title: A Newly Identified Missense Mutation in FARS2 Causes Autosomal-Recessive Spastic Paraplegia.
abstract: Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by spasticity of the lower limbs due to pyramidal tract dysfunction. Here, we report that a missense homozygous mutation c.424G>T (p.D142Y) in the FARS2 gene, which encodes a mitochondrial phenylalanyl tRNA synthetase (mtPheRS), causes HSP in a Chinese consanguineous family by using combination of homozygous mapping and whole-exome sequencing. Immunohistochemical experiments were performed showing that the FARS2 protein was highly expressed in the Purkinje cells of rat cerebellum. The aminoacylation activity of mtPheRS was severely disrupted by the p.D142Y substitution in vitro not only in the first aminoacylation step but also in the last transfer step. Taken together, our results indicate that a missense mutation in FARS2 contributes to HSP, which has the clinical significance of the regulation of tRNA synthetases in human neurodegenerative diseases.
authors.affiliation: Department of Biochemistry and Molecular Biology, Xi'an, Shaanxi, 710032, China.|Center for DNA Typing, Xi'an, Shaanxi, 710032, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of physiotherapy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Center for RNA Research, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Chinese Academy of Sciences, Shanghai, 710031, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Anatomy, Histology and Embryology & K.K. Leung Brain Research Centre, Preclinical School of Medicine, Fourth Military Medical University, Xi'an, Shaanxi, 200032, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Shi
authors.affiliation: Center for DNA Typing, Xi'an, Shaanxi, 710032, China.
authors.forename: Fengyu
authors.initials: F
authors.lastname: Che
authors.affiliation: Department of Biochemistry and Molecular Biology, Xi'an, Shaanxi, 710032, China.|Center for DNA Typing, Xi'an, Shaanxi, 710032, China.
authors.forename: Chunxia
authors.initials: C
authors.lastname: He
authors.affiliation: Department of Biochemistry and Molecular Biology, Xi'an, Shaanxi, 710032, China.
authors.forename: Libo
authors.initials: L
authors.lastname: Yao
authors.affiliation: Center for RNA Research, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Chinese Academy of Sciences, Shanghai, 710031, China.
authors.forename: Enduo
authors.initials: E
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Xi'an, Shaanxi, 710032, China.|Center for DNA Typing, Xi'an, Shaanxi, 710032, China.
authors.forename: Yuanming
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000818:Animals; D001483:Base Sequence; D003241:Consanguinity; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D015870:Gene Expression; D006720:Homozygote; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010652:Phenylalanine-tRNA Ligase / Q000235:genetics* / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D051381:Rats; D016415:Sequence Alignment; D015419:Spastic Paraplegia, Hereditary / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
chemical_list: D024101:Mitochondrial Proteins; C000611567:FARS2 protein, human; D010652:Phenylalanine-tRNA Ligase
keywords: FARS2; Purkinje cells; hereditary spastic paraplegia; neurodegenerative disorder