title: A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy.
abstract: Distal hereditary motor neuropathy is a heterogeneous group of inherited neuropathies characterized by distal limb muscle weakness and atrophy. Although at least 15 genes have been implicated in distal hereditary motor neuropathy, the genetic causes remain elusive in many families. To identify an additional causal gene for distal hereditary motor neuropathy, we performed exome sequencing for two affected individuals and two unaffected members in a Taiwanese family with an autosomal dominant distal hereditary motor neuropathy in which mutations in common distal hereditary motor neuropathy-implicated genes had been excluded. The exome sequencing revealed a heterozygous mutation, c.770A > G (p.His257Arg), in the cytoplasmic tryptophanyl-tRNA synthetase (TrpRS) gene (WARS) that co-segregates with the neuropathy in the family. Further analyses of WARS in an additional 79 Taiwanese pedigrees with inherited neuropathies and 163 index cases from Australian, European, and Korean distal hereditary motor neuropathy families identified the same mutation in another Taiwanese distal hereditary motor neuropathy pedigree with different ancestries and one additional Belgian distal hereditary motor neuropathy family of Caucasian origin. Cell transfection studies demonstrated a dominant-negative effect of the p.His257Arg mutation on aminoacylation activity of TrpRS, which subsequently compromised protein synthesis and reduced cell viability. His257Arg TrpRS also inhibited neurite outgrowth and led to neurite degeneration in the neuronal cell lines and rat motor neurons. Further in vitro analyses showed that the WARS mutation could potentiate the angiostatic activities of TrpRS by enhancing its interaction with vascular endothelial-cadherin. Taken together, these findings establish WARS as a gene whose mutations may cause distal hereditary motor neuropathy and alter canonical and non-canonical functions of TrpRS.
authors.affiliation: Department of Neurology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.|Department of Neurology, National Yang-Ming University School of Medicine, Taipei 11221, Taiwan.|Brain Research Center, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Pei-Chien
authors.initials: PC
authors.lastname: Tsai
authors.affiliation: Department of Neurology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.|Department of Neurology, National Yang-Ming University School of Medicine, Taipei 11221, Taiwan.|Brain Research Center, National Yang-Ming University, Taipei 11221, Taiwan.|Institute of Neuroscience, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Bing-Wen
authors.initials: BW
authors.lastname: Soong
authors.affiliation: Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerpen 2610, Belgium.|Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerpen 2610, Belgium.
authors.forename: Inès
authors.initials: I
authors.lastname: Mademan
authors.affiliation: Institute of Biomedical Informatics, National Yang-Ming University, Taipei 11221, Taiwan.|Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Yen-Hua
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Chia-Rung
authors.initials: CR
authors.lastname: Liu
authors.affiliation: Department of Neurology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.|Department of Neurology, National Yang-Ming University School of Medicine, Taipei 11221, Taiwan.
authors.forename: Cheng-Tsung
authors.initials: CT
authors.lastname: Hsiao
authors.affiliation: Department of Neurology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.|Department of Radiology, National Yang-Ming University School of Medicine, Taipei 11221, Taiwan.
authors.forename: Hung-Ta
authors.initials: HT
authors.lastname: Wu
authors.affiliation: Genome Research Center, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Tze-Tze
authors.initials: TT
authors.lastname: Liu
authors.affiliation: Department of Neurology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.|Department of Neurology, National Yang-Ming University School of Medicine, Taipei 11221, Taiwan.
authors.forename: Yo-Tsen
authors.initials: YT
authors.lastname: Liu
authors.affiliation: Department of Neurology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.|Department of Neurology, National Yang-Ming University School of Medicine, Taipei 11221, Taiwan.
authors.forename: Yen-Ting
authors.initials: YT
authors.lastname: Tseng
authors.affiliation: Department of Neurology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.|Department of Neurology, National Yang-Ming University School of Medicine, Taipei 11221, Taiwan.
authors.forename: Kon-Ping
authors.initials: KP
authors.lastname: Lin
authors.affiliation: Institute of Biomedical Informatics, National Yang-Ming University, Taipei 11221, Taiwan.|Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Ueng-Cheng
authors.initials: UC
authors.lastname: Yang
authors.affiliation: Department of Biological Sciences, Kongju National University, Gongju 32588, Korea.
authors.forename: Ki Wha
authors.initials: KW
authors.lastname: Chung
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
authors.forename: Byung-Ok
authors.initials: BO
authors.lastname: Choi
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute; Molecular Medicine Laboratory, Concord Hospital; Sydney Medical School University of Sydney, NSW 2139, Sydney, Australia.
authors.forename: Garth A
authors.initials: GA
authors.lastname: Nicholson
authors.affiliation: Northcott Neuroscience Laboratory, ANZAC Research Institute; Molecular Medicine Laboratory, Concord Hospital; Sydney Medical School University of Sydney, NSW 2139, Sydney, Australia.
authors.forename: Marina L
authors.initials: ML
authors.lastname: Kennerson
authors.affiliation: Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei 10051, Taiwan.|Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
authors.forename: Chih-Chiang
authors.initials: CC
authors.lastname: Chan
authors.affiliation: Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerpen 2610, Belgium.|Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerpen 2610, Belgium.|Department of Neurology, Antwerp University Hospital, Antwerpen 2650, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.affiliation: Brain Research Center, National Yang-Ming University, Taipei 11221, Taiwan.|Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Tzu-Hao
authors.initials: TH
authors.lastname: Cheng
authors.affiliation: Department of Neurology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.|Department of Neurology, National Yang-Ming University School of Medicine, Taipei 11221, Taiwan.
authors.forename: Yi-Chu
authors.initials: YC
authors.lastname: Liao
authors.affiliation: Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami, Miami, FL 33136, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.affiliation: Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerpen 2610, Belgium.|Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerpen 2610, Belgium.|Department of Neurology, Antwerp University Hospital, Antwerpen 2650, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
authors.affiliation: Department of Neurology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.|Department of Neurology, National Yang-Ming University School of Medicine, Taipei 11221, Taiwan.|Brain Research Center, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Yi-Chung
authors.initials: YC
authors.lastname: Lee
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D016501:Neurites / Q000473:pathology / Q000502:physiology; D010375:Pedigree; D014176:Protein Biosynthesis / Q000235:genetics; D011506:Proteins; D017422:Sequence Analysis, DNA; D014369:Tryptophan-tRNA Ligase / Q000235:genetics* / Q000378:metabolism
chemical_list: D011506:Proteins; D014369:Tryptophan-tRNA Ligase; C073175:WARS1 protein, human
keywords: WARS; dHMN; distal hereditary motor neuropathy; exome sequencing; tryptophanyl-tRNA synthetase