A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
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Calì Elisa, Lin Sheng-Jia, Rocca Clarissa, Sahin Yavuz, Al Shamsi Aisha, El Chehadeh Salima, Chaabouni Myriam, Mankad Kshitij, Galanaki Evangelia, Efthymiou Stephanie, Sudhakar Sniya, Athanasiou-Fragkouli Alkyoni, Çelik Tamer, Narlı Nejat, Bianca Sebastiano, Murphy David, De Carvalho Moreira Francisco Martins, SYNaPS Study Group, Andrea Accogli, Petree Cassidy, Huang Kevin, Monastiri Kamel, Edizadeh Masoud, Nardello Rosaria, Ognibene Marzia, De Marco Patrizia, Ruggieri Martino, Zara Federico, Striano Pasquale, Şahin Yavuz, Al-Gazali Lihadh, Abi Warde Marie Therese, Gerard Benedicte, Zifarelli Giovanni, Beetz Christian, Fortuna Sara, Soler Miguel, Valente Enza Maria, Varshney Gaurav, Maroofian Reza, Salpietro Vincenzo, Houlden Henry
Аннотация
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.