---
_id: '14355'
abstract:
- lang: eng
text: '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.'
article_processing_charge: No
article_type: original
author:
- first_name: Elisa
full_name: Cali, Elisa
last_name: Cali
- first_name: Sheng-Jia
full_name: Lin, Sheng-Jia
last_name: Lin
- first_name: Clarissa
full_name: Rocca, Clarissa
last_name: Rocca
- first_name: Yavuz
full_name: Sahin, Yavuz
last_name: Sahin
- first_name: Aisha
full_name: Al Shamsi, Aisha
last_name: Al Shamsi
- first_name: Salima
full_name: El Chehadeh, Salima
last_name: El Chehadeh
- first_name: Myriam
full_name: Chaabouni, Myriam
last_name: Chaabouni
- first_name: Kshitij
full_name: Mankad, Kshitij
last_name: Mankad
- first_name: Evangelia
full_name: Galanaki, Evangelia
last_name: Galanaki
- first_name: Stephanie
full_name: Efthymiou, Stephanie
last_name: Efthymiou
- first_name: Sniya
full_name: Sudhakar, Sniya
last_name: Sudhakar
- first_name: Alkyoni
full_name: Athanasiou-Fragkouli, Alkyoni
last_name: Athanasiou-Fragkouli
- first_name: Tamer
full_name: Celik, Tamer
last_name: Celik
- first_name: Nejat
full_name: Narli, Nejat
last_name: Narli
- first_name: Sebastiano
full_name: Bianca, Sebastiano
last_name: Bianca
- first_name: David
full_name: Murphy, David
last_name: Murphy
- first_name: Francisco Martins De Carvalho
full_name: Moreira, Francisco Martins De Carvalho
last_name: Moreira
- first_name: Andrea
full_name: Accogli, Andrea
last_name: Accogli
- first_name: Cassidy
full_name: Petree, Cassidy
last_name: Petree
- first_name: Kevin
full_name: Huang, Kevin
id: 3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3
last_name: Huang
orcid: 0000-0002-2512-7812
- first_name: Kamel
full_name: Monastiri, Kamel
last_name: Monastiri
- first_name: Masoud
full_name: Edizadeh, Masoud
last_name: Edizadeh
- first_name: Rosaria
full_name: Nardello, Rosaria
last_name: Nardello
- first_name: Marzia
full_name: Ognibene, Marzia
last_name: Ognibene
- first_name: Patrizia
full_name: De Marco, Patrizia
last_name: De Marco
- first_name: Martino
full_name: Ruggieri, Martino
last_name: Ruggieri
- first_name: Federico
full_name: Zara, Federico
last_name: Zara
- first_name: Pasquale
full_name: Striano, Pasquale
last_name: Striano
- first_name: Yavuz
full_name: Sahin, Yavuz
last_name: Sahin
- first_name: Lihadh
full_name: Al-Gazali, Lihadh
last_name: Al-Gazali
- first_name: Marie Therese Abi
full_name: Warde, Marie Therese Abi
last_name: Warde
- first_name: Benedicte
full_name: Gerard, Benedicte
last_name: Gerard
- first_name: Giovanni
full_name: Zifarelli, Giovanni
last_name: Zifarelli
- first_name: Christian
full_name: Beetz, Christian
last_name: Beetz
- first_name: Sara
full_name: Fortuna, Sara
last_name: Fortuna
- first_name: Miguel
full_name: Soler, Miguel
last_name: Soler
- first_name: Enza Maria
full_name: Valente, Enza Maria
last_name: Valente
- first_name: Gaurav
full_name: Varshney, Gaurav
last_name: Varshney
- first_name: Reza
full_name: Maroofian, Reza
last_name: Maroofian
- first_name: Vincenzo
full_name: Salpietro, Vincenzo
last_name: Salpietro
- first_name: Henry
full_name: Houlden, Henry
last_name: Houlden
- first_name: SYNaPS Study
full_name: Grp, SYNaPS Study
last_name: Grp
citation:
ama: Cali E, Lin S-J, Rocca C, et al. A homozygous MED11 C-terminal variant causes
a lethal neurodegenerative disease. Genetics in Medicine. 2022;24(10):2194-2203.
