A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease
Microcephaly
Loss function
DOI:
10.1016/j.gim.2022.07.013
Publication Date:
2022-08-24T05:19:57Z
AUTHORS (169)
ABSTRACT
The mediator (MED) multisubunit-complex modulates the activity of transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated neurologic diseases. In this study, we identified a recurrent homozygous variant MED11 (c.325C>T; p.Arg109Ter) 7 affected individuals from 5 unrelated families.To investigate cause disease, exome or genome sequencing were performed families via research networks Matchmaker Exchange. Deep clinical brain imaging evaluations by pediatric neurologists neuroradiologists. functional effect candidate on both RNA protein was assessed using reverse transcriptase polymerase chain reaction western blotting fibroblast cell lines derived 1 individual controls through computational approaches. Knockouts zebrafish generated clustered regularly interspaced short palindromic repeats/Cas9.The disease characterized microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, premature death. Functional studies patient-derived fibroblasts did not show loss function but rather disruption C-terminal MED11, likely impairing binding to other subunits. A knockout model recapitulates key phenotypes.Loss subunit 11 may affect its efficiency subunits, thus implicating MED-complex stability development neurodegeneration.
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