Details

Autor(en) / Beteiligte

• Calì, Elisa
• Lin, Sheng-Jia
• El Chehadeh, Salima
• Chaabouni, Myriam
• Mankad, Kshitij
• Galanaki, Evangelia
• Sudhakar, Sniya
• Athanasiou-Fragkouli, Alkyoni
• Çelik, Tamer
• Narlı, Nejat
• Bianca, Sebastiano
• El Khorassani, Mohamed
• Groppa, Stanislav
• Karashova, Blagovesta Marinova
• Di Rosa, Gabriella
• Avdjieva, Daniela
• Kathom, Hadil
• Tincheva, Radka
• Veggiotti, Pierangelo
• Savasta, Salvatore
• Ruiz, Alfons Macaya
• Garavaglia, Barbara
• Borgione, Eugenia
• Papacostas, Savvas
• Compagnoni, Chiara
• Piccirilli, Alessandra
• Vikelis, Michail
• Chelban, Viorica
• Cortese, Andrea
• Sullivan, Roisin
• Papanicolaou, Eleni Zamba
• Dardiotis, Efthymios
• Ibrahim, Shahnaz
• Kirmani, Salman
• Atawneh, Osama
• Lim, Shen-Yang
• Shaikh, Farooq
• Scardamaglia, Annarita
• Mangano, Salvatore
• Scuderi, Carmela
• Morello, Giovanna
• Zollo, Massimo
• Heimer, Gali
• Alkuraya, Fowzan S.
• Guliyeva, Ulviyya
• Salayev, Kamran
• Fiorillo, Chiara
• Rissotto, Federico
• Gagliano, Antonella
• Chimenz, Roberto
• Gitto, Eloisa
• Cuppari, Caterina
• Magrinelli, Francesca
• Zagaroli, Luca
• Caloisi, Claudia
• Fabiano, Cecilia
• Bottone, Gabriella
• Di Fabio, Sandra
• Obeid, Makram
• Bakhtadze, Sophia
• Saadi, Nebal W.
• Zaki, Maha S.
• Kara, Majdi
• Specchio, Nicola
• Karimiani, Ehsan G.
• Salih, Ahmed M.
• David, Emanuele
• Curró, Riccardo
• Iezzi, Maria Laura
• Iapadre, Giulia
• Brancati, Francesco
• Di Falco, Giovanna
• Operto, Francesca F.
• Valenzise, Mariella
• Della Rocca, Ylenia
• Alesse, Edoardo
• Pironti, Erica
• Amore, Greta
• Ceravolo, Giorgia
• Zafar, Faisal
• Ullah, Ehsan
• Afzal, Erum
• Rahman, Fatima
• Parisi, Pasquale
• Genomics, Queen Square
• Andrea Accogli
• Petree, Cassidy
• Huang, Kevin
• Monastiri, Kamel
• Nardello, Rosaria
• Ognibene, Marzia
• Ruggieri, Martino
• Zara, Federico
• Abi Warde, Marie Therese
• Gerard, Benedicte
• Beetz, Christian
• Fortuna, Sara
• Soler, Miguel
• Varshney, Gaurav
• Salpietro, Vincenzo

Titel

A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease

Ist Teil von

• Genetics in medicine, 2022-10, Vol.24 (10), p.2194-2203

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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. 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. 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.