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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease
Genetics in Medicine, Volume 24, No. 10, Year 2022
Notification
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Description
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. © 2022 The Authors
Authors & Co-Authors
Calì, Elisa
United Kingdom, London
Ucl Queen Square Institute of Neurology
Lin, Sheng Jia
United States, Oklahoma City
Oklahoma Medical Research Foundation
Rocca, Clarissa
United Kingdom, London
Ucl Queen Square Institute of Neurology
Şahin, Yavuz
Turkey, Ankara
Genoks Genetic Laboratory
Turkey, Istanbul
Biruni Üniversitesi
Al-Shamsi, Aisha Mohamed
United Arab Emirates, Al Ain
Tawam Hospital
El-Chehadeh, Salima
Unknown Affiliation
Chaabouni, Myriam
Tunisia, Tunis
Jasmins Medical Center
Mankad, Kshitij
United Kingdom, London
Great Ormond Street Hospital for Children Nhs Foundation Trust
Galanaki, Evangelia
United Kingdom, London
Ucl Queen Square Institute of Neurology
Efthymiou, Stephanie
United Kingdom, London
Ucl Queen Square Institute of Neurology
Sudhakar, Sniya Valsa
United Kingdom, London
Great Ormond Street Hospital for Children Nhs Foundation Trust
Athanasiou-Fragkouli, Alkyoni
United Kingdom, London
Ucl Queen Square Institute of Neurology
Çelik, Tamer
Turkey, Adana
Private Practice
Narli, Nejat
Turkey, Adana
Çukurova Üniversitesi
Bianca, Sebastiano
Italy, Catania
Arnas Garibaldi
Murphy, David P.
Italy, Palermo
Università Degli Studi Di Palermo
de Carvalho Moreira, Francisco Martins
United Kingdom, London
Ucl Queen Square Institute of Neurology
Hannah, Michael G.
Unknown Affiliation
Bugiardini, Enrico
Unknown Affiliation
Kriouile, Y.
Unknown Affiliation
El-Khorassani, Mohammed
Unknown Affiliation
Aguennouz, M’Hammed H.
Unknown Affiliation
Groppa, Stanislav A.
Unknown Affiliation
Karashova, Blagovesta Marinova
Unknown Affiliation
Di Rosa, Gabriella
Unknown Affiliation
Goraya, Jatinder Singh
Unknown Affiliation
Sultan, Tipu
Unknown Affiliation
Avdjieva - Tzavella, Daniela Mircheva
Unknown Affiliation
Kathom, Hadil Mohamed
Unknown Affiliation
Tincheva, Radka Stefanova
Unknown Affiliation
Banu, Selina H.
Unknown Affiliation
Veggiotti, Pierangelo
Unknown Affiliation
Verrottï, Alberto
Unknown Affiliation
Savasta, Salvatore M.
Unknown Affiliation
Ruiz, Alfons Macaya
Unknown Affiliation
Garavaglia, Barbara M.
Unknown Affiliation
Borgione, Eugenia
Unknown Affiliation
Papacostas, Savvas S.
Unknown Affiliation
Compagnoni, Chiara
Unknown Affiliation
Piccirilli, Alessandra
Unknown Affiliation
Vikelis, Michail
Unknown Affiliation
Chelban, Viorica
Unknown Affiliation
Kaiyrzhanov, Rauan
Unknown Affiliation
Cortese, A.
Unknown Affiliation
Sullivan, Roisin
Unknown Affiliation
Papanicolaou, Eleni Zamba
Unknown Affiliation
Dardiotis, Efthymios
Unknown Affiliation
Maqbool, Shazia
Unknown Affiliation
Ibrahim, Shahnaz Hamid
Unknown Affiliation
Kirmani, Salman
Unknown Affiliation
Rana, Nuzhat Noureen
Unknown Affiliation
Atawneh, Osama M.
Unknown Affiliation
Lim, Shenyang
Unknown Affiliation
Shaikh, Farooq
Unknown Affiliation
Scardamaglia, Annarita
Unknown Affiliation
Koutsis, Georgios
Unknown Affiliation
Mangano, Salvatore
Unknown Affiliation
Scuderi, Carmela
Unknown Affiliation
Morello, Giovanna
Unknown Affiliation
ZOLLO, M.
Unknown Affiliation
Heimer, Gali
Unknown Affiliation
Striano, Pasquale
Italy, Genoa
Università Degli Studi Di Genova
Italy, Genoa
Istituto Giannina Gaslini
Al-Khawaja, Issam
Unknown Affiliation
Al-Mutairi, Fuad
Unknown Affiliation
Alkuraya., Fowzan S.
Unknown Affiliation
Rizig, Mie A.
Unknown Affiliation
Shashkin, Chingiz
Unknown Affiliation
Zharkinbekova, N. A.
