Atypical clinical presentations associated with the MELAS mutation at position 3243 of human mitochondrial DNA

Moraes, Carlos T.; Ciacci, Federica; Silvestri, Gabriella; Shanske, Sara; Sciacco, Monica; Hirano, Michio; Schon, Eric A.; Bonilla, Eduardo; DiMauro, Salvatore

doi:10.1016/0960-8966(93)90040-q

Cited by 219 publications

(103 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, this accounts only for 50 % of the cases, the molecular basis of the others remains unclear, although an association of the MELAS mutation at nucleotide pair 3243 has been reported for patients with PEO (12). The c1assical CPEO genotype (mtDNA deletion) results in a reduced OXPHOS activity.…”

Section: Discussionmentioning

confidence: 99%

“…As a result of deleted genomes within single mitochondria, a decreased protein synthesis rate could cause the described OXPHOS deficiencies in patients with CPEO. Compatible with the latter described pathogenicity of mtDNA deletions is the recent observation that the mitochondrial tRNA Leu mutation at nucleotide pair 3243, previously attributed to cause mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), can be associated with progressive external ophthalmoplegia (PEO) (12). In fact, it has been demonstrated that mutations in tRNA genes lead to an impaired mitochondrial protein synthesis in cultured cells of patients with myoclonic epilepsy and ragged-red fibers disease (MERRF) (13) and MELAS (14).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Chronic Progressive External Ophthalmoplegia Is Associated with a Novel Mutation in the Mitochondrial tRNAAsn Gene

Seibel

Lauber

Klopstock

et al. 1994

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Chronic progressive extern al ophthalmoplegia (CPEO) is caused by a decreased oxidative phosphorylation (OXPHOS) activity due to large-scale deletions of the mitochondrial genome in 50 % of the patients. The deletions encompass structural OXPHOS genes as weil as tRNA genes, required for their expression so that the pathogenesis could be due to the deleted OXPHOS subunits or to an impaired mitochondrial translation. We have analyzed the mitochondrial genome of a patient presenting with CPEO for single base substitutions and discovered a novel heteroplasmic mutation in the tRNAA,n gene at position 5692 that converts a highly conserved adenine into a guanine. This mutation is unique because it is located at the transition of the anticodon loop to the anticodon stern and it leads to an additional base pair, thus reducing the number of loop-forming nucleotides from seven to five. Our findings suggest that CPEO can be caused by a single base substition in a mitochondrial tRNA gene so that the mitochondrial protein synthesis becomes the rate limiting step in OXPHOS fidelity.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Chronic Progressive External Ophthalmoplegia Is Associated with a Novel Mutation in the Mitochondrial tRNAAsn Gene

Seibel

Lauber

Klopstock

et al. 1994

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

show abstract

“…The majority (80%) of MELAS patients possess an A to G transition at nucleotide position (np) 3243 (3,4), whereas, in Ϸ10% of the patients, a T to C transition is observed at np 3271 (5). The mutation at np 3243 has also been observed in maternally inherited diabetes with deafness (6) and in progressive external ophthalmoplegia (7,8). An A to G transition at np 8344 in the tRNA Lys gene is found in most patients with myoclonus epilepsy associated with ragged red fibers (MERRF) (9), another major clinical subgroup of the mitochondrial encephalomyopathies.…”

mentioning

confidence: 98%

Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease

Kirino

Yasukawa

Ohta

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

252

224

View full text Add to dashboard Cite

Point mutations in the mitochondrial (mt) tRNA Leu(UUR) gene are responsible for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), a subgroup of mitochondrial encephalomyopathic diseases. We previously showed that mt tRNA Leu(UUR) with an A3243G or T3271C mutation derived from patients with MELAS are deficient in a normal taurinecontaining modification ( m 5 U; 5-taurinomethyluridine) at the anticodon wobble position. To examine decoding disorder of the mutant tRNA due to the wobble modification deficiency independent of the pathogenic point mutation itself, we used a molecular surgery technique to construct an mt tRNA Leu(UUR) molecule lacking the taurine modification but without the pathogenic mutation. This ''operated'' mt tRNA Leu(UUR) without the taurine modification showed severely reduced UUG translation but no decrease in UUA translation. We thus concluded that the UUG codon-specific translational defect of the mutant mt tRNAs Leu(UUR) is the primary cause of MELAS at the molecular level. This result could explain the complex I deficiency observed clinically in MELAS.

show abstract

“…4.9kb "common" deletion loci from ATP6 through COIII, ND3, ND4L, ND4, to ND5 contribute to KSS [25] . While A3243G mutation associates with maternally inherited PEO with RRF [26] and diabetes and deafness [27] .Aon MA, et al introduced a novel conception "mitochondrial criticality" to describe the state in which the mitochondrial network of cardiomyocytes becomes very sensitive to small perturbations in reactive oxygen species (ROS), resulting in the scaling of local mitochondrial uncoupling and ΔΨ m loss to the whole cell, and the myocardial syncytium. The energetic changes are translated into effects on the electrical excitability of the cell, inducing temporal heterogeneity of excitability in the heart, underlies the genesis of potentially lethal cardiac arrhythmias [28] .…”

Section: Mitochondria and Heart Diseasesmentioning

confidence: 99%

Mitochondrial Mutations in Essential Hypertension

Zhu¹,

Wang²

2012

Genetics and Pathophysiology of Essential Hypertension

View full text Add to dashboard Cite

Atypical clinical presentations associated with the MELAS mutation at position 3243 of human mitochondrial DNA

Cited by 219 publications

References 27 publications

Chronic Progressive External Ophthalmoplegia Is Associated with a Novel Mutation in the Mitochondrial tRNAAsn Gene

Chronic Progressive External Ophthalmoplegia Is Associated with a Novel Mutation in the Mitochondrial tRNAAsn Gene

Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease

Mitochondrial Mutations in Essential Hypertension

Contact Info

Product

Resources

About