title: Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy.
abstract: Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features. We previously assigned the locus for autosomal dominant intermediate CMT neuropathy type C (DI-CMTC) to chromosome 1p34-p35. Here we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC. Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins, and mutations in YARS, or in its yeast ortholog TYS1, reduce yeast growth. YARS localizes to axonal termini in differentiating primary motor neuron and neuroblastoma cultures. This specific distribution is significantly reduced in cells expressing mutant YARS proteins. YARS is the second aminoacyl-tRNA synthetase found to be involved in CMT, thereby linking protein-synthesizing complexes with neurodegeneration.
authors.affiliation: Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Universiteitsplein 1, 2610 Antwerpen, Belgium.
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
authors.forename: Joy
authors.initials: J
authors.lastname: Irobi
authors.forename: Florian P
authors.initials: FP
authors.lastname: Thomas
authors.forename: Patrick
authors.initials: P
authors.lastname: Van Dijck
authors.forename: Kris
authors.initials: K
authors.lastname: Meerschaert
authors.forename: Maarten
authors.initials: M
authors.lastname: Dewil
authors.forename: Ines
authors.initials: I
authors.lastname: Dierick
authors.forename: An
authors.initials: A
authors.lastname: Jacobs
authors.forename: Els
authors.initials: E
authors.lastname: De Vriendt
authors.forename: Velina
authors.initials: V
authors.lastname: Guergueltcheva
authors.forename: Chitharanjan V
authors.initials: CV
authors.lastname: Rao
authors.forename: Ivailo
authors.initials: I
authors.lastname: Tournev
authors.forename: Francisco A A
authors.initials: FA
authors.lastname: Gondim
authors.forename: Marc
authors.initials: M
authors.lastname: D'Hooghe
authors.forename: Veerle
authors.initials: V
authors.lastname: Van Gerwen
authors.forename: Patrick
authors.initials: P
authors.lastname: Callaerts
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
authors.forename: Jean-Pièrre
authors.initials: JP
authors.lastname: Timmermans
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Jan
authors.initials: J
authors.lastname: Gettemans
authors.forename: Johan M
authors.initials: JM
authors.lastname: Thevelein
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Ivo
authors.initials: I
authors.lastname: Kremensky
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D001681:Biological Assay; D019556:COS Cells; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D002522:Chlorocebus aethiops; D005799:Genes, Dominant / Q000235:genetics*; D005816:Genetic Complementation Test; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D021381:Protein Transport; D011994:Recombinant Proteins; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000254:growth & development; D016415:Sequence Alignment; D014448:Tyrosine-tRNA Ligase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; D014448:Tyrosine-tRNA Ligase