@article{14355,
  abstract     = {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.},
  author       = {Cali, Elisa and Lin, Sheng-Jia and Rocca, Clarissa and Sahin, Yavuz and Al Shamsi, Aisha and El Chehadeh, Salima and Chaabouni, Myriam and Mankad, Kshitij and Galanaki, Evangelia and Efthymiou, Stephanie and Sudhakar, Sniya and Athanasiou-Fragkouli, Alkyoni and Celik, Tamer and Narli, Nejat and Bianca, Sebastiano and Murphy, David and Moreira, Francisco Martins De Carvalho and Accogli, Andrea and Petree, Cassidy and Huang, Kevin and Monastiri, Kamel and Edizadeh, Masoud and Nardello, Rosaria and Ognibene, Marzia and De Marco, Patrizia and Ruggieri, Martino and Zara, Federico and Striano, Pasquale and Sahin, Yavuz and Al-Gazali, Lihadh and Warde, Marie Therese Abi and Gerard, Benedicte and Zifarelli, Giovanni and Beetz, Christian and Fortuna, Sara and Soler, Miguel and Valente, Enza Maria and Varshney, Gaurav and Maroofian, Reza and Salpietro, Vincenzo and Houlden, Henry and Grp, SYNaPS Study},
  issn         = {1098-3600},
  journal      = {Genetics in Medicine},
  keywords     = {Human mediator complex, MED11, MEDopathies},
  number       = {10},
  pages        = {2194--2203},
  publisher    = {Elsevier},
  title        = {{A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease}},
  doi          = {10.1016/j.gim.2022.07.013},
  volume       = {24},
  year         = {2022},
}