{"oa_version":"Published Version","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."}],"volume":24,"license":"https://creativecommons.org/licenses/by/4.0/","extern":"1","ddc":["570"],"page":"2194-2203","language":[{"iso":"eng"}],"department":[{"_id":"GradSch"}],"keyword":["Human mediator complex","MED11","MEDopathies"],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","file":[{"file_name":"2022_GeneticsMedicine_Calin.pdf","success":1,"checksum":"8117175a89129eb5022d81ffe7625f9f","file_size":1434037,"content_type":"application/pdf","creator":"dernst","file_id":"14371","date_updated":"2023-09-25T08:56:06Z","date_created":"2023-09-25T08:56:06Z","access_level":"open_access","relation":"main_file"}],"year":"2022","quality_controlled":"1","article_type":"original","status":"public","month":"10","oa":1,"article_processing_charge":"No","intvolume":"        24","scopus_import":"1","publisher":"Elsevier","title":"A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease","date_published":"2022-10-01T00:00:00Z","type":"journal_article","has_accepted_license":"1","date_updated":"2023-09-25T08:57:07Z","file_date_updated":"2023-09-25T08:56:06Z","day":"01","doi":"10.1016/j.gim.2022.07.013","issue":"10","tmp":{"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)","image":"/images/cc_by.png"},"date_created":"2023-09-20T20:57:18Z","author":[{"first_name":"Elisa","full_name":"Cali, Elisa","last_name":"Cali"},{"first_name":"Sheng-Jia","last_name":"Lin","full_name":"Lin, Sheng-Jia"},{"first_name":"Clarissa","full_name":"Rocca, Clarissa","last_name":"Rocca"},{"last_name":"Sahin","full_name":"Sahin, Yavuz","first_name":"Yavuz"},{"first_name":"Aisha","last_name":"Al Shamsi","full_name":"Al Shamsi, Aisha"},{"last_name":"El Chehadeh","full_name":"El Chehadeh, Salima","first_name":"Salima"},{"last_name":"Chaabouni","full_name":"Chaabouni, Myriam","first_name":"Myriam"},{"last_name":"Mankad","full_name":"Mankad, Kshitij","first_name":"Kshitij"},{"last_name":"Galanaki","full_name":"Galanaki, Evangelia","first_name":"Evangelia"},{"full_name":"Efthymiou, Stephanie","last_name":"Efthymiou","first_name":"Stephanie"},{"last_name":"Sudhakar","full_name":"Sudhakar, Sniya","first_name":"Sniya"},{"last_name":"Athanasiou-Fragkouli","full_name":"Athanasiou-Fragkouli, Alkyoni","first_name":"Alkyoni"},{"first_name":"Tamer","last_name":"Celik","full_name":"Celik, Tamer"},{"last_name":"Narli","full_name":"Narli, Nejat","first_name":"Nejat"},{"full_name":"Bianca, Sebastiano","last_name":"Bianca","first_name":"Sebastiano"},{"first_name":"David","last_name":"Murphy","full_name":"Murphy, David"},{"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"},{"full_name":"Petree, Cassidy","last_name":"Petree","first_name":"Cassidy"},{"orcid":"0000-0002-2512-7812","full_name":"Huang, Kevin","last_name":"Huang","first_name":"Kevin","id":"3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3"},{"first_name":"Kamel","full_name":"Monastiri, Kamel","last_name":"Monastiri"},{"first_name":"Masoud","last_name":"Edizadeh","full_name":"Edizadeh, Masoud"},{"last_name":"Nardello","full_name":"Nardello, Rosaria","first_name":"Rosaria"},{"full_name":"Ognibene, Marzia","last_name":"Ognibene","first_name":"Marzia"},{"full_name":"De Marco, Patrizia","last_name":"De Marco","first_name":"Patrizia"},{"full_name":"Ruggieri, Martino","last_name":"Ruggieri","first_name":"Martino"},{"first_name":"Federico","full_name":"Zara, Federico","last_name":"Zara"},{"first_name":"Pasquale","last_name":"Striano","full_name":"Striano, Pasquale"},{"last_name":"Sahin","full_name":"Sahin, Yavuz","first_name":"Yavuz"},{"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"},{"last_name":"Gerard","full_name":"Gerard, Benedicte","first_name":"Benedicte"},{"first_name":"Giovanni","full_name":"Zifarelli, Giovanni","last_name":"Zifarelli"},{"first_name":"Christian","last_name":"Beetz","full_name":"Beetz, Christian"},{"first_name":"Sara","last_name":"Fortuna","full_name":"Fortuna, Sara"},{"full_name":"Soler, Miguel","last_name":"Soler","first_name":"Miguel"},{"first_name":"Enza Maria","full_name":"Valente, Enza Maria","last_name":"Valente"},{"first_name":"Gaurav","last_name":"Varshney","full_name":"Varshney, Gaurav"},{"first_name":"Reza","full_name":"Maroofian, Reza","last_name":"Maroofian"},{"first_name":"Vincenzo","last_name":"Salpietro","full_name":"Salpietro, Vincenzo"},{"full_name":"Houlden, Henry","last_name":"Houlden","first_name":"Henry"},{"first_name":"SYNaPS Study","full_name":"Grp, SYNaPS Study","last_name":"Grp"}],"publication_identifier":{"issn":["1098-3600"]},"citation":{"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.","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.","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>","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>.","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.","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>"},"publication_status":"published","_id":"14355","publication":"Genetics in Medicine"}