Familial dysautonomia (FD) patients have reduced levels of the modified wobble nucleoside mcmsU in tRNA |
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Authors: | Tony Karlsborn Hasan Tükenmez Changchun Chen Anders S Byström |
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Institution: | 1. Department of Molecular Biology, Umeå University, 901 87 Umeå, Sweden;2. Division of Cell Biology, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK |
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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 (mcm5s2U). Our findings indicate that FD could be caused by inefficient translation due to lower levels of wobble uridine nucleosides. |
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Keywords: | cm5U 5-carboxymethyluridine ncm5U 5-carbamoylmethyluridine mcm5U 5-methoxycarbonylmethyluridine mcm5s2U 5-methoxycarbonylmethyl-2-thiouridine |
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