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Query: UMLS:C0162671 (MELAS)
 587 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review provides a compact overview on the contribution of mutations in mtDNA to the pathogenesis of diabetes mellitus, with emphasis on the A3243G mutation in the tRNA(Leu, UUR) gene. This mutation associates in most individuals with maternally inherited diabetes and deafness (MIDD) whereas in some other carriers the MELAS syndrome or a progressive kidney failure is seen. Possible pathogenic mechanisms are discussed especially the question why particular mutations in mtDNA associate with distinct clinical entities. Mutations in mtDNA can affect the ATP production, thereby leading to particular clinical phenotypes such as muscle weakness. On the other hand mtDNA mutations may also alter the intracellular concentration of mitochondrial metabolites which can act as signalling molecules, such as Ca or glutamate. This situation may contribute to the development of particular phenotypes that are associated with distinct mtDNA mutations.
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PMID:Molecular and clinical aspects of mitochondrial diabetes mellitus. 1140 93

Using RNase protection analysis, we found a novel C to G mutation at nucleotide position 3093 of mitochondrial DNA (mtDNA) in a previously reported 35-year-old woman exhibiting clinical features of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome together with diabetes mellitus, hyperthyroidism and cardiomyopathy. The patient also had an A3243G mutation in the tRNA(Leu(UUR)) gene and a 260-base pair duplication in the D-loop of mtDNA. The fibroblasts of the patient were cultured and used for the construction of cybrids using cytoplasmic transfer of the patient's mtDNA to the mtDNA-less rho(0) cells. RNA isolated from the cybrids was subjected to RNase protection analysis, and a C3093G transversion at the 16S rRNA gene and a MELAS-associated A3243G mutation of mtDNA were detected. The novel C3093G mutation together with the A3243G transition were found in muscle biopsies, hair follicles and blood cells of this patient and also in her skin fibroblasts and cybrids. The proportion of the C3093G mutant mtDNA in muscle biopsies of the patient was 51%. In contrast, the mutation was not detected in three sons of the proband. To characterize the impact of the mtDNA mutation-associated defects on mitochondrial function, we determined the respiratory enzyme activities of the primary culture of fibroblasts established from the proband, her mother and her three sons. The proportions of mtDNA with the C3093G transversion and the A3243G transition in the fibroblasts of the proband were 45 and 58%, respectively. However, the fibroblasts of the proband's mother and children harbored lower levels of mtDNA with the A3243G mutation but did not contain the C3093G mutation. The complex I activity in the proband's fibroblasts was decreased to 47% of the control but those of the fibroblasts of the mother and three sons of the proband were not significantly changed. These findings suggest that the C3093G transversion together with the A3243G transition of mtDNA impaired the respiratory function of mitochondria and caused the atypical MELAS syndrome associated with diabetes mellitus, hyperthyroidism and cardiomyopathy in this patient.
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PMID:A novel mutation in the mitochondrial 16S rRNA gene in a patient with MELAS syndrome, diabetes mellitus, hyperthyroidism and cardiomyopathy. 1145 95

Mitochondrial DNA (mtDNA) disorders are clinically very heterogeneous, ranging from single organ involvement to severe multisystem disease. One of the most frequently observed mtDNA mutations is the A-to-G transition at position 3243 of the tRNA(Leu (UUR)) gene. This mutation is often related to MELAS syndrome. However, not all patients with the A3243G mutation share the same clinical disease expression and, on the contrary, patients clinically exhibiting MELAS syndrome may have other mtDNA mutations. Here we describe two patients with a very early infantile presentation of disease associated with the A3243G mutation. Patient 1 presented with hypotonia, feeding difficulties and failure to thrive (FTT) at the age of 3 months. Laboratory investigations showed persistent hyperlactic acidemia, elevated lactate/pyruvate ratios and elevated alanine concentrations in blood. Developmental delay was progressive and he developed cardiomyopathy and seizures. Death occurred at the age of 3.5 years. Patient 2 was born prematurely and had persistent, severe lactic acidosis from birth on. Moderate biventricular hypertrophy was seen on ultrasound studies of the heart and, suffering from progressive lactic acidosis, he died at the age of 13 days. Because of the rarity of this very early presentation, we searched the literature for other infantile cases associated with the A3243G mutation and found 8 additional ones. In infants presenting with lactic acidosis/hyperlactic acidemia, failure to thrive, hypotonia, seizures and/or cardiomyopathy, mtDNA mutational analysis, also for the disease entities, usually only observed in juveniles or adults is warranted.
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PMID:Infantile presentation of the mtDNA A3243G tRNA(Leu (UUR)) mutation. 1157 98

