Publication:
Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy.

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Date

2016-08-18

Authors

Colin, Estelle
Daniel, Jens
Ziegler, Alban
Wakim, Jamal
Scrivo, Aurora
Haack, Tobias B
Khiati, Salim
Denomme, Anne-Sophie
Amati-Bonneau, Patrizia
Charif, Majida

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Cell Press
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Abstract

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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MeSH Terms

Age of Onset
Alleles
Brain Diseases
Brain Mapping
Caenorhabditis elegans Proteins
Child
Child, Preschool
Endoplasmic Reticulum
Epilepsy
Exome
Female
Genes, Recessive
Humans
Magnetic Resonance Imaging
Male
Movement Disorders
Synaptic Transmission
Ubiquitin
Ubiquitins
Zebrafish

DeCS Terms

Proteínas
Mutación
Secuenciación del Exoma
Encefalopatías
Microcefalia
Transmisión Sináptica
Trastornos del movimiento
Epilepsia Refractaria

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Keywords

Animals, Caenorhabditis elegans, Cholinergic Neurons, Fibroblasts, Intellectual Disability, Microcephaly, Mutation, Proteins, Ubiquitin-Activating Enzymes, Zebrafish Proteins

Citation

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.