Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011053 (deafness)
 10,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Wolfram or DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness) syndrome, which has long been known as an autosomal-recessive disorder, has recently been proposed to be a mitochondrial-mediated disease with either a nuclear or a mitochondrial genetic background. The phenotypic characteristics of the syndrome resemble those found in other mitochondrial (mt)DNA mediated disorders such as Leber's hereditary optic neuropathy (LHON) or maternally inherited diabetes and deafness (MIDD). Therefore, we looked for respective mtDNA alterations in blood samples from 7 patients with DIDMOAD syndrome using SSCP-analysis of PCR-amplified fragments, encompassing all mitochondrial ND and tRNA genes, followed by direct sequencing. Subsequently, we compared mtDNA variants identified in this disease group with those detected in a group of LHON patients (n = 17) and in a group of 69 healthy controls. We found that 4/7 (57%) DIDMOAD patients harbored a specific set of point mutations in tRNA and ND genes including the so-called class II or secondary LHON mutations at nucleotide positions (nps) 4216 and 4917 (haplogroup B). In contrast, LHON-patients were frequently (10/17, 59%) found in association with another cluster of mtDNA variants including the secondary LHON mutations at nps 4216 and 13708 and further mtDNA polymorphisms in ND genes (haplogroup A), overlapping with haplogroup B only by variants at nps 4216 and 11251. The frequencies of both haplogroups were significantly lower in the control group versus the respective disease groups. We propose that haplogroup B represents a susceptibility factor for DIDMOAD which, by interaction with further exogeneous or genetic factors, might increase the risk for disease.
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PMID:Analysis of the mitochondrial DNA from patients with Wolfram (DIDMOAD) syndrome. 930 89

We describe a childhood mitochondrial disorder in which the clinical symptoms began and remained confined to the gastrointestinal (GI) system during the first 4 y. Seizures heralded the onset of progressive encephalopathy at age 7. Peripheral neuropathy, retinitis pigmentosa, and neural deafness developed subsequently. Laboratory investigations disclosed elevated levels of plasma lactate, and a muscle biopsy revealed ragged red fibers lacking cytochrome c oxidase activity and diminished levels of respiratory chain enzyme complexes. Molecular genetic tests failed to show any of the previously reported pathogenic mitochondrial DNA (mtDNA) mutations. We therefore screened the whole mitochondrial genome by coupling restriction digestions with single-strand conformational polymorphism (SSCP) patterns. We identified a unique SSCP in the segment that encompassed the tRNA(Lys) gene, and direct sequencing of this segment revealed a G-->A transition at an evolutionarily conserved nucleotide at mtDNA position 8313. This G8313A transition was heteroplasmic in muscle and fibroblasts of the patient, but was absent in the white blood cells and platelets from his maternal relatives. This report illustrates how GI symptoms can be the initial manifestation in a mitochondrial disorder and suggests that mitochondrial dysfunction should be considered in differentials of unexplained chronic GI symptoms, especially when lactic acidosis or other unrelated clinical signs or symptoms are present.
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PMID:A novel mitochondrial G8313A mutation associated with prominent initial gastrointestinal symptoms and progressive encephaloneuropathy. 938 Apr 35

Mutation in the mitochondrial gene at position 3243 was recently identified in a large pedigree of diabetes mellitus and deafness. As the mitochondria play an important role in glucose-stimulated insulin secretion in pancreatic beta-cells, we therefore searched for such mutations to detect a candidate gene for diabetes. We screened 10 diabetic subjects with clinical features suggesting mitochondrial DNA mutations. An adenine to guanine point mutation in tRNA(Lys) in at position 8296 (the 8296 mutation) was newly identified. Subsequently, we screened 1216 diabetic subjects, 44 patients with sensorineural deafness subjects and 300 non-diabetic control subjects for this mutation. We identified the mutation in 11 (0.90%) unrelated diabetic subjects, one (2.3%) patient with deafness and no non-diabetic control subject. Seven of these 12 subjects showed maternal inheritance. Deafness was seen in 7 of 12 probands. Four family pedigrees showed maternal inheritance of diabetes over two or three generations. Subjects carrying the 8296 mutation may develop diabetes and the mutation can explain as high as ca. 1% of the causes of diabetes.
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PMID:Novel mitochondrial DNA mutation in tRNA(Lys) (8296A-->G) associated with diabetes. 957 Nov 88

