Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 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.
Exp Clin Endocrinol Diabetes 2001
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

Investigation of the clinical manifestations of MELAS-specific A3243G mitochondrial DNA (mtDNA) point mutation has suggested that the A3243G mutation of mtDNA can cause certain subtypes of diabetes mellitus (DM) and contributes about 0.15% of the overall incidence of diabetes. However, a relationship between the diabetic syndrome and the proportion of mutant mtDNA in affected tissues remains unclear. In this article, we report the results of our investigation of 14 diabetic and 23 non-diabetic patients who had the A3243G mutant mtDNA. The proportions of mutant mtDNA in different tissues were noted to change variably and neither heteroplasmy of mutant mtDNA in various tissues nor the proportion of mutated mtDNA in a specific tissue showed a correlation with the clinical phenotype of DM. Generation of a diabetic syndrome was not predictable from either the content of mutant mtDNA in leukocytes, hair follicles, or in muscle tissues. Further study showed that muscle tissue has the highest proportion of mutant mtDNA followed by hair follicles and by blood cells. Moreover, we observed that as the patient's age increased, all tissue showed a declining proportion of mutant mtDNA. These findings suggest that age may play a role in the manifestation of diabetes in patients with A3243G mutation of mtDNA.
Diabetes Res Clin Pract 2001 Dec
PMID:Molecular analysis of diabetes mellitus-associated A3243G mitochondrial DNA mutation in Taiwanese cases. 1173 8

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.
Diabetes Res Clin Pract 2001 Dec
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

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

Thirty-five mitochondrial (mt) DNAs from Spain that harbor the mutation A3243G in association with either MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) syndrome or a wide array of disease phenotypes (ranging from diabetes and deafness to a mixture of chronic progressive external ophthalmoplegic symptoms and strokelike episodes) were studied by use of high-resolution restriction fragment length polymorphism analysis and control-region sequencing. A total of 34 different haplotypes were found, indicating that all instances of the A3243G mutation are probably due to independent mutational events. Haplotypes were distributed into 13 haplogroups whose frequencies were close to those of the general Spanish population. Moreover, there was no statistically significant difference in haplogroup distribution between patients with MELAS and those with disease phenotypes other than MELAS. Overall, these data indicate that the A3243G mutation harbors all the evolutionary features expected from a severely deleterious mtDNA mutation under strong negative selection, and they reveal that European mtDNA backgrounds do not play a substantial role in modulating the mutation's phenotypic expression.
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PMID:Mitochondrial DNA haplogroups do not play a role in the variable phenotypic presentation of the A3243G mutation. 1261 63

The pathogenetic mechanism of the most extensively investigated A3243G mutated tRNALeu(UUR) gene, which causes the MELAS encephalomyopathy, maternally inherited diabetes, or chronic progressive external ophlthalmoplegia, is still unresolved, despite the numerous investigations on the topic. Previous evidences presented in published work suggested that the mitochondrial DNA harboring A3243G mutation result decreases in the rates of mitochondrial protein synthesis. To search for differences in aminoacylation of mitochondrial DNA-encoded wild-type and mutant human tRNALeu(UUR), we have expressed and purified the two kinds of tRNAsLeu(UUR), and have expressed human mitochondrial leucyl-tRNA synthetase for in vitro assays of aminoacylation of wild-type and mutant human tRNALeu(UUR). The results indicate human mitochondrial tRNALeu(UUR) gene A3243G point mutant can remarkably reduce its aminoacylation, suggesting it could be one of the mechanisms that the mutation can produce in such clinical phenotypes.
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PMID:Search for difference in aminoacylation of mitochondrial DNA-encoded wild-type and mutant human tRNALeu (UUR). 1282 90

The mitochondrial transfer ribonucleic acid for leucine is encoded by nucleotides 3230-3304. A-to-G transition at nucleotide 3243 can cause maternally transmitted diabetes mellitus-deafness syndrome, and MELAS syndrome. MELAS syndrome is a rare disorder of mitochondrial energy production, and is an acronym for myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Cortical malformations are heterogeneous and result from abnormal cell proliferation/apoptosis, migration, and/or differentiation of neuroepithelial cells. They are an important and relatively common cause of intractable epilepsy and neurodevelopmental disorders. The association between these A3243G mutations and cortical malformation has never before been reported. Here a 14-year-old female with A3243G mutation and polymicrogyria is described and possible aetiologies of this association are discussed.
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PMID:A3243G mitochondrial mutation associated with polymicrogyria. 1451 43

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

We prenatally diagnosed MELAS syndrome in a fetus whose mother and older brother had the MELAS-specific A3243G mutation. The mutant mtDNA level of the amniotic fluid cells was not significantly different from that of the postnatal peripheral blood and hair follicle samples. The obstetrical course was uncomplicated except for transient exacerbation of the mother's diabetes, which required insulin control. At term, the infant was macrosomic, and the delivery was complicated by shoulder dystocia. MELAS syndrome in itself does not influence either the prenatal course of the mother or the fetal outcome. In contrast to the fulminating clinical course of this mother's first child, MELAS symptoms did not develop in her second child until age four, despite similar high tissue levels of mutant mtDNA. The phenotypic diversity in two offspring with similar higher levels of mutant mtDNA suggests that prenatal genetic diagnosis of cultured amniotic cells may yield results that are poor prognosticators of fetal outcome.
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PMID:Prenatal diagnosis of a fetus harboring an intermediate load of the A3243G mtDNA mutation in a maternal carrier diagnosed with MELAS syndrome. 1516 11


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