Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q96FX7 (tRNA)
 26,753 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The A----G transition at nucleotide 3243 of the mitochondrial tRNA(Leu)(UUR)) gene has been associated with MELAS, a maternally-inherited mitochondrial disorder. We recently transferred mitochondria harboring this mtDNA mutation into a human cell line devoid of endogenous mtDNA (rho degrees cells), and showed: (1) decreased rate of synthesis and of steady-state levels of mitochondrial translational products, (2) reduced respiratory chain function and (3) increased amounts of a novel unprocessed RNA species (termed by us RNA 19) derived from transcription of the 16S rRNA + tRNA(Leu)(UUR) + ND 1 genes. Because RNA 19 contains rRNA sequences, we propose that this molecule is incorporated into mitochondrial ribosomes, and interferes disproportionately with mitochondrial translation, thereby causing the phenotypic changes associated with MELAS.
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PMID:The mitochondrial tRNA(Leu)(UUR)) mutation in MELAS: a model for pathogenesis. 137 59

We report a patient with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes treated with riboflavin and nicotinamide for 18 months, during which time previously frequent encephalopathic spells ceased. To confirm clinical benefit, we withdrew treatment and monitored response with muscle 31P magnetic resonance spectroscopy (MRS) and sural nerve conduction studies. Of three prospectively chosen MRS variables, two changed coincidentally with clinical end points; phosphocreatine (PCr)/adenosine triphosphate recovery rates fell in parallel with sural nerve sensory amplitudes, and a drop in muscle bioenergetic efficiency (relationship of inorganic phosphate/PCr to the accelerating force of contracting muscle) coincided with development of encephalopathy. Investigations revealed a deficiency of respiratory complex I and mutation of the mitochondrial tRNA(Leu)(UUR). We suggest that a defective cellular energy state in mitochondrial disease may be partially treatable and that changes seen in appropriate muscle spectroscopy studies may parallel improvement in brain and peripheral nerve function.
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PMID:MELAS syndrome with mitochondrial tRNA(Leu)(UUR) mutation: correlation of clinical state, nerve conduction, and muscle 31P magnetic resonance spectroscopy during treatment with nicotinamide and riboflavin. 143 26

The mitochondrial DNA (mtDNA) of two unrelated infants with lethal respiratory chain defects was studied using denaturing gradient gel analysis. This analysis revealed melting behavior differences suggesting a point mutation(s) in a restriction fragment containing the apocytochrome b and tRNA(thr) genes. Sequencing revealed that patient 1 had an A to G mutation at nt 15924 which is the last base pair of the anticodon stem adjacent to the anticodon loop of tRNA(thr). Patient 2 had an A to G mutation at nt 15923 which is the last base of the anticodon loop. The results suggest that mtDNA mutations affecting the anticodon loop structure of tRNA(thr) cause mitochondrial disease that is fatal in infancy.
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PMID:Mitochondrial tRNA(thr) mutation in fatal infantile respiratory enzyme deficiency. 164 37

Cytoplasts from two unrelated patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) harboring an A----G transition at nucleotide position 3243 in the tRNA(Leu(UUR)) gene of the mitochondrial genome were fused with human cells lacking endogenous mitochondrial DNA (mtDNA) (rho 0 cells). Selected cybrid lines, containing less than 15 or greater than or equal to 95% mutated genomes, were examined for differences in genetic, biochemical, and morphological characteristics. Cybrids containing greater than or equal to 95% mutant mtDNA, but not those containing normal mtDNA, exhibited decreases in the rates of synthesis and in the steady-state levels of the mitochondrial translation products. In addition, NADH dehydrogenase subunit 1 (ND 1) exhibited a slightly altered mobility on polyacrylamide gel electrophoresis. The mutation also correlated with a severe respiratory chain deficiency. A small but consistent increase in the steady-state levels of an RNA transcript corresponding to 16S rRNA + tRNA(Leu(UUR)) + ND 1 genes was detected. However, there was no evidence of major errors in processing of the heavy-strand-encoded transcripts or of altered steady-state levels or ratios of mitochondrial rRNAs or mRNAs. These results provide evidence for a direct relationship between the tRNALeu(UUR) mutation and the pathogenesis of this mitochondrial disease.
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PMID:Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNA(Leu(UUR)) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. 173 28

An A to G transition at nucleotide 3,243 in the tRNA(Leu)(UUR) gene of mitochondrial DNA has recently been identified as a pathogenic point mutation which is associated with diabetes mellitus and sensorineural deafness in several pedigrees. We have also reported a family showing the association of deafness and diabetes mellitus as the predominant clinical features with this mutation. Audiologic data from two patients in this family are presented. Both had a bilaterally symmetrical sensorineural hearing loss at all frequencies. As is often the case with deafness associated with a mitochondrial disorder, the pure-tone threshold values were maximal at high frequencies in both patients. The audiologic work-up presented not only cochlear characteristics but also signs suggestive of retrocochlear disturbance with poor speech discrimination scores as compared to pure-tone thresholds, although auditory brain-stem responses showed neither wave delay nor prolonged interpeak latencies.
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PMID:[Audiologic evaluation in a family showing diabetes mellitus and deafness associated with a mutation in mitochondrial DNA]. 747 62

MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes), a maternally inherited mitochondrial disorder, has been associated with an A-->G transition at nucleotide 3243 and a T-->C transition at nucleotide 3271, both in the mitochondrial tRNA(Leu(UUR)) gene. We transferred mitochondria harboring these mutations into human cells lacking endogenous mtDNA (rho o cells), and analyzed the resulting transmitochondrial cytoplasmic hybrid (cybrid) cell lines for the relationship of genotype to phenotype. 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). Overall effects on mitochondrial functions were more severe for the MELAS 3243 cybrids as compared to the MELAS 3271 cybrids. These data, combined with our previous observations, suggest that RNA 19 may play an important, but as yet uncharacterized, role in the pathogenesis of this mitochondrial disorder.
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PMID:Analysis of cybrids harboring MELAS mutations in the mitochondrial tRNA(Leu(UUR)) gene. 760 12

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disorder associated with heteroplasmic point mutations in the mitochondrial tRNA(Leu)(UUR) gene. While previous studies have shown that the MELAS mutation at nt-3243 results in impairments in mitochondrial protein synthesis and respiratory chain function, it was not clear whether these were associated with structural alterations in mature RNAs derived from transcription of the region containing the mutation. We have performed fine mapping and high-resolution. Northern analysis of RNAs from cybrids derived from two MELAS patients harboring the nt-3243 mutation. No differences in the size or steady-state levels of transcripts from the 16S rRNA, tRNA(Leu)(UUR), or ND 1 genes (which are contiguous in the mtDNA) were observed between cell lines containing mutated or wild-type mtDNAs. Therefore, it is not likely that the protein synthesis defects observed in cybrids with the MELAS-3243 mutation are directly caused by qualitative alterations in either transcription termination or processing of these mitochondrial RNAs.
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PMID:Fine mapping of mitochondrial RNAs derived from the mtDNA region containing a point mutation associated with MELAS. 768 Jan 23

We report the clinical, biochemical, and molecular genetic findings in a family with an unusual mitochondrial disease phenotype harboring a novel mtDNA tRNA glutamic acid mutation at position 14709. The proband and his sister presented with congenital myopathy and mental retardation and subsequently developed cerebellar ataxia. Other family members had either adult-onset diabetes mellitus with muscle weakness or adult-onset diabetes mellitus alone. Ragged-red and cytochrome c oxidase (COX)-negative fibers were present in muscle biopsies. Biochemical studies of muscle mitochondria showed reduced complex I and IV activities. The mtDNA mutation was heteroplasmic in blood and muscle in all matrilineal relatives analyzed. Primary myoblast, but not fibroblast, cultures containing high proportions of mutant mtDNA exhibited impaired mitochondrial translation. These observations indicate that mtDNA tRNA point mutations should be considered in the differential diagnosis of congenital myopathy. In addition they illustrate the diversity of phenotypes associated with this mutation in the same family and further highlight the association between mtDNA mutations and diabetes mellitus.
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PMID:Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation. 772 55

Cytoplasts from patients with myoclonus epilepsy with ragged-red fibers harboring a pathogenic point mutation at either nucleotide 8344 or 8356 in the human mitochondrial tRNA(Lys) gene were fused with human cells lacking endogenous mitochondrial DNA (mtDNA). For each mutation, cytoplasmic hybrid (cybrid) cell lines containing 0 or 100% mutated mtDNAs were isolated and their genetic, biochemical, and morphological characteristics were examined. Both mutations resulted in the same biochemical and molecular genetic phenotypes. Specifically, cybrids containing 100% mutated mtDNAs, but not those containing the corresponding wild-type mtDNAs, exhibited severe defects in respiratory chain activity, in the rates of protein synthesis, and in the steady-state levels of mitochondrial translation products. In addition, aberrant mitochondrial translation products were detected with both mutations. No significant alterations were observed in the processing of polycistronic RNA precursor transcripts derived from the region containing the tRNA(Lys) gene. These results demonstrate that two different mtDNA mutations in tRNA(Lys), both associated with the same mitochondrial disorder, result in fundamentally identical defects at the cellular level and strongly suggest that specific protein synthesis abnormalities contribute to the pathogenesis of myoclonus epilepsy with ragged-red fibers.
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PMID:In vitro analysis of mutations causing myoclonus epilepsy with ragged-red fibers in the mitochondrial tRNA(Lys)gene: two genotypes produce similar phenotypes. 773 67

We report a clinically heterogeneous, multigenerational pedigree with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) associated with a mutation at nucleotide 3243 in the mitochondrial DNA tRNA(Leu)(UUR) gene. Our findings suggest that the mutation at nucleotide 3243 is not always associated with the classic MELAS phenotype and that other symptoms (notably cardiac and gastrointestinal abnormalities) should raise the suspicion of a mitochondrial disorder.
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PMID:Familial recurrence of atypical symptoms in an extended pedigree with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). 796 31


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