RT Journal Article
T1 Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy.
A1 Colin, Estelle
A1 Daniel, Jens
A1 Ziegler, Alban
A1 Wakim, Jamal
A1 Scrivo, Aurora
A1 Haack, Tobias B
A1 Khiati, Salim
A1 Denomme, Anne-Sophie
A1 Amati-Bonneau, Patrizia
A1 Charif, Majida
A1 Procaccio, Vincent
A1 Reynier, Pascal
A1 Aleck, Kyrieckos A
A1 Botto, Lorenzo D
A1 Herper, Claudia Lena
A1 Kaiser, Charlotte Sophia
A1 Nabbout, Rima
A1 N'Guyen, Sylvie
A1 Mora-Lorca, Jose Antonio
A1 Assmann, Birgit
A1 Christ, Stine
A1 Meitinger, Thomas
A1 Strom, Tim M
A1 Prokisch, Holger
A1 Miranda-Vizuete, Antonio
A1 Hoffmann, Georg F
A1 Lenaers, Guy
A1 Bomont, Pascale
A1 Liebau, Eva
A1 Bonneau, Dominique
K1 Animals
K1 Caenorhabditis elegans
K1 Cholinergic Neurons
K1 Fibroblasts
K1 Intellectual Disability
K1 Microcephaly
K1 Mutation
K1 Proteins
K1 Ubiquitin-Activating Enzymes
K1 Zebrafish Proteins
AB 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.
PB Cell Press
YR 2016
FD 2016-08-18
LK http://hdl.handle.net/10668/10376
UL http://hdl.handle.net/10668/10376
LA en
NO Colin E, Daniel J, Ziegler A, Wakim J, Scrivo A, Haack TB, et al. Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy. Am J Hum Genet. 2016 Sep 1;99(3):695-703.
DS RISalud
RD Apr 7, 2025