title: Familial dysautonomia (FD) patients have reduced levels of the modified wobble nucleoside mcm(5)s(2)U in tRNA.
abstract: Familial dysautonomia (FD) is a recessive neurodegenerative genetic disease. FD is caused by a mutation in the IKBKAP gene resulting in a splicing defect and reduced levels of full length IKAP protein. IKAP homologues can be found in all eukaryotes and are part of a conserved six subunit protein complex, Elongator complex. Inactivation of any Elongator subunit gene in multicellular organisms cause a wide range of phenotypes, suggesting that Elongator has a pivotal role in several cellular processes. In yeast, there is convincing evidence that the main role of Elongator complex is in formation of modified wobble uridine nucleosides in tRNA and that their absence will influence translational efficiency. To date, no study has explored the possibility that FD patients display defects in formation of modified wobble uridine nucleosides as a consequence of reduced IKAP levels. In this study, we show that brain tissue and fibroblast cell lines from FD patients have reduced levels of the wobble uridine nucleoside 5-methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U). Our findings indicate that FD could be caused by inefficient translation due to lower levels of wobble uridine nucleosides.
authors.affiliation: Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Tony
authors.initials: T
authors.lastname: Karlsborn
authors.affiliation: Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Hasan
authors.initials: H
authors.lastname: Tükenmez
authors.affiliation: Division of Cell Biology, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Changchun
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden. Electronic address: Anders.Bystrom@molbiol.umu.se.
authors.forename: Anders S
authors.initials: AS
authors.lastname: Byström
mesh_terms: D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D004402:Dysautonomia, Familial / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D012343:RNA, Transfer / Q000737:chemistry* / Q000378:metabolism; D013891:Thiouridine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism
chemical_list: C011701:5-carbomethoxymethyl-2-thiouridine; D013891:Thiouridine; D012343:RNA, Transfer
keywords: 5-Methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U); ELP1; Elongator complex; Familial dysautonomia (FD); IKBKAP; tRNA modification