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Colin, E.* ; Daniel, J.* ; Ziegler, A.* ; Wakim, J.* ; Scrivo, A.* ; Haack, T.B.* ; Khiati, S.* ; Denommé, A.S.* ; Amati-Bonneau, P.* ; Charif, M.* ; Procaccio, V.* ; Reynier, P.* ; Aleck, K.A.* ; Botto, L.D.* ; Herper, C.L.* ; Kaiser, C.S.* ; Nabbout, R.* ; N'Guyen, S.* ; Mora-Lorca, J.A.* ; Assmann, B.* ; Christ, S.* ; Meitinger, T. ; Strom, T.M. ; Prokisch, H. ; Miranda-Vizuete, A.* ; Hoffmann, G.F.* ; Lenaers, G.* ; Bomont, P.* ; Liebau, E.* ; Bonneau, D.*

Biallelic variants in UBA5 reveal that disruption of the UFM1 cascade can result in early-onset encephalopathy.

Am. J. Hum. Genet. 99, 695-703 (2016)
Publ. Version/Full Text Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Via whole-exome sequencing, we identified rare autosomal-recessive variants in UBA5 in five children from four unrelated families affected with a similar pattern of severe intellectual deficiency, microcephaly, movement disorders, and/or early-onset intractable epilepsy. UBA5 encodes the E1-activating enzyme of ubiquitin-fold modifier 1 (UFM1), a recently identified ubiquitin-like protein. Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from affected individuals revealed that UBA5 mutations impair the process of ufmylation, resulting in an abnormal endoplasmic reticulum structure. In Caenorhabditis elegans, knockout of uba-5 and of human orthologous genes in the UFM1 cascade alter cholinergic, but not glutamatergic, neurotransmission. In addition, uba5 silencing in zebrafish decreased motility while inducing abnormal movements suggestive of seizures. These clinical, biochemical, and experimental findings support our finding of UBA5 mutations as a pathophysiological cause for early-onset encephalopathies due to abnormal protein ufmylation.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Ubiquitin-fold Modifier; Caenorhabditis-elegans; Nervous-system; Protein; Epilepsy; Receptors; Regulator; Mutation; Mice; Nlbp
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 99, Issue: 3, Pages: 695-703 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)