Mitochondrial tRNA(Leu)(UUR) gene mutation is one of the candidates in the pathogenesis of NIDDM. Especially the 3243 (A-->G) mutation is associated with the maternally-inherited diabetes and deafness. To evaluate the prevalence and characteristics of the 3243 point mutation in Koreans, we screened 433 Korean diabetic patients (220 men and 213 women). Genomic DNA was extracted from peripheral white blood cells and PCR was carried out with mitochondrial DNA primers (3130-3149, 3558-3539) encompassing the 3243 position. After digestion with Apa-1, five subjects showed polymorphism suggesting 3243 point mutation but when we directly sequenced the amplified DNA with an automatic sequencer, only 2 of the 5 patients were shown to have 3243 (A-->G) mutation and the other 3 subjects had 3426 (A-->G) mutation rather than 3243 mutation. Two diabetic patients with 3243 mutation were lean (BMI = 14.4, 17.0 kg/m2), had relatively lower fasting C-peptide concentrations (0.9 ng/ml each), and required insulin for management. In contrast, those with 3426 point mutation were not lean (BMI = 22.6-28.0 kg/m2), had relatively higher C-peptide levels (3.9-5.4 ng/ml), and could be managed with oral hypoglycemic agents. None of the 5 patients had deafness. In conclusion, the prevalence of 3243 point mutation in Korean diabetic patients was approximately 0.5% and we found a new mutation mimicking 3243 mutation by PCR-RFLP (restriction fragment length polymorphism) pattern. We suggest that sequencing of the PCR product or designing smaller PCR fragment size to enhance the specificity may help to identify the exact location of the point mutation.
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PMID:A new point mutation (3426, A to G) in mitochondrial NADH dehydrogenase gene in Korean diabetic patients which mimics 3243 mutation by restriction fragment length polymorphism pattern. 962 53

The pathogenetic mechanism of the deafness-associated mitochondrial DNA (mtDNA) T7445C mutation has been investigated in several lymphoblastoid cell lines from members of a New Zealand pedigree exhibiting the mutation in homoplasmic form and from control individuals. We show here that the mutation flanks the 3' end of the tRNASer(UCN) gene sequence and affects the rate but not the sites of processing of the tRNA precursor. This causes an average reduction of approximately 70% in the tRNASer(UCN) level and a decrease of approximately 45% in protein synthesis rate in the cell lines analyzed. The data show a sharp threshold in the capacity of tRNASer(UCN) to support the wild-type protein synthesis rate, which corresponds to approximately 40% of the control level of this tRNA. Strikingly, a 7445 mutation-associated marked reduction has been observed in the level of the mRNA for the NADH dehydrogenase (complex I) ND6 subunit gene, which is located approximately 7 kbp upstream and is cotranscribed with the tRNASer(UCN) gene, with strong evidence pointing to a mechanistic link with the tRNA precursor processing defect. Such reduction significantly affects the rate of synthesis of the ND6 subunit and plays a determinant role in the deafness-associated respiratory phenotype of the mutant cell lines. In particular, it accounts for their specific, very significant decrease in glutamate- or malate-dependent O2 consumption. Furthermore, several homoplasmic mtDNA mutations affecting subunits of NADH dehydrogenase may play a synergistic role in the establishment of the respiratory phenotype of the mutant cells.
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PMID:The deafness-associated mitochondrial DNA mutation at position 7445, which affects tRNASer(UCN) precursor processing, has long-range effects on NADH dehydrogenase subunit ND6 gene expression. 974 4

Patients who have mitochondrial myopathy can present with specific pathological conditions (eg, diabetes mellitus and deafness). A 36-year-old woman presented with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). An investigation was conducted into whether the abnormalitiy of mitochondrial DNA (a T to C transition at position 3271 in the mitochondrial tRNA [Leu(UUR)] gene) influences nuclear DNA synthesis by cells in the heart, skeletal muscles, and brain. Myocardium, skeletal muscle, and brain tissues were stained with hematoxylin-eosin, and Masson trichrome for histopathology. Target nuclei taken from the myocardial and skeletal muscles and brain tissue were purified after removing debris by the modified Hedley method. These nuclei were stained with propidium iodide (PI) for analysis by flow cytometry. The number of nuclei in the G2M phase was bigger in myocytes of MELAS than in normal myocytes (Control) (MELAS myocyte: Control myocyte=24.9+/-7.3: 6.1+/-1.6%, p<0.005), but there was no significant increase in the G2M phase in brain tissue. The G1 phase was far more reduced in MELAS myocytes and skeletal muscle than in Controls (MELAS myocyte: Control myocyte=65.8+/-9.1: 88.0+/-3.2%, p<0.005; MELAS skeletal muscle: Control skeletal muscle=85.1+/-2.2: 90.1+/-3.2%, p<0.05), while there was no significant decrease of nuclei in the G1 phase in brain tissue. Increased amount of nuclei in the G2M phase in cardiac myocytes and skeletal muscle cells compared with that in neurons might depend on the capacity for proliferation and differentiation of these cells as compared with brain tissue. It was concluded that the mitochondrial DNA mutation (3271T-to-C) of MELAS may influence the nuclear DNA synthesis of cells in various tissues depending on their level of mitotic activity.
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PMID:Cell cycle of myocytes of cardiac and skeletal muscle in mitochondrial myopathy. 976 10

