title: Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy.
abstract: The ubiquitin fold modifier 1 (UFM1) cascade is a recently identified evolutionarily conserved ubiquitin-like modification system whose function and link to human disease have remained largely uncharacterized. By using exome sequencing in Finnish individuals with severe epileptic syndromes, we identified pathogenic compound heterozygous variants in UBA5, encoding an activating enzyme for UFM1, in two unrelated families. Two additional individuals with biallelic UBA5 variants were identified from the UK-based Deciphering Developmental Disorders study and one from the Northern Finland Intellectual Disability cohort. The affected individuals (n = 9) presented in early infancy with severe irritability, followed by dystonia and stagnation of development. Furthermore, the majority of individuals display postnatal microcephaly and epilepsy and develop spasticity. The affected individuals were compound heterozygous for a missense substitution, c.1111G>A (p.Ala371Thr; allele frequency of 0.28% in Europeans), and a nonsense variant or c.164G>A that encodes an amino acid substitution p.Arg55His, but also affects splicing by facilitating exon 2 skipping, thus also being in effect a loss-of-function allele. Using an in vitro thioester formation assay and cellular analyses, we show that the p.Ala371Thr variant is hypomorphic with attenuated ability to transfer the activated UFM1 to UFC1. Finally, we show that the CNS-specific knockout of Ufm1 in mice causes neonatal death accompanied by microcephaly and apoptosis in specific neurons, further suggesting that the UFM1 system is essential for CNS development and function. Taken together, our data imply that the combination of a hypomorphic p.Ala371Thr variant in trans with a loss-of-function allele in UBA5 underlies a severe infantile-onset encephalopathy.
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00290, Finland; Folkhälsan Institute of Genetics, Helsinki 00290, Finland; Neuroscience Center, University of Helsinki, Helsinki 00290, Finland; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki 00290, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Muona
authors.affiliation: Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata 951-8510, Japan; Laboratory of Protein Metabolism, The Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Ishimura
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki 00290, Finland; Neuroscience Center, University of Helsinki, Helsinki 00290, Finland; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki 00290, Finland.
authors.forename: Anni
authors.initials: A
authors.lastname: Laari
authors.affiliation: Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Ichimura
authors.affiliation: Department of Child Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki 00290, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Linnankivi
authors.affiliation: PEDEGO Research Unit, University of Oulu, Oulu 90014, Finland; Medical Research Center Oulu, University of Oulu, Oulu 90014, Finland; Department of Clinical Genetics, Oulu University Hospital, Oulu 90029, Finland.
authors.forename: Riikka
authors.initials: R
authors.lastname: Keski-Filppula
authors.affiliation: Department of Pathology, Cancer and Translational Medicine Research Unit, Medical Research Center Oulu (MRC Oulu), Oulu University Hospital and University of Oulu, Oulu 90014, Finland.
authors.forename: Riitta
authors.initials: R
authors.lastname: Herva
authors.affiliation: PEDEGO Research Unit, University of Oulu, Oulu 90014, Finland; Medical Research Center Oulu, University of Oulu, Oulu 90014, Finland; Department of Children and Adolescents, Division of Paediatric Neurology, Oulu University Hospital, Oulu 90029, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Rantala
authors.affiliation: Department of Pathology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00290, Finland.
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.affiliation: Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki 00290, Finland.
authors.forename: Minna
authors.initials: M
authors.lastname: Pöyhönen
authors.affiliation: Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Obata
authors.affiliation: Department of Anatomy and Histology, Fukushima Medical University School of Medicine, Hikarigaoka, Fukushima 960-1295, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Uemura
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki 00290, Finland; Neuroscience Center, University of Helsinki, Helsinki 00290, Finland; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki 00290, Finland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Karhu
authors.affiliation: Division of Neurobiology and Anatomy, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Bizen
authors.affiliation: Division of Neurobiology and Anatomy, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Hirohide
authors.initials: H
authors.lastname: Takebayashi
authors.affiliation: Department of Genetic Medicine, Belfast City Hospital, Belfast BT9 7AB, UK.
authors.forename: Shane
authors.initials: S
authors.lastname: McKee
authors.affiliation: Sheffield Children's Hospital NHS Foundation Trust, Western Bank, Sheffield S10 2TH, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parker
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Nadia
authors.initials: N
authors.lastname: Akawi
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: McRae
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.affiliation: PEDEGO Research Unit, University of Oulu, Oulu 90014, Finland; Medical Research Center Oulu, University of Oulu, Oulu 90014, Finland; Department of Clinical Genetics, Oulu University Hospital, Oulu 90029, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Kuismin
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00290, Finland; Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio 70029, Finland; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02141, USA.
authors.forename: Mitja I
authors.initials: MI
authors.lastname: Kurki
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki 00290, Finland; Neuroscience Center, University of Helsinki, Helsinki 00290, Finland; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki 00290, Finland; Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki 00290, Finland.
authors.forename: Anna-Kaisa
authors.initials: AK
authors.lastname: Anttonen
authors.affiliation: Laboratory of Protein Metabolism, The Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00290, Finland; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02141, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02141, USA; Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02114, USA; Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.affiliation: Department of Anatomy and Histology, Fukushima Medical University School of Medicine, Hikarigaoka, Fukushima 960-1295, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Waguri
authors.affiliation: Folkhälsan Institute of Genetics, Helsinki 00290, Finland; Neuroscience Center, University of Helsinki, Helsinki 00290, Finland; Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki 00290, Finland. Electronic address: anna-elina.lehesjoki@helsinki.fi.
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
authors.affiliation: Department of Biochemistry, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata 951-8510, Japan. Electronic address: komatsu-ms@med.niigata-u.ac.jp.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
mesh_terms: D000483:Alleles; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001927:Brain Diseases / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D004827:Epilepsy / Q000235:genetics; D059472:Exome / Q000235:genetics; D005091:Exons / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005387:Finland; D005787:Gene Frequency; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D013036:Spasms, Infantile / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics*
chemical_list: D011506:Proteins; C502095:UBA5 protein, human; C502094:UFM1 protein, human; D025801:Ubiquitin; D044764:Ubiquitin-Activating Enzymes