Molecular dysfunction associated with the human mitochondrial 3302A>G mutation in the MTTL1 (mt-tRNALeu⁽UUR⁾) gene

The gene encoding mt-tRNALeu⁽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-tRNALeu⁽UUR⁾ and...

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Bibliographic Details
Published in:Nucleic acids research 2006-12, Vol.34 (22), p.6404-6415
Main Authors: Maniura-Weber, Katharina, Helm, Mark, Engemann, Katrin, Eckertz, Sabrina, Möllers, Myriam, Schauen, Matthias, Hayrapetyan, Armine, von Kleist-Retzow, Jürgen-Christoph, Lightowlers, Robert N, Bindoff, Laurence A, Wiesner, Rudolf J
Format: Article
Language:English
Subjects:
aminoacylation
Cell Proliferation
Clone Cells
cybrids
Electron Transport
etiology
genes
Genes, Mitochondrial
Genotype
Humans
mitochondria
Mitochondria - metabolism
Mitochondrial Myopathies - genetics
Mitochondrial Myopathies - metabolism
Molecular Biology
Muscle, Skeletal - metabolism
muscles
mutation
patients
Point Mutation
ribosomal RNA
RNA - chemistry
RNA - genetics
RNA - metabolism
RNA Precursors - metabolism
RNA Stability
RNA, Transfer, Leu - chemistry
RNA, Transfer, Leu - genetics
RNA, Transfer, Leu - metabolism
transfer RNA
Transfer RNA Aminoacylation
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Summary:The gene encoding mt-tRNALeu⁽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-tRNALeu⁽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-tRNALeu⁽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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkl727