad, Seyed Mehdi last_name: Jafarnejad - first_name: Elsebet full_name: Østergaard, Elsebet last_name: Østergaard - first_name: Carlos E. full_name: Prada, Carlos E. last_name: Prada - first_name: Daniele full_name: Ghezzi, Daniele last_name: Ghezzi - first_name: Vykuntaraju K. full_name: Gowda, Vykuntaraju K. last_name: Gowda - first_name: Robert W. full_name: Taylor, Robert W. last_name: Taylor - first_name: Nahum full_name: Sonenberg, Nahum last_name: Sonenberg - first_name: Henry full_name: Houlden, Henry last_name: Houlden - first_name: Marie full_name: Sissler, Marie last_name: Sissler - first_name: Gaurav K. full_name: Varshney, Gaurav K. last_name: Varshney - first_name: Reza full_name: Maroofian, Reza last_name: Maroofian citation: ama: Accogli A, Lin S-J, Severino M, et al. Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder. Genetics in Medicine. 2023;25(11). doi:10.1016/j.gim.2023.100938 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. Genetics in Medicine. Elsevier. https://doi.org/10.1016/j.gim.2023.100938 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.” Genetics in Medicine. Elsevier, 2023. https://doi.org/10.1016/j.gim.2023.100938. ieee: A. Accogli et al., “Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder,” Genetics in Medicine, vol. 25, no. 11. Elsevier, 2023. 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.” Genetics in Medicine, vol. 25, no. 11, 100938, Elsevier, 2023, doi:10.1016/j.gim.2023.100938. 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). date_created: 2023-09-25T08:44:29Z date_published: 2023-11-01T00:00:00Z date_updated: 2023-09-25T08:50:10Z day: '01' ddc: - '570' doi: 10.1016/j.gim.2023.100938 extern: '1' file: - access_level: open_access checksum: 440f0cd8a2ffcbe03c015c1746728387 content_type: application/pdf creator: dernst date_created: 2023-09-25T08:48:54Z date_updated: 2023-09-25T08:48:54Z file_id: '14369' file_name: 2023_GeneticsMedicine_Accogli.pdf file_size: 4105513 relation: main_file success: 1 file_date_updated: 2023-09-25T08:48:54Z has_accepted_license: '1' intvolume: ' 25' issue: '11' keyword: - Genetics (clinical) language: - iso: eng month: '11' oa: 1 oa_version: Published Version publication: Genetics in Medicine publication_identifier: issn: - 1098-3600 publication_status: published publisher: Elsevier quality_controlled: '1' scopus_import: '1' status: public title: Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 25 year: '2023' ... --- _id: '14355' 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.' article_processing_charge: No article_type: original author: - first_name: Elisa full_name: Cali, Elisa last_name: Cali - first_name: Sheng-Jia full_name: Lin, Sheng-Jia last_name: Lin - first_name: Clarissa full_name: Rocca, Clarissa last_name: Rocca - first_name: Yavuz full_name: Sahin, Yavuz last_name: Sahin - first_name: Aisha full_name: Al Shamsi, Aisha last_name: Al Shamsi - first_name: Salima full_name: El Chehadeh, Salima last_name: El Chehadeh - first_name: Myriam full_name: Chaabouni, Myriam last_name: Chaabouni - first_name: Kshitij full_name: Mankad, Kshitij last_name: Mankad - first_name: Evangelia full_name: Galanaki, Evangelia last_name: Galanaki - first_name: Stephanie full_name: Efthymiou, Stephanie last_name: Efthymiou - first_name: Sniya full_name: Sudhakar, Sniya last_name: Sudhakar - first_name: Alkyoni full_name: Athanasiou-Fragkouli, Alkyoni last_name: Athanasiou-Fragkouli - first_name: Tamer full_name: Celik, Tamer last_name: Celik - first_name: Nejat full_name: Narli, Nejat last_name: Narli - first_name: Sebastiano full_name: Bianca, Sebastiano last_name: Bianca - first_name: David full_name: Murphy, David last_name: Murphy - first_name: Francisco