Unknown Affiliation
Koneyev, Kairgali
Unknown Affiliation
Manizha, Ganieva
Unknown Affiliation
Isrofilov, Maksud
Unknown Affiliation
Guliyeva, Ulviyya
Unknown Affiliation
Salayev, Kamran A.
Unknown Affiliation
Khachatryan, Samson G.
Unknown Affiliation
Xiromerisiou, Georgia
Unknown Affiliation
Spanaki, Cleanthe
Unknown Affiliation
Tucci, Arianna
Unknown Affiliation
Fiorillo, Chiara
Unknown Affiliation
Rissotto, Federico
Unknown Affiliation
Munell, Francina
Unknown Affiliation
Gagliano, Antonella
Unknown Affiliation
Jan, Farida
Unknown Affiliation
Chimenz, Roberto R.
Unknown Affiliation
Gitto, E.
Unknown Affiliation
Cuppari, Caterina
Unknown Affiliation
Romeo, Carmelo
Unknown Affiliation
Magrinelli, Francesca
Unknown Affiliation
Gupta, Neerja
Unknown Affiliation
Kabra, Madhulika
Unknown Affiliation
Benrhouma, Hanène
Unknown Affiliation
Tazir, Mériem
Unknown Affiliation
Zagaroli, Luca
Unknown Affiliation
Caloisi, Claudia
Unknown Affiliation
Fabiano, Cecilia
Unknown Affiliation
Bottone, Gabriella
Unknown Affiliation
Farello, Giovanni
Unknown Affiliation
Di Fabio, Sandra
Unknown Affiliation
Obeid, Makram
Unknown Affiliation
Bakhtadze, Sophia Z.
Unknown Affiliation
Saadi, Nebal Waill
Unknown Affiliation
Zaki, Maha S.
Unknown Affiliation
Triki, Chahnez Charfi
Unknown Affiliation
Kara, Majdi
Unknown Affiliation
Specchio, Nicola
Unknown Affiliation
Karimiani, Ehsan Ghayoor
Unknown Affiliation
David, Emanuele
Unknown Affiliation
Brancati, Francesco
Unknown Affiliation
Barrano, Giuseppe
Unknown Affiliation
Elia, Maurizio
Unknown Affiliation
Terrone, Gaetano
Unknown Affiliation
Manti, Filippo
Unknown Affiliation
Galosi, Serena
Unknown Affiliation
Leuzzi, Vincenzo
Unknown Affiliation
Pironti, Erica
Unknown Affiliation
Zafar, Faisal
Unknown Affiliation
Rahman, Fatima
Unknown Affiliation
Parisi, Pasquale
Unknown Affiliation
Mangano, Giuseppe Donato
Unknown Affiliation
Chiarelli, Francesco G.
Unknown Affiliation
Genomics, Queen Square
Unknown Affiliation
Petree, Cassidy
United States, Oklahoma City
Oklahoma Medical Research Foundation
Huang, Kevin
United States, Oklahoma City
Oklahoma Medical Research Foundation
Monastiri, Kamel
Tunisia, Monastir
Chu Fattouma-bourguiba
De-Marco, Patrizia
Italy, Genoa
Istituto Giannina Gaslini
Ruggieri, Martino
Italy, Catania
Università Degli Studi Di Catania
Zara, Federico
Italy, Genoa
Istituto Giannina Gaslini
Italy, Genoa
Università Degli Studi Di Genova
Al-Gazali, Lihadh I.
United Arab Emirates, Al Ain
United Arab Emirates University
Abi-Wardé, Marie Thérèse
France, Strasbourg
Les Hôpitaux Universitaires de Strasbourg
Gérard, Bénédicte
France, Strasbourg
Hopital Civil
Zifarelli, Giovanni
Germany, Rostock
Centogene ag
Beetz, Christian
Germany, Rostock
Centogene ag
Fortuna, Sara
Italy, Trieste
Università Degli Studi Di Trieste
Valente, Enza Maria
Italy, Pavia
Università Degli Studi Di Pavia
Italy, Pavia
Irccs Fondazione Mondino
Varshney, Gaurav Kumar
United States, Oklahoma City
Oklahoma Medical Research Foundation
Maroofian, Reza
United Kingdom, London
Ucl Queen Square Institute of Neurology
Salpietro, Vincenzo Damiano
United Kingdom, London
Ucl Queen Square Institute of Neurology
Italy, L'aquila
Università Degli Studi Dell'aquila
Houlden, Henry H.
United Kingdom, London
Ucl Queen Square Institute of Neurology
Statistics
Citations: 1
Authors: 137
Affiliations: 26
Identifiers
Doi:
10.1016/j.gim.2022.07.013
ISSN:
10983600
Research Areas
Genetics And Genomics
Health System And Policy
Maternal And Child Health