Mitochondrial oxidative phosphorylation and the ATP production in pancreatic beta cells play significant roles in insulin secretion in response to glucose and other nutrients. An A to G mutation in the tRNA(Leu(UUR)) gene at nucleotide position (np) 3243 of mitochondrial DNA (mtDNA) has been observed in patients with MELAS syndrome and mitochondrial diabetes. Recently, some patients with mitochondrial diabetes associated with the A3243G mtDNA mutation were found to respond to coenzyme Q10 therapy. Thus, we investigated oxidative stress and peroxidative damage in a series of cybrids carrying either the wild-type adenine or the mutant-type guanine at np 3243 but having otherwise identical mtDNA sequence. The cybrids harboring >90% of the A3243G mutant mtDNA were found to have significantly lower oxygen consumption rate and electron transfer activities, and thereby had lower ATP/ADP ratios and declined energy charge. Importantly, the defective respiratory function elicited by the A3243G mtDNA mutation caused an increased oxidative stress as indicated by the decreased GSH/GSSG ratio and enhanced oxidative damage to lipids. Moreover, the cybrids harboring high proportions of the A3243G mtDNA mutation were found to be much more vulnerable to an exogenous oxidant, tert-butylhydroperoxide. We thus suggest that enhanced oxidative damage and elevated oxidative stress contribute to the decline of mitochondrial function and may be involved in the initiation and progression of the MELAS syndrome and mitochondrial diabetes.
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PMID:Enhanced oxidative damage in human cells harboring A3243G mutation of mitochondrial DNA: implication of oxidative stress in the pathogenesis of mitochondrial diabetes. 1173 9

More than 70 different point mutations in human mitochondrial tRNA genes are correlated with severe disorders, including fatal cardiopathies, encephalopathies, myopathies, and others. So far, investigation of the molecular impact(s) of mutations has focused on the affected tRNA itself by seeking structural and/or functional perturbations capable of interfering with synthesis of the 13 mitochondrion-encoded subunits of respiratory chain complexes. Here, a proteomic approach was used to investigate whether such mutations would affect the pattern of mitochondrial proteins at a broader level. Analysis of several hundred mitochondrial proteins from sibling cybrid cell lines by two-dimensional electrophoresis, an approach that takes into account all regulatory steps of mitochondrial and nuclear gene expression, indeed reveals a number of up- and downregulated proteins when healthy and single-point-mutation-carrying mitochondria representative of either MELAS or MERRF syndrome were compared. Assignment by mass spectrometry of the two proteins which exhibit obvious large quantitative decreases in the levels of both pathologic mitochondria identified nuclear-encoded subunits of cytochrome c oxidase, a respiratory chain complex. This clearly shows a linkage between the effects of mutations in mitochondrial tRNA genes and the steady-state level of nuclear-encoded proteins in mitochondria. It opens new routes toward a large-scale exploration of potential proteic partners involved in the genotype-phenotype correlation of mitochondrial disorders.
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PMID:Comparative proteomics as a new tool for exploring human mitochondrial tRNA disorders. 1177 11

Mutations in the mitochondrial tRNA(leu) (UUR) gene have been associated with diabetes mellitus and deafness. We screened for the presence of mtDNA mutations in the tRNA(leu) (UUR) gene and adjacent ND1 sequences in 12 diabetes mellitus pedigrees with a possible maternal inheritance of the disease. One patient carried a G to A substitution at nt 3243 (tRNA(leu) (UUR) gene) in heteroplasmic state. In a second pedigree a patient had an A to G substitution at nt 3397 in the ND1 gene. All maternal relatives of the proband had the 3397 substitution in homoplasmic state. This substitution was not present in 246 nonsymptomatic Caucasian controls. The 3397 substitution changes a highly conserved methionine to a valine at aa 31 and has previously been found in Alzheimer's (AD) and Parkinson's (PD) disease patients. Substitutions in the mitochondrial ND1 gene at aa 30 and 31 have associated with a number of different diseases (e.g. AD/PD, MELAS, cardiomyopathy and diabetes mellitus, LHON, Wolfram-syndrome and maternal inherited diabetes) suggesting that changes at these two codons may be associated with very diverse pathogenic processes. In a further attempt to search for mtDNA mutations outside the tRNAleu gene associated with diabetes, the whole mtDNA genome sequence was determined for two patients with maternally inherited diabetes and deafness. Except for substitutions previously reported as polymorphisms, none of the two patients showed any non-synonymous substitutions either in homoplasmic or heteroplasmic state. These results imply that the maternal inherited diabetes and deafness in these patients must result from alterations of nuclear genes and/or environmental factors.
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PMID:MtDNA mutations in maternally inherited diabetes: presence of the 3397 ND1 mutation previously associated with Alzheimer's and Parkinson's disease. 1203 16