Martins De Carvalho full_name: Moreira, Francisco Martins De Carvalho last_name: Moreira - first_name: Andrea full_name: Accogli, Andrea last_name: Accogli - first_name: Cassidy full_name: Petree, Cassidy last_name: Petree - first_name: Kevin full_name: Huang, Kevin id: 3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3 last_name: Huang orcid: 0000-0002-2512-7812 - first_name: Kamel full_name: Monastiri, Kamel last_name: Monastiri - first_name: Masoud full_name: Edizadeh, Masoud last_name: Edizadeh - first_name: Rosaria full_name: Nardello, Rosaria last_name: Nardello - first_name: Marzia full_name: Ognibene, Marzia last_name: Ognibene - first_name: Patrizia full_name: De Marco, Patrizia last_name: De Marco - first_name: Martino full_name: Ruggieri, Martino last_name: Ruggieri - first_name: Federico full_name: Zara, Federico last_name: Zara - first_name: Pasquale full_name: Striano, Pasquale last_name: Striano - first_name: Yavuz full_name: Sahin, Yavuz last_name: Sahin - first_name: Lihadh full_name: Al-Gazali, Lihadh last_name: Al-Gazali - first_name: Marie Therese Abi full_name: Warde, Marie Therese Abi last_name: Warde - first_name: Benedicte full_name: Gerard, Benedicte last_name: Gerard - first_name: Giovanni full_name: Zifarelli, Giovanni last_name: Zifarelli - first_name: Christian full_name: Beetz, Christian last_name: Beetz - first_name: Sara full_name: Fortuna, Sara last_name: Fortuna - first_name: Miguel full_name: Soler, Miguel last_name: Soler - first_name: Enza Maria full_name: Valente, Enza Maria last_name: Valente - first_name: Gaurav full_name: Varshney, Gaurav last_name: Varshney - first_name: Reza full_name: Maroofian, Reza last_name: Maroofian - first_name: Vincenzo full_name: Salpietro, Vincenzo last_name: Salpietro - first_name: Henry full_name: Houlden, Henry last_name: Houlden - first_name: SYNaPS Study full_name: Grp, SYNaPS Study last_name: Grp citation: ama: Cali E, Lin S-J, Rocca C, et al. A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease. Genetics in Medicine. 2022;24(10):2194-2203. doi:10.1016/j.gim.2022.07.013 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. Genetics in Medicine. Elsevier. https://doi.org/10.1016/j.gim.2022.07.013 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.” Genetics in Medicine. Elsevier, 2022. https://doi.org/10.1016/j.gim.2022.07.013. ieee: E. Cali et al., “A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease,” Genetics in Medicine, vol. 24, no. 10. Elsevier, pp. 2194–2203, 2022. 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.” Genetics in Medicine, vol. 24, no. 10, Elsevier, 2022, pp. 2194–203, doi:10.1016/j.gim.2022.07.013. 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. date_created: 2023-09-20T20:57:18Z date_published: 2022-10-01T00:00:00Z date_updated: 2023-09-25T08:57:07Z day: '01' ddc: - '570' department: - _id: GradSch doi: 10.1016/j.gim.2022.07.013 extern: '1' file: - access_level: open_access checksum: 8117175a89129eb5022d81ffe7625f9f content_type: application/pdf creator: dernst date_created: 2023-09-25T08:56:06Z date_updated: 2023-09-25T08:56:06Z file_id: '14371' file_name: 2022_GeneticsMedicine_Calin.pdf file_size: 1434037 relation: main_file success: 1 file_date_updated: 2023-09-25T08:56:06Z has_accepted_license: '1' intvolume: ' 24' issue: '10' keyword: - Human mediator complex - MED11 - MEDopathies language: - iso: eng month: '10' oa: 1 oa_version: Published Version page: 2194-2203 publication: Genetics in Medicine publication_identifier: issn: - 1098-3600 publication_status: published publisher: Elsevier quality_controlled: '1' scopus_import: '1' status: public title: A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 24 year: '2022' ...