title: Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy.
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.
authors.affiliation: Department of Biochemistry and Genetics, University Hospital, 49933 Angers Cedex 9, France; UMR CNRS 6214-INSERM 1083 and PREMMI, University of Angers, 49933 Angers Cedex 9, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Colin
authors.affiliation: Department of Molecular Physiology, Westfälische Wilhelms-University Münster, 48143 Münster, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Daniel
authors.affiliation: Department of Biochemistry and Genetics, University Hospital, 49933 Angers Cedex 9, France; UMR CNRS 6214-INSERM 1083 and PREMMI, University of Angers, 49933 Angers Cedex 9, France.
authors.forename: Alban
authors.initials: A
authors.lastname: Ziegler
authors.affiliation: UMR CNRS 6214-INSERM 1083 and PREMMI, University of Angers, 49933 Angers Cedex 9, France.
authors.forename: Jamal
authors.initials: J
authors.lastname: Wakim
authors.affiliation: Avenir-Atip team, INSERM U1051, Institute of Neurosciences of Montpellier, University of Montpellier, 34091 Montpellier Cedex 5, France.
authors.forename: Aurora
authors.initials: A
authors.lastname: Scrivo
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 München, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: UMR CNRS 6214-INSERM 1083 and PREMMI, University of Angers, 49933 Angers Cedex 9, France.
authors.forename: Salim
authors.initials: S
authors.lastname: Khiati
authors.affiliation: Department of Biochemistry and Genetics, University Hospital, 49933 Angers Cedex 9, France; UMR CNRS 6214-INSERM 1083 and PREMMI, University of Angers, 49933 Angers Cedex 9, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Denommé
authors.affiliation: Department of Biochemistry and Genetics, University Hospital, 49933 Angers Cedex 9, France; UMR CNRS 6214-INSERM 1083 and PREMMI, University of Angers, 49933 Angers Cedex 9, France.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Amati-Bonneau
authors.affiliation: UMR CNRS 6214-INSERM 1083 and PREMMI, University of Angers, 49933 Angers Cedex 9, France.
authors.forename: Majida
authors.initials: M
authors.lastname: Charif
authors.affiliation: Department of Biochemistry and Genetics, University Hospital, 49933 Angers Cedex 9, France; UMR CNRS 6214-INSERM 1083 and PREMMI, University of Angers, 49933 Angers Cedex 9, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Procaccio
authors.affiliation: Department of Biochemistry and Genetics, University Hospital, 49933 Angers Cedex 9, France; UMR CNRS 6214-INSERM 1083 and PREMMI, University of Angers, 49933 Angers Cedex 9, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Reynier
authors.affiliation: Department of Genetics and Metabolism, Phoenix Children's Medical Group, Phoenix, AZ 85016, USA.
authors.forename: Kyrieckos A
authors.initials: KA
authors.lastname: Aleck
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: Lorenzo D
authors.initials: LD
authors.lastname: Botto
authors.affiliation: Department of Molecular Physiology, Westfälische Wilhelms-University Münster, 48143 Münster, Germany.
authors.forename: Claudia Lena
authors.initials: CL
authors.lastname: Herper
authors.affiliation: Department of Molecular Physiology, Westfälische Wilhelms-University Münster, 48143 Münster, Germany.
authors.forename: Charlotte Sophia
authors.initials: CS
authors.lastname: Kaiser
authors.affiliation: Department of Pediatric Neurology, National Reference Center for Rare Epilepsies, University Hospital Necker-Enfants-Malades, 75015 Paris, France.
authors.forename: Rima
authors.initials: R
authors.lastname: Nabbout
authors.affiliation: Department of Pediatric Neurology, University Hospital, 49933 Angers Cedex 9, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: N'Guyen
authors.affiliation: Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, 41013 Seville, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Mora-Lorca
authors.affiliation: Department of General Pediatrics, Division of Pediatric Metabolic Medicine and Neuropediatrics, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Assmann
authors.affiliation: Department of General Pediatrics, Division of Pediatric Metabolic Medicine and Neuropediatrics, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Stine
authors.initials: S
authors.lastname: Christ
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Institute of Biomedicine of Seville, University Hospital Virgen del Rocío/CSIC/University of Seville, 41013 Seville, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Miranda-Vizuete
authors.affiliation: Department of General Pediatrics, Division of Pediatric Metabolic Medicine and Neuropediatrics, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.affiliation: UMR CNRS 6214-INSERM 1083 and PREMMI, University of Angers, 49933 Angers Cedex 9, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Lenaers
authors.affiliation: Avenir-Atip team, INSERM U1051, Institute of Neurosciences of Montpellier, University of Montpellier, 34091 Montpellier Cedex 5, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Bomont
authors.affiliation: Department of Molecular Physiology, Westfälische Wilhelms-University Münster, 48143 Münster, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Liebau
authors.affiliation: Department of Biochemistry and Genetics, University Hospital, 49933 Angers Cedex 9, France; UMR CNRS 6214-INSERM 1083 and PREMMI, University of Angers, 49933 Angers Cedex 9, France. Electronic address: dobonneau@chu-angers.fr.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
mesh_terms: D017668:Age of Onset; D000483:Alleles; D000818:Animals; D001927:Brain Diseases / Q000235:genetics*; D001931:Brain Mapping; D017173:Caenorhabditis elegans / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D059329:Cholinergic Neurons / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D004827:Epilepsy / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D005347:Fibroblasts; D005808:Genes, Recessive / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D008831:Microcephaly / Q000235:genetics; D009069:Movement Disorders; D009154:Mutation / Q000235:genetics*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000235:genetics; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D011506:Proteins; C502095:UBA5 protein, human; C000617998:UBA5 protein, zebrafish; C000617999:UFM-1 protein, C elegans; C502094:UFM1 protein, human; D025801:Ubiquitin; D014452:Ubiquitins; D029961:Zebrafish Proteins; D044764:Ubiquitin-Activating Enzymes; C000617997:uba-5 protein, C elegans