Molecular Investigations on tRNAs Involved in Human Mitochondrial Disorders

  title={Molecular Investigations on tRNAs Involved in Human Mitochondrial Disorders},
  author={Catherine Florentz},
  journal={Bioscience Reports},
  • C. Florentz
  • Published 1 February 2002
  • Biology
  • Bioscience Reports
Over the last decade, human neurodegenerative disorders which correlate with point mutations in mitochondrial tRNA genes became more and more numerous. Both the number of mutations (more than 70) and the variety of phenotypes (cardiopathies, myopathies, encephalopathies as well as diabetes, deafness or others) render the understanding of the genotype/phenotype relationships very complex. Here we first summarize the efforts undertaken to decipher the initial impact of various mutations on the… 

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.

Evolution Meets Disease: Penetrance and Functional Epistasis of Mitochondrial tRNA Mutations

It is proposed that both the nature of the pathogenic mechanism combined with the existence of a compensatory mechanism can explain the penetrance pattern of this mutation, which can allow a scenario for the evolution of mitochondrial tRNAs in which the fixation of two alleles that are individually deleterious can proceed in two steps and not require the simultaneous mutation of both.

Proteomic Consequences of a Human Mitochondrial tRNA Mutation beyond the Frame of Mitochondrial Translation*

This comparative proteomic approach gives the first insight for nuclear encoded proteins that undergo the largest quantitative changes, and pinpoints new potential molecular partners involved in the cascade of events that connect genotype to phenotype.

A novel mitochondrial transfer RNA(Asn) mutation causing multiorgan failure.

Data suggest that the m.5728A>G transition is a pathogenic mutation and is the cause of the respiratory chain dysfunction in the propositus.

Mutational Screening for Mitochondrial tRNA Genes in 100 Women with Pre-Eclampsia

The data indicated that variants in mt-tRNA genes were the important contributors to PE; screening for mt- tRNA variants was recommended for early detection and prevention of PE.

Genetic, pathogenetic, and phenotypic implications of the mitochondrial A3243G tRNALeu(UUR) mutation

  • J. Finsterer
  • Biology, Medicine
    Acta neurologica Scandinavica
  • 2007
This review aims to give an overview on the actual knowledge about the genetic, pathogenetic, and phenotypic implications of the A3243G mtDNA mutation.

Structural probing of a pathogenic tRNA dimer.

Results indicate that the unique dimeric complex formed by the hs mt tRNALeuUUR A3243G mutant exhibits interesting similarities to biological RNA dimers, and may play a role in the loss of function caused by this mutation in vivo.

Mitochondrial and nuclear gene mutations in the type 2 diabetes patients of Coimbatore population

The results suggest that the T8356C and GLUT1 gene mutations may have an important role in developing late-onset T2D in Coimbatore population, particularly, individuals with GLut1 gene may develop kidney dysfunction at their later age.

SURVEY AND SUMMARY Mitochondrial tRNA 3 0 end metabolism and human disease

Here, the effectiveness and reliability of evidence obtained from reactions with in vitro transcripts that pathogenesis-associated mutant mitochondrial tRNAs can lead to deficiencies in tRNA 3 0 end metabolism (3 0 end cleavage, CCA addition and aminoacylation) are critically reviewed toward an understanding of molecular mechanisms underlying human tRNA disorders.



Comparative proteomics as a new tool for exploring human mitochondrial tRNA disorders.

Analysis of mitochondrial proteins from sibling cybrid cell lines reveals a linkage between the effects of mutations in mitochondrial tRNA genes and the steady-state level of nuclear-encoded proteins in mitochondria, which opens new routes toward a large-scale exploration of potential proteic partners involved in the genotype-phenotype correlation of mitochondrial disorders.

Disease‐related versus polymorphic mutations in human mitochondrial tRNAs

It is revealed that these standard parameters for mutant analysis are not sufficient to predict the pathogenicity of mt tRNA mutations, and case by case molecular investigation remains the only means of assessing the growing family of pathogenic mutations in mt tRNAs.

Pathophysiology of the MELAS 3243 Transition Mutation*

The results suggest that the malfunctioning mitochondrial tRNALeu(UUR) leads to an alteration of amino acid incorporation into the mitochondrially synthesized subunits of the oxidative phosphorylation system, thus altering it’s structure and function.

Molecular genetic aspects of human mitochondrial disorders.

This review focuses on mutations of mitochondrial DNA (mtDNA) which are an important cause of mitochondrial disorders in humans and are also associated with common neurodegenerative disorders and

Genetic biochemical and pathophysiological characterization of a familial mitochondrial encephalomyopathy (MERRF)

Functional defects of pathogenic human mitochondrial tRNAs related to structural fragility

The function of mutant tRNAs was rescued by single compensatory mutations that restored Watson-Crick base pairing and reintroduced stability into regions of predicted secondary structure, even though the pairs introduced were different from those found in the wild type tRNA.

Apoptosis in mitochondrial encephalomyopathies with mitochondrial DNA mutations: a potential pathogenic mechanism.

This study suggests that apoptosis is not simply a means whereby cells with dysfunctional mitochondria are eliminated, but that it seems to play a role in the pathogenesis of mitochondrial disorders associated with mtDNA defects affecting mitochondrial protein synthesis.

A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies

An A-to-G transition mutation at nucleotide pair 3,243 in the dihydrouridine loop of mitochondrial tRNALeu(UUR) that is specific to patients with MELAS is reported, which creates an Apal restriction site and could perform a simple molecular diagnostic test for the disease.

Analysis of cybrids harboring MELAS mutations in the mitochondrial tRNALeu(UUR) gene

Cybrids containing high levels of mutated genomes showed decreased rates of synthesis of mitochondrial translation products, reduced respiratory chain function, and increased amounts of a novel unprocessed RNA species (RNA 19), suggesting that RNA 19 may play an important, but as yet uncharacterized, role in the pathogenesis of this mitochondrial disorder.