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dc.contributor.author
Nahorski, Michael S.
dc.contributor.author
Maddirevula, Sateesh
dc.contributor.author
Ishimura, Ryosuke
dc.contributor.author
Alsahli, Saud
dc.contributor.author
Brady, Angela F.
dc.contributor.author
Begemann, Anaïs
dc.contributor.author
Mizushima, Tsunehiro
dc.contributor.author
Guzman-Vega, Francisco J.
dc.contributor.author
Obata, Miki
dc.contributor.author
Ichimura, Yoshinobu
dc.contributor.author
Alsaif, Hessa S.
dc.contributor.author
Anazi, Shams
dc.contributor.author
Ibrahim, Niema
dc.contributor.author
Abdulwahab, Firdous
dc.contributor.author
Hashem, Mais
dc.contributor.author
Monies, Dorota
dc.contributor.author
Abouelhoda, Mohamed
dc.contributor.author
Meyer, Brian F.
dc.contributor.author
Alfadhel, Majid
dc.contributor.author
Eyaid, Wafa
dc.contributor.author
Zweier, Markus
dc.contributor.author
Steindl, Katharina
dc.contributor.author
Rauch, Anita
dc.contributor.author
Arold, Stefan T.
dc.contributor.author
Woods, C. Geoffrey
dc.contributor.author
Komatsu, Masaaki
dc.contributor.author
Alkuraya, Fowzan S.
dc.date.accessioned
2019-12-06T13:39:10Z
dc.date.available
2018-07-25T05:44:03Z
dc.date.available
2018-07-25T11:06:19Z
dc.date.available
2019-12-06T13:39:10Z
dc.date.issued
2018-07-01
dc.identifier.issn
0006-8950
dc.identifier.issn
1460-2156
dc.identifier.other
10.1093/brain/awy135
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/278043
dc.identifier.doi
10.3929/ethz-b-000278043
dc.description.abstract
The post-translational modification of proteins through the addition of UFM1, also known as ufmylation, plays a critical developmental role as revealed by studies in animal models. The recent finding that biallelic mutations in UBA5 (the E1-like enzyme for ufmylation) cause severe early-onset encephalopathy with progressive microcephaly implicates ufmylation in human brain development. More recently, a homozygous UFM1 variant was proposed as a candidate aetiology of severe early-onset encephalopathy with progressive microcephaly. Here, we establish a locus for severe early-onset encephalopathy with progressive microcephaly based on two families, and map the phenotype to a novel homozygous UFM1 mutation. This mutation has a significantly diminished capacity to form thioester intermediates with UBA5 and with UFC1 (the E2-like enzyme for ufmylation), with resulting impaired ufmylation of cellular proteins. Remarkably, in four additional families where eight children have severe early-onset encephalopathy with progressive microcephaly, we identified two biallelic UFC1 mutations, which impair UFM1-UFC1 intermediate formation with resulting widespread reduction of cellular ufmylation, a pattern similar to that observed with UFM1 mutation. The striking resemblance between UFM1- and UFC1-related clinical phenotype and biochemical derangements strongly argues for an essential role for ufmylation in human brain development. The hypomorphic nature of UFM1 and UFC1 mutations and the conspicuous depletion of biallelic null mutations in the components of this pathway in human genome databases suggest that it is necessary for embryonic survival, which is consistent with the embryonic lethal nature of knockout models for the orthologous genes.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Oxford University Press (OUP)
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.subject
ufmylation
en_US
dc.subject
UFM1
en_US
dc.subject
UFC1
en_US
dc.subject
encephalopathy
en_US
dc.subject
epilepsy
en_US
dc.title
Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
dc.date.published
2018-06-02
ethz.journal.title
Brain: A Journal of Neurology
ethz.journal.volume
141
en_US
ethz.journal.issue
7
en_US
ethz.journal.abbreviated
Brain
ethz.pages.start
1934
en_US
ethz.pages.end
1945
en_US
ethz.size
12 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Oxford
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02070 - Dep. Gesundheitswiss. und Technologie / Dep. of Health Sciences and Technology::02202 - Zentrum für Neurowissenschaften / Neuroscience Center Zurich
en_US
ethz.date.deposited
2018-07-25T05:44:35Z
ethz.source
WOS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2018-07-25T11:06:21Z
ethz.rosetta.lastUpdated
2021-02-15T06:59:03Z
ethz.rosetta.versionExported
true
ethz.COinS
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