doi:10.1016/j.gim.2022.07.013
apa: Cali, E., Lin, S.-J., Rocca, C., Sahin, Y., Al Shamsi, A., El Chehadeh, S.,
… Grp, Syn. S. (2022). A homozygous MED11 C-terminal variant causes a lethal neurodegenerative
disease. Genetics in Medicine. Elsevier. https://doi.org/10.1016/j.gim.2022.07.013
chicago: Cali, Elisa, Sheng-Jia Lin, Clarissa Rocca, Yavuz Sahin, Aisha Al Shamsi,
Salima El Chehadeh, Myriam Chaabouni, et al. “A Homozygous MED11 C-Terminal Variant
Causes a Lethal Neurodegenerative Disease.” Genetics in Medicine. Elsevier,
2022. https://doi.org/10.1016/j.gim.2022.07.013.
ieee: E. Cali et al., “A homozygous MED11 C-terminal variant causes a lethal
neurodegenerative disease,” Genetics in Medicine, vol. 24, no. 10. Elsevier,
pp. 2194–2203, 2022.
ista: Cali 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, Celik T,
Narli N, Bianca S, Murphy D, Moreira FMDC, Accogli A, Petree C, Huang K, Monastiri
K, Edizadeh M, Nardello R, Ognibene M, De Marco P, Ruggieri M, Zara F, Striano
P, Sahin Y, Al-Gazali L, Warde MTA, Gerard B, Zifarelli G, Beetz C, Fortuna S,
Soler M, Valente EM, Varshney G, Maroofian R, Salpietro V, Houlden H, Grp SynS.
2022. A homozygous MED11 C-terminal variant causes a lethal neurodegenerative
disease. Genetics in Medicine. 24(10), 2194–2203.
mla: Cali, Elisa, et al. “A Homozygous MED11 C-Terminal Variant Causes a Lethal
Neurodegenerative Disease.” Genetics in Medicine, vol. 24, no. 10, Elsevier,
2022, pp. 2194–203, doi:10.1016/j.gim.2022.07.013.
short: E. Cali, S.-J. Lin, C. Rocca, Y. Sahin, A. Al Shamsi, S. El Chehadeh, M.
Chaabouni, K. Mankad, E. Galanaki, S. Efthymiou, S. Sudhakar, A. Athanasiou-Fragkouli,
T. Celik, N. Narli, S. Bianca, D. Murphy, F.M.D.C. Moreira, A. Accogli, C. Petree,
K. Huang, K. Monastiri, M. Edizadeh, R. Nardello, M. Ognibene, P. De Marco, M.
Ruggieri, F. Zara, P. Striano, Y. Sahin, L. Al-Gazali, M.T.A. Warde, B. Gerard,
G. Zifarelli, C. Beetz, S. Fortuna, M. Soler, E.M. Valente, G. Varshney, R. Maroofian,
V. Salpietro, H. Houlden, Syn.S. Grp, Genetics in Medicine 24 (2022) 2194–2203.
date_created: 2023-09-20T20:57:18Z
date_published: 2022-10-01T00:00:00Z
date_updated: 2023-09-25T08:57:07Z
day: '01'
ddc:
- '570'
department:
- _id: GradSch
doi: 10.1016/j.gim.2022.07.013
extern: '1'
file:
- access_level: open_access
checksum: 8117175a89129eb5022d81ffe7625f9f
content_type: application/pdf
creator: dernst
date_created: 2023-09-25T08:56:06Z
date_updated: 2023-09-25T08:56:06Z
file_id: '14371'
file_name: 2022_GeneticsMedicine_Calin.pdf
file_size: 1434037
relation: main_file
success: 1
file_date_updated: 2023-09-25T08:56:06Z
has_accepted_license: '1'
intvolume: ' 24'
issue: '10'
keyword:
- Human mediator complex
- MED11
- MEDopathies
language:
- iso: eng
month: '10'
oa: 1
oa_version: Published Version
page: 2194-2203
publication: Genetics in Medicine
publication_identifier:
issn:
- 1098-3600
publication_status: published
publisher: Elsevier
quality_controlled: '1'
scopus_import: '1'
status: public
title: A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 24
year: '2022'
...