title: UBA5 Mutations Cause a New Form of Autosomal Recessive Cerebellar Ataxia.
abstract: Autosomal recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders. For many affected patients, the genetic cause remains undetermined. Through whole-exome sequencing, we identified compound heterozygous mutations in ubiquitin-like modifier activating enzyme 5 gene (UBA5) in two Chinese siblings presenting with ARCA. Moreover, copy number variations in UBA5 or ubiquitin-fold modifier 1 gene (UFM1) were documented with the phenotypes of global developmental delays and gait disturbances in the ClinVar database. UBA5 encodes UBA5, the ubiquitin-activating enzyme of UFM1. However, a crucial role for UBA5 in human neurological disease remains to be reported. Our molecular study of UBA5-R246X revealed a dramatically decreased half-life and loss of UFM1 activation due to the absence of the catalytic cysteine Cys250. UBA5-K310E maintained its interaction with UFM1, although with less stability, which may affect the ability of this UBA5 mutant to activate UFM1. Drosophila modeling revealed that UBA5 knockdown induced locomotive defects and a shortened lifespan accompanied by aberrant neuromuscular junctions (NMJs). Strikingly, we found that UFM1 and E2 cofactor knockdown induced markedly similar phenotypes. Wild-type UBA5, but not mutant UBA5, significantly restored neural lesions caused by the absence of UBA5. The finding of a UBA5 mutation in cerebellar ataxia suggests that impairment of the UFM1 pathway may contribute to the neurological phenotypes of ARCA.
authors.affiliation: The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan province, China.
authors.forename: Ranhui
authors.initials: R
authors.lastname: Duan
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan province, China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Shi
authors.affiliation: The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan province, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.affiliation: The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan province, China.
authors.forename: Gehan
authors.initials: G
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan province, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan province, China.
authors.forename: Yunting
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan province, China.|The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan province, China.|The Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan province, China.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan province, China.|The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan province, China.|The Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan province, China.
authors.forename: Junling
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan province, China.|The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan province, China.|The Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan province, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan province, China.|The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan province, China.|The Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan province, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu province, China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan province, China.|The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan province, China.|The Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan province, China.
authors.forename: Beisha
authors.initials: B
authors.lastname: Tang
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002524:Cerebellar Ataxia / Q000201:enzymology / Q000235:genetics*; D004252:DNA Mutational Analysis; D004331:Drosophila melanogaster; D004795:Enzyme Stability; D005260:Female; D015870:Gene Expression; D005808:Genes, Recessive; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics* / Q000378:metabolism
chemical_list: D011506:Proteins; C502095:UBA5 protein, human; C502094:UFM1 protein, human; D044764:Ubiquitin-Activating Enzymes