MtDNA tRNA mutations

Fourteen mtDNA tRNA mutations have been associated with maternally inherited disease. Such mutations are typically associated with severe mitochondrial myopathies, characterized by ragged red skeletal muscle fibers upon Gomori trichrome staining and the accumulation of structurally abnormal mitochondria in muscle. Mutations in tRNAs exemplify the threshold effect whereby (due to replicative segragation) individuals may not exhibit clinical signs until the proportion of mutant mtDNA exceeds 80-90%. Myoclonic epilepsy and ragged red fiber (MERRF) disease, mitochondrial encephalomyo-pathy tactic acidosis (MELAS), as well as maternally inherited myopathy and cardiomyopathy (MMC) are well-characterized mitochondrial diseases. 

Myoclonic epilepsy with ragged-red fibers (MERPF) is a rare syndrome which shows clear maternal inheritance and a variable clinical pattern including progressive myoclonus, cerebellar ataxia, dementia, and muscle weakness. It is associated with an A-to-G transition at position 8344 of the tRNA Lys gene in the mtDNA. The mutation is heteroplasmic and produces similar multicomplex deficiencies as are seen in KSS. 

The mtDNA is a small 16,569 nucleotide pair, double-stranded, circular DNA. It encodes 13 subunits of the complexes involved in oxidative phosphorylation 7 of the 42 subunits of complex I (NADH dehydrogenase complex), 1 of the 11 subunits of complex III (cytochrome b-Ci complex), 3 of 13 of the subunits of complex IV (cytochrome oxidase), and two subunits of the Fq portion ATP-synthase complex. In addition, mtDNA encodes the necessary components for translation of its mRNA a large and small rRNA and 22 tRNAs. Mutations in mtDNA have been identified as deletions, duplications, or point mutations (Table 21.1). 

II. mtDNA point mutations in tRNA or ribosomal RNA genes ... 

A mutation in any of the 13 protein subunits, the 22 tRNAs, or the two rRNAs whose genes are carried in mitochondrial DNA may possibly cause disease. The 13 protein subunits are all involved in electron transport or oxidative phosphorylation. The syndromes resulting from mutations in mtDNA frequently affect oxidative phosphorylation (OXPHOS) causing what are often called "OXPHOS diseases."3-6 Mitochondrial oxidative phosphorylation also depends upon 100 proteins encoded in the nucleus. Therefore, OXPHOS diseases may result from defects in either mitochondrial or nuclear genes. The former are distinguished by the fact that they are inherited almost exclusively maternally. Most mitochondrial diseases are rare. However, mtDNA is subject to rapid mutation, and it is possible that accumulating mutants in mtDNA may be an important component of aging.h k... 

Point Mutations in rRNA/tRNA Genes of mtDNA Associated with Mitochondrial Diseases 2... 

A number of distinctive syndromes have been shown to be associated with specific point mutations of mtDNA (Table 1) (M15, S4, S14). Several point mutations have been reported to occur at tRNA genes in the mitochondrial genome. For example, the A8344G mutation is present in patients with MERRF syndrome (S9), whereas the A3243G mutation of mtDNA was first identified in a subgroup of patients with MELAS syndrome (G4). MERRF syndrome was the first... 

SI 1. Shoubridge, E. A., Johns, T., and Karpati, G., Complete restoration of a wild-type mtDNA genotype in regenerating muscle fibres in a patient with a tRNA point mutation and mitochondrial... 

Mitochondrial DNA (mtDNA) is present in mitochondria as a circular molecule and in most species codes for 13 or 14 proteins involved in the electron transfer chain, 2 rRNA subunits and 22 tRNA molecules (all necessary for protein synthesis) (Table 16.1). Given that 80% of mtDNA codes for functional mitochondrial proteins involved in energy production, it is not surprising that mtDNA mutations commonly lead to functional problems that manifest as muscle disorders (myopathies). 

Kearns-Sayre syndrome Onset before 20 years of age, characterized by opthalmoplegia, atypical retinitis pigmentosa, mitochondrial myopathy, and one of the following cardiac conduction defect, cerebellar syndrome, or elevated CSF proteins. Deletion of contiguous segments of tRNA and OXPHOS polypeptides, or duplication mutations consisting of tandemly arranged normal mtDNA and an mtDNA with a deletion mutation. 

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