We have taken advantage of the similarity between human and yeast (Saccharomyces cerevisiae) mitochondrial tRNA(Leu)(UUR), and of the possibility of transforming yeast mitochondria, to construct yeast mitochondrial mutations in the gene encoding tRNA(Leu)(UUR) equivalent to the human A3243G, C3256T and T3291C mutations that have been found in patients with the neurodegenerative disease MELAS (for mitochondrial 'myopathy, encephalopathy, lactic acidosis and stroke-like episodes'). The resulting yeast cells (bearing the equivalent mutations A14G, C26T and T69C) were defective for growth on respiratory substrates, exhibited an abnormal mitochondrial morphology, and accumulated mitochondrial DNA deletions at a very high rate, a trait characteristic of severe mitochondrial defects in protein synthesis. This effect was specific at least in the pathogenic mutation T69C, because when we introduced A or G instead of C, the respiratory defect was absent or very mild. All defective phenotypes returned to normal when the mutant cells were transformed by multicopy plasmids carrying the gene encoding the mitochondrial elongation factor EF-Tu. The ability to create and analyse such mutated strains and to select correcting genes should make yeast a good model for the study of tRNAs and their interacting partners and a practical tool for the study of pathological mutations and of tRNA sequence polymorphisms.
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PMID:The yeast counterparts of human 'MELAS' mutations cause mitochondrial dysfunction that can be rescued by overexpression of the mitochondrial translation factor EF-Tu. 1252 21

MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) is a disease mainly due to a mutation at position 3243 (A --> G) in the leucine tRNA gene in mitochondrial DNA. Symptoms of the disorder are complex and the exact pathogenesis is not understood. A review of the literature on the subject is presented.
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PMID:MELAS as an example of a mitochondrial disease. 1456 41

The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS) is typically associated with a single point mutation in the mitochondrial genome (mtDNA). Because mtDNA is known to have a higher mutation rate than nuclear DNA, we speculate that some patients with MELAS syndrome may harbor more than one mutation in mtDNA. For this purpose, mtDNA extracted from muscle containing dysmorphic mitochondria from a 32-year-old man with MELAS was sequenced in its entirety to identify all possible mutations. The result showed a homoplasmic A14693G and a heteroplasmic A3243G. The A14693G transition was not present in 205 unrelated control individuals, was not seen in 76 species randomly selected from GenBank, and appears to disrupt the base pairing within the T-loop of mtDNA tRNA(Glu). His asymptomatic siblings' blood showed wild-type at these positions, whereas the blood of the patient's oligosymptomatic diabetic mother had a heteroplasmic A14693G and an apparent homoplasmic wild-type A3243, suggesting an association of A14693G with diabetes mellitus. This case demonstrates the importance of sequencing the mtDNA in its entirety to evaluate the molecular basis of mitochondriopathy.
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PMID:Melas with point mutations involving tRNALeu (A3243G) and tRNAGlu(A14693g). 1457 59

Ten patients with migraine with prolonged aura were studied for the presence of mitochondrial DNA point mutations utilizing DNA isolated from blood and hair samples. We analyzed for nine point mutations reported in patients with MELAS (A3243G, C3256T, T3271C, T3291C, A5814G, T8356C, T9957C, G13513A, and A13514G) and three secondary LHON mutations (T4216C, A4917G, and G13708A). None of the patients tested had any of these mutations in mitochondrial DNA. However, one patient was found to have a tRNA(Gln) A4336G mitochondrial DNA variant. From this study it appears that migraine with prolonged aura is not an oligosymptomatic form of MELAS and is not related to secondary LHON mutations. The significance of the tRNA A4336G variant is unknown.
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PMID:Study of mitochondrial DNA mutations in patients with migraine with prolonged aura. 1520 89


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