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Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNA(Leu(UUR)) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes
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Cytoplasts from two unrelated patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) harboring an A----G transition at nucleotide position 3243 in the tRNA(Leu(UUR)) gene of the mitochondrial genome were fused with human cells lacking endogenous mitochondrial DNA (mtDNA) (rho 0 cells). Selected cybrid lines, containing less than 15 or greater than or equal to 95% mutated genomes, were examined for differences in genetic, biochemical, and morphological characteristics. Cybrids containing greater than or equal to 95% mutant mtDNA, but not those containing normal mtDNA, exhibited decreases in the rates of synthesis and in the steady-state levels of the mitochondrial translation products. In addition, NADH dehydrogenase subunit 1 (ND 1) exhibited a slightly altered mobility on polyacrylamide gel electrophoresis. The mutation also correlated with a severe respiratory chain deficiency. A small but consistent increase in the steady-state levels of an RNA transcript corresponding to 16S rRNA + tRNA(Leu(UUR)) + ND 1 genes was detected. However, there was no evidence of major errors in processing of the heavy-strand-encoded transcripts or of altered steady-state levels or ratios of mitochondrial rRNAs or mRNAs. These results provide evidence for a direct relationship between the tRNALeu(UUR) mutation and the pathogenesis of this mitochondrial disease.
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“Correct transcription of 16S mt-rRNA is impaired by the common mt-tRNA Leu(UUR) m.3243A N G mutation, which interferes with a transcription termination site located at the boundary of the 16S mt-rRNA and mt-tRNA Leu(UUR) genes, causing accumulation of an unprocessed RNA intermediate (RNA19) including 16S mt-rRNA, mt-tRNA Leu(UUR) and MTND1 [191][192][193].”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [192]
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Karicheva, O., Kolesnikova, O., Schirtz, T., Vysokikh, M., Mager-Heckel, A., Lombès, A., Boucheham, A., Krasheninnikov, I., Martin, R., Entelis, N., et al. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr546 · Cited by 86
Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients
Börner, G. V. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.4.467 · Cited by 92
van den Ouweland, J. M. W., Maechler, P., Wollheim, C. B., Maassen, J. A., & Attardi, G. M. (1999) · Diabetologia · doi:10.1007/s001250051183 · Cited by 91
Mitochondrial DNA (mtDNA) diseases: correlation of genotype to phenotype
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Pathophysiology of the MELAS 3243 Transition Mutation
Flierl, A., Reichmann, H., & Seibel, P. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.43.27189 · Cited by 90
Metadata
- Authors
- King, M. P., Koga, Y., Davidson, M., & Schon, E. A.
- Affiliations
- Columbia University (US)
- ORCID
- Koga, Y
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1992-02
- Volume
- 12
- Issue
- 2
- Pages
- 480-490
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC364194
- OpenAlex
- W1877954338
- Cited by
- 458
- References
- 44
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 11 · 2023: 5 · 2022: 8 · 2021: 12 · 2020: 8 · 2019: 7 · 2018: 6 · 2017: 10 · 2016: 3 · 2015: 8 · 2014: 11 · 2013: 10 · 2012: 14
- FWCI
- 10.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Muscular Dystrophy Association
- New York Academy of Medicine
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS028828, NS 28828)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- MELAS, mitochondrial myopathy, mitochondrial DNA, mitochondrial translation, respiratory chain deficiency, cybrid cells, ND1, 12S rRNA, pathogenesis, lactic acidosis
- MeSH terms
- Acidosis, Lactic, Adolescent, Brain Diseases, Metabolic, Cell Line, Cerebrovascular Disorders, Child, DNA, Mitochondrial, Female, Humans, Hybrid Cells, Immunohistochemistry, Mitochondria, Mutation, Oxygen Consumption, RNA, Transfer, Leu, Syndrome, Protein Biosynthesis, Blotting, Northern
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