title: Molecular dysfunction associated with the human mitochondrial 3302A>G mutation in the MTTL1 (mt-tRNALeu(UUR)) gene.
abstract: The gene encoding mt-tRNA(Leu(UUR)), MT-TL1, is a hotspot for pathogenic mtDNA mutations. Amongst the first to be described was the 3302A>G transition which resulted in a substantial accumulation in patient muscle of RNA19, an unprocessed RNA intermediate including mt-16S rRNA, mt-tRNA(Leu(UUR)) and MTND1. We have now been able to further assess the molecular aetiology associated with 3302A>G in transmitochondrial cybrids. Increased steady-state levels of RNA19 was confirmed, although not to the levels previously reported in muscle. This data was consistent with an increase in RNA19 stability. The mutation resulted in decreased mt-tRNA(Leu(UUR)) levels, but its stability was unchanged, consistent with a defect in RNA19 processing responsible for low tRNA levels. A partial defect in aminoacylation was also identified, potentially caused by an alteration in tRNA structure. These deficiencies lead to a severe defect in respiration in the transmitochondrial cybrids, consistent with the profound mitochondrial disorder originally associated with this mutation.
authors.affiliation: Institute of Vegetative Physiology, Medical Faculty, University of Köln, Robert-Koch-Strasse 39, D-50931 Köln, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Maniura-Weber
authors.forename: Mark
authors.initials: M
authors.lastname: Helm
authors.forename: Katrin
authors.initials: K
authors.lastname: Engemann
authors.forename: Sabrina
authors.initials: S
authors.lastname: Eckertz
authors.forename: Myriam
authors.initials: M
authors.lastname: Möllers
authors.forename: Matthias
authors.initials: M
authors.lastname: Schauen
authors.forename: Armine
authors.initials: A
authors.lastname: Hayrapetyan
authors.forename: Jürgen-Christoph
authors.initials: JC
authors.lastname: von Kleist-Retzow
authors.forename: Robert N
authors.initials: RN
authors.lastname: Lightowlers
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Bindoff
authors.forename: Rudolf J
authors.initials: RJ
authors.lastname: Wiesner
mesh_terms: D049109:Cell Proliferation; D002999:Clone Cells; D004579:Electron Transport; D050259:Genes, Mitochondrial; D005838:Genotype; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D017240:Mitochondrial Myopathies / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D017354:Point Mutation; D012313:RNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012322:RNA Precursors / Q000378:metabolism; D020871:RNA Stability; D000077278:RNA, Mitochondrial; D012356:RNA, Transfer, Leu / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D046249:Transfer RNA Aminoacylation
chemical_list: D012322:RNA Precursors; D000077278:RNA, Mitochondrial; D012356:RNA, Transfer, Leu; C091001:pre-tRNA(Leu); D012313:RNA