PUBLICATION
A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease
- Authors
- Calì, E., Lin, S.J., Rocca, C., Sahin, Y., Al Shamsi, A., El Chehadeh, S., Chaabouni, M., Mankad, K., Galanaki, E., Efthymiou, S., Sudhakar, S., Athanasiou-Fragkouli, A., Çelik, T., Narlı, N., Bianca, S., Murphy, D., De Carvalho Moreira, F.M., SYNaPS Study Group, Andrea Accogli, ., Petree, C., Huang, K., Monastiri, K., Edizadeh, M., Nardello, R., Ognibene, M., De Marco, P., Ruggieri, M., Zara, F., Striano, P., Şahin, Y., Al-Gazali, L., Abi Warde, M.T., Gerard, B., Zifarelli, G., Beetz, C., Fortuna, S., Soler, M., Valente, E.M., Varshney, G., Maroofian, R., Salpietro, V., Houlden, H.
- ID
- ZDB-PUB-220825-2
- Date
- 2022
- Source
- Genetics in medicine : official journal of the American College of Medical Genetics 24(10): 2194-2203 (Journal)
- Registered Authors
- Lin, Sheng-Jia, Varshney, Gaurav
- Keywords
- Human mediator complex, MED11, MEDopathies
- MeSH Terms
-
- Animals
- Homozygote
- Humans
- Mediator Complex*/genetics
- Microcephaly*/genetics
- Neurodegenerative Diseases*/genetics
- RNA
- Zebrafish/genetics
- PubMed
- 36001086 Full text @ Genet. Med.
Citation
Calì, E., Lin, S.J., Rocca, C., Sahin, Y., Al Shamsi, A., El Chehadeh, S., Chaabouni, M., Mankad, K., Galanaki, E., Efthymiou, S., Sudhakar, S., Athanasiou-Fragkouli, A., Çelik, T., Narlı, N., Bianca, S., Murphy, D., De Carvalho Moreira, F.M., SYNaPS Study Group, Andrea Accogli, ., Petree, C., Huang, K., Monastiri, K., Edizadeh, M., Nardello, R., Ognibene, M., De Marco, P., Ruggieri, M., Zara, F., Striano, P., Şahin, Y., Al-Gazali, L., Abi Warde, M.T., Gerard, B., Zifarelli, G., Beetz, C., Fortuna, S., Soler, M., Valente, E.M., Varshney, G., Maroofian, R., Salpietro, V., Houlden, H. (2022) A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease. Genetics in medicine : official journal of the American College of Medical Genetics. 24(10):2194-2203.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping