Mitochondrial tRNA mutations and disease

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 MTTmutations 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 MTTsubstitutions. Nevertheless significant progress is being made and we shall review the methods employed to identify and characterize MTTmutations 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 MTTmutations (m.8344A > G and m.3243A > G) as well as other potential pathogenic mechanisms. Knowledge of factors influencing the inheritance of MTTmutations, 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.