Mitochondrial tRNA mutations and disease

  title={Mitochondrial tRNA mutations and disease},
  author={John W. Yarham and Joanna L Elson and Emma L Blakely and Robert Mcfarland and Robert W. Taylor},
  journal={Wiley Interdisciplinary Reviews: RNA},
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… 

Pathogenic Mitochondrial tRNA Point Mutations: Nine Novel Mutations Affirm Their Importance as a Cause of Mitochondrial Disease

The identification of nine novel mt‐tRNA variants in nine families, in which the probands presented with a diverse range of clinical phenotypes including mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes, isolated progressive external ophthalmoplegia, epilepsy, deafness and diabetes are described.

The molecular pathology of pathogenic mitochondrial tRNA variants

The role of mitochondrial–nuclear crosstalk in the manifestation of mt‐tRNA‐associated disease is discussed and research in this area not only has the potential to uncover molecular mechanisms responsible for the vast clinical heterogeneity associated with these variants but also pave the way to develop treatment options for these devastating diseases.

Pathogenic mitochondrial mt-tRNAAla variants are uniquely associated with isolated myopathy

Interestingly, both patients showed very high-mutation levels in all tissues, inferring that the threshold for impairment of oxidative phosphorylation, as evidenced by COX deficiency, appears to be extremely high for these mt-tRNAAla variants.

Mitochondrial tRNA-serine (AGY) m.C12264T mutation causes severe multisystem disease with cataracts.

This case is the first report to directly implicate a single mtDNA mutation in the pathogenesis of ocular cataracts and clearly illustrates the important contribution of normal metabolic activity to the function of the ocular lens.

MELAS-associated m.5541C>T mutation caused instability of mitochondrial tRNATrp and remarkable mitochondrial dysfunction

Surprisingly, it is identified that the supplementation of taurine almost completely restored mitochondrial tRNATrp levels and mitochondrial respiration deficiency at the in vitro cell level.

Mitochondrial tRNAThr A15951G mutation may not be associated with Leber’s Hereditary Optic Neuropathy

Recently, the A15951G mutation in mt-tRNAThr gene has been reported to be a “modified” factor in increasing the penetrance and expressivity of LHON-associated ND4 G11778A mutation in three Chinese families, but evolutionary conservation analysis of this mutation suggested a poor conservation index and the pathogenicity scoring system showed that this mutation was a neutral polymorphism.

Mitochondrial DNA sequence context in the penetrance of mitochondrial t-RNA mutations: A study across multiple lineages with diagnostic implications

A number of mutations which appear compensatory and which could prevent the pathogenicity associated with this change in humans are found, which might provide a partial explanation for the conflicting results in the literature that examines the role of mtDNA variants in complex traits.

Mitochondrial DNA variations associated with hypertrophic cardiomyopathy.

Mitochondrial tRNAThr 15891C>G mutation was not associated with Leber’s hereditary optic neuropathy in Han Chinese patients

The role of a point mutation in mt-tRNAThr gene which had been reported to be a mutation associated with LHON is reassessed and the pathogenicity of this mutation has been discussed in this context.



Mitochondrial tRNA Mutations: Clinical and Functional Perturbations

All the clinical phenotypes associated with mitochondrial tRNA pathogenic mutations that have been reported so far are summarized and categorize them per tRNA species and per associated disease.

Pathogenic mitochondrial tRNA mutations – Which mutations are inherited and why?

Data show that the most important factor in predicting whether a mutation is transmitted to offspring is whether the mt‐tRNA mutation is selected against in a rapidly replicating tissue such as blood, which is entirely compatible with recent observations on the mitochondrial genetic bottleneck in early development.

Mitochondrial DNA mutations in human disease

This review considers the basic principles of mitochondrial genetics which govern both the behaviour and investigation of pathogenic mtDNA mutations summarizing recent advances, and an assessment of the ongoing debate into the role of somatic mt DNA mutations in neurodegenerative disease, ageing and cancer.

Novel mitochondrial transfer RNA(Phe) gene mutation associated with late-onset neuromuscular disease.

The case of a 66-year-old woman with a 4-year history of walking difficulties due to exercise intolerance and paresthesia in the feet serves to illustrate that primary defects of the mitochondrial genome should be considered even in older patients with late-onset, mild neuromuscular symptoms.

A functionally dominant mitochondrial DNA mutation.

A novel mtDNA mutation is reported that contradicts this rule, since it caused a severe multisystem disorder and respiratory chain deficiency even at low levels of heteroplasmy in a 13-year-old boy with clinical, radiological and biochemical evidence of a mitochondrial disorder.

Mitochondrial disorders.

  • M. Zeviani
  • Biology, Medicine
    Supplements to Clinical neurophysiology
  • 2004
An increasing number of nuclear disease genes have been discovered in association with syndromes caused by oxidative phosphorylation failure and provide both diagnostic tools and new pathogenetic insights in a rapidly expanding area of neurogenetics.

Overexpression of human mitochondrial valyl tRNA synthetase can partially restore levels of cognate mt-tRNAVal carrying the pathogenic C25U mutation

Evidence is presented that the generalized decrease in steady-state mt-tRNAVal observed in the homoplasmic 1624C>T-cell lines is caused by a rapid degradation of the deacylated form of the abnormal mt- tRNAVal, and variations in the levels of VARS2L between tissue types and patients could underlie the difference in clinical presentation.

Sporadic myopathy and exercise intolerance associated with the mitochondrial 8328G>A tRNALys mutation

A second patient with this mutation causing exercise intolerance, proximal muscle weakness and bilateral ptosis is reported, which emphasises the variable phenotypic expression of MTTK gene mutations, which are often associated with devastating, neurological presentations including myoclonus and epilepsy.

Functional consequences of mitochondrial tRNATrp and tRNAArg mutations causing combined OXPHOS defects

The results show that these tRNATrp and tRNAArg mutations cause the combined OXPHOS deficiencies in the patients, adding to the still expanding group of pathogenic mitochondrial tRNA mutations.