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Mitochondrial tRNA mutations and disease

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Mitochondrial (mt‐) tRNA (MTT) gene mutations are an important cause of human morbidity and are associated with a wide range of pathology, from isolated organ‐specific diseases such as myopathy or hearing loss, through to multisystem disorders with encephalopathy, gastrointestinal dysmotility, and life‐threatening cardiomyopathy. Our understanding of how MTT mutations cause disease remains poor and progress has been hampered by the complex interaction of genotype with phenotype that can result in patients who harbor the same mutation exhibiting starkly contrasting phenotypes, whereas other (genetically heterogeneous) patients manifest clinically identical syndromes. A further complexity is the highly polymorphic nature of mitochondrial DNA (mtDNA), which must temper any reflex assumptions of pathogenicity for novel MTT substitutions. Nevertheless significant progress is being made and we shall review the methods employed to identify and characterize MTT mutations as pathogenic. Also important is our understanding of the molecular processes involved and we shall discuss the data available on two of the most studied MTT mutations (m.8344A > G and m.3243A > G) as well as other potential pathogenic mechanisms. Knowledge of factors influencing the inheritance of MTT mutations, and therefore the likelihood of disease transmission, is of particular importance to female patients. At present, the factors determining transmission remain elusive, but we shall examine several possible mechanisms and discuss the evidence for each. Finally, a number of different yeast and mouse models are currently used to investigate mitochondrial disease and we will assess the importance of and difficulties associated with each model as well as the future of possible therapies for patients with mitochondrial disease. Copyright © 2010 John Wiley & Sons, Inc.

Figure 1.

The structure and organization of human mitochondrial DNA. Thirteen polypeptide genes are shown: seven encoding subunits of complex I (blue), one encoding MTCYB of complex III (purple), three encoding subunits of complex IV (green), and two encoding subunits of complex V (yellow). Two mt‐rRNAs are indicated (brown), as are the 22 mt‐tRNAs (red boxes). The two non‐coding regions are shown by the thick black line with the origin of heavy strand replication in the D‐loop and the origin of light strand replication between mt‐tRNAs for asparagine and cysteine. The clinical variability of MTT mutations can be seen by the variety of different phenotypes reported on the MitoMAP23 and Mamit‐tRNA databases,143 and the fact that MTT mutations in different MTTs can result in the same clinical presentation. MERRF, myoclonic epilepsy and ragged‐red fibers; DMDF, diabetes mellitus and deafness; MELAS, mitochondrial encephalomyopathy; lactic acidosis and stroke‐like episodes; CPEO, chronic progressive external ophthalmoplegia; PEO, progressive external ophthalmoplegia; MNGIE, mitochondrial neurogastrointestinal encephalomyopathy; SNHL, sensorineural hearing loss; DMECHO, dementia and chorea; KSS, Kearns–Sayre syndrome.23,143.

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Figure 2.

Laboratory investigation of novel mt‐tRNA variants based on a previously published m.15967G > A MTTP mutation.65 Two muscle fibers (highlighted by an asterisk) are shown in a sequential series of transverse muscle sections from the patient highlighting the following histochemical activities: (a) cytochrome c oxidase (COX) histochemistry showing COX‐deficient fibers within a population of normal fibers, a typical ‘mosaic’ distribution. (b) Succinate dehydrogenase (SDH) which reveals a subsarcolemmal accumulation of mitochondrial activity, so called ‘ragged‐blue’ fibers. (c) sequential COX/SDH histochemistry highlighting individual COX‐deficient fibers which retain SDH activity. (d) Direct sequencing of the entire mitochondrial genome reveals the heteroplasmic m.15967G > A change. (e) Quantitative PCR‐RFLP analysis of tissue samples demonstrating varying levels of the m.15967G > A mutation segregation in different tissues. U, uncut; C, controls. In patient samples, the 131 bp fragment represents mutated mtDNA whereas cut fragments (94 bp) indicate wild‐type mtDNA. (f) Analysis of individual COX‐positive and COX‐deficient fibers shows COX‐positive fibers clearly have a greater proportion of wild‐type mtDNA compared with the COX‐deficient fibers. (g) Graphical representation of these single‐fiber data highlighting a segregation of mutation load with a biochemical (COX) defect and an estimated threshold level for the m.15967G > A mutation in this tissue. (h) mt‐tRNAPro secondary structure highlighting the location of the mutation which disrupts a Watson–Crick base pair within a stem structure. (i) Sequence alignment of several evolutionarily diverse organisms indicates that the position of the m.15967G > A mutation (boxed in red) is moderately conserved, although the base pair is highly conserved.

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Figure 3.

The mitochondrial genetic bottleneck. Schematic diagram showing a heteroplasmic oocyte being fertilized followed by the development of the embryo. During this development primary oocytes develop from a founder population of 40 PGCs recruited by induction from the epiblast in the posterior‐proximal embryonic pole.144 The PGCs are believed to have a low mitochondrial number of around 200. The red circles represent wild‐type mtDNA, blue circles represent mutant‐type mtDNA; cells with mutant mtDNA having passed a threshold will have a biochemical defect and are shown in blue.

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Figure 4.

Secondary structures of mt‐tRNALys and mt‐tRNALeu(UUR). (a) The cloverleaf structure of mt‐tRNALys is shown with the common m.8344A > G mutation highlighted. Conservational sequence alignment of evolutionarily diverse organisms reveals that the position of the m.8344A > G mutation is not highly conserved, contrary to the expected canonical criteria for pathogenicity. (b) The cloverleaf structure of mt‐tRNALeu(UUR) is shown with the common m.3243A > G mutation highlighted. Conservational sequence alignment of evolutionarily diverse organisms reveals that the position of the m.3243A > G mutation is very highly conserved as expected for pathogenic changes. Both mutations occur within loop structures which is interesting since pathogenic changes usually occur within the structurally important Watson–Crick pairs in the stems.

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Figure 5.

mtDNA mutations associated with the MERRF and MELAS phenotypes. (a) Pathogenic mtDNA mutations reported to be associated with the MERRF phenotype are indicated including m.8344A > G in bold. (b) Pathogenic mtDNA mutations reported to be associated with the MELAS phenotype are indicated including m.3243A > G in bold. Although all the mutations shown are reported as pathogenic on the MitoMAP database,23 this image merely lists them and does not confirm their pathogenicity.

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