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dc.contributor.authorNahorski, Michael S
dc.contributor.authorMaddirevula, Sateesh
dc.contributor.authorIshimura, Ryosuke
dc.contributor.authorAlsahli, Saud
dc.contributor.authorBrady, Angela F
dc.contributor.authorBegemann, Anaïs
dc.contributor.authorMizushima, Tsunehiro
dc.contributor.authorGuzmán-Vega, Francisco J.
dc.contributor.authorObata, Miki
dc.contributor.authorIchimura, Yoshinobu
dc.contributor.authorAlsaif, Hessa S
dc.contributor.authorAnazi, Shams
dc.contributor.authorIbrahim, Niema
dc.contributor.authorAbdulwahab, Firdous
dc.contributor.authorHashem, Mais
dc.contributor.authorMonies, Dorota
dc.contributor.authorAbouelhoda, Mohamed
dc.contributor.authorMeyer, Brian F
dc.contributor.authorAlfadhel, Majid
dc.contributor.authorEyaid, Wafa
dc.contributor.authorZweier, Markus
dc.contributor.authorSteindl, Katharina
dc.contributor.authorRauch, Anita
dc.contributor.authorArold, Stefan T.
dc.contributor.authorWoods, C Geoffrey
dc.contributor.authorKomatsu, Masaaki
dc.contributor.authorAlkuraya, Fowzan S
dc.date.accessioned2018-09-03T13:21:46Z
dc.date.available2018-09-03T13:21:46Z
dc.date.issued2018-06-02
dc.identifier.citationNahorski MS, Maddirevula S, Ishimura R, Alsahli S, Brady AF, et al. (2018) Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development. Brain 141: 1934–1945. Available: http://dx.doi.org/10.1093/brain/awy135.
dc.identifier.issn0006-8950
dc.identifier.issn1460-2156
dc.identifier.doi10.1093/brain/awy135
dc.identifier.urihttp://hdl.handle.net/10754/628411
dc.description.abstractThe 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.
dc.description.sponsorshipM.N. is supported by the Wellcome Trust. R.I. is supported by Grant-in-Aid for JSPS Research Fellows (JP16J07037). C.G.W. acknowledges support from the NIHR Cambridge Biomedical Research Campus. M.K. is supported by Grant-in-Aid for Scientific Research on Innovative Areas (JP25111006 and 15K21749 to M.K.), a Japan Society for the Promotion of Science (an A3 foresight program, to M.K.), and the Takeda Science Foundation (to M.K.). F.S.A. is supported by King Salman Center for Disability Research and King Abdulaziz City for Science and Technology (13-BIO1113-20, and Saudi Human Genome Program). S.T.A. and F.J.G.V. are supported by funding from King Abdullah University of Science and Technology (KAUST). A.R. is supported by radiz—Rare Disease Initiative Zürich, Clinical Research Priority Program for Rare Diseases of the University of Zurich.
dc.publisherOxford University Press (OUP)
dc.relation.urlhttps://academic.oup.com/brain/article/141/7/1934/5032368
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectufmylation
dc.subjectUFM1
dc.subjectUFC1
dc.subjectencephalopathy
dc.subjectepilepsy
dc.titleBiallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development
dc.typeArticle
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Division
dc.contributor.departmentBioscience Program
dc.contributor.departmentComputational Bioscience Research Center (CBRC)
dc.identifier.journalBrain
dc.eprint.versionPublisher's Version/PDF
dc.contributor.institutionCambridge Institute for Medical Research, Wellcome Trust MRC Building Addenbrookes Hospital, Hills Rd, Cambridge CB2 0QQ, UK
dc.contributor.institutionDepartment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
dc.contributor.institutionDepartment of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata 951-8510, Japan
dc.contributor.institutionNorth West Thames Genetics Service, Level 8V, St Mark’s Hospital, Northwick Park Hospital Watford Road, Harrow, HA1 3UJ, UK
dc.contributor.institutionInstitute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland
dc.contributor.institutionPicobiology Institute, Graduate School of Life Science, University of Hyogo, Ako-gun, Hyogo 678-1297, Japan
dc.contributor.institutionSaudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
dc.contributor.institutionKing Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Division of Genetics, Department of Pediatrics, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia
dc.contributor.institutionNeuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich 8057, Switzerland
dc.contributor.institutionDepartment of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
kaust.personGuzman Vega, Francisco
kaust.personArold, Stefan T.
refterms.dateFOA2018-09-10T11:38:43Z
dc.date.published-online2018-06-02
dc.date.published-print2018-07-01


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This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Except where otherwise noted, this item's license is described as This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.