We report seven unrelated families with mitochondrial tRNA(Ser(UCN)) gene mutations at three different loci. A novel G7497A mutation is found in two families, both of which present with progressive myopathy, ragged-red fibers, lactic acidosis, and deficiency of respiratory chain complexes I and IV. This mutation presumably affects the tertiary tRNA(Ser(UCN)) dihydrouridine interaction. Mutations 7472 insC and T7512C, found in three and two families, respectively, are associated with myoclonus epilepsy, deafness, ataxia, cognitive impairment, and complex IV deficiency. No ragged-red fibers or ultrastructural abnormalities are seen. It is interesting that 6 of our 7 index patients are apparently homoplasmic, indicating a minor pathogenetic power of the tRNA(Ser(UCN)) mutations.
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PMID:Progressive myoclonus epilepsy and mitochondrial myopathy associated with mutations in the tRNA(Ser(UCN)) gene. 977 62

Autopsy reports of patients with mitochondrial encephalopathy with lactic acidosis and strokelike episode (MELAS) are rare. This report documents the clinical and autopsy findings of a 47-year-old woman with MELAS syndrome. The diagnosis was corroborated by documenting a mitochondrial DNA mutation tRNA-Leu (UUR) at position 3243. The patient's clinical history was marked by schizophrenia, peptic ulcer disease, constipation requiring hemicolectomy, migraine headaches, deafness, and a left temporal lobe infarct. At autopsy, a muscle biopsy demonstrated numerous ragged red fibers and a partial cytochrome C oxidase deficiency. By electron microscopy, increased numbers of slightly hypertrophic mitochondria were observed focally within myocytes and vessel walls; paracrystalline mitochondrial inclusions were not seen. The brain at autopsy showed mild cerebral atrophy and diffuse cortical gliosis. Prominent bilateral basal ganglia calcifications and vascular sclerosis were present, and a small remote left temporal lobe infarct was seen.
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PMID:Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome: an autopsy report. 982 26

COX deficiency is believed to be the most common defect in neonates and infants with mitochondrial diseases. To explore the causes of this group of disorders, we examined 25 mitochondrial genes (three COX subunit genes and 22 tRNA genes) and 10 nuclear COX subunit genes for disease associated mutations using PCR-SSCP and direct sequencing of polymorphic SSCP fragments. DNA from one patient with severe COX deficiency and with consanguineous parents was entirely sequenced. The patient population consisted of 21 unrelated index patients with mitochondrial disorders and predominant (n=7) or isolated (n=14) COX deficiency. We detected two distinct tRNA(Ser)(UCN) mutations, which have been recently described in single kindreds, in a subgroup of four patients with COX deficiency, deafness, myoclonic epilepsy, ataxia, and mental retardation. Besides a number of nucleotide variants, a single novel missense mutation, which may contribute to the disease phenotype, was found in the mitochondrial encoded COX 1 gene (G6480A). Mutations in nuclear encoded COX subunit genes were not detected in this study.
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PMID:A systematic mutation screen of 10 nuclear and 25 mitochondrial candidate genes in 21 patients with cytochrome c oxidase (COX) deficiency shows tRNA(Ser)(UCN) mutations in a subgroup with syndromal encephalopathy. 983 34

The mitochondrial A3243G mutation of the tRNA(Leu) has been described in pedigrees with maternally inherited diabetes mellitus and deafness. Ten diabetic patients with sensorineural deafness were studied. Polymerase chain reaction and enzyme restriction analysis with Apa I were performed. The mutation was found in heteroplasmy in only one patient (1/10). She was a 43-years-old woman with maternally inherited diabetes and deafness since she was 29. The association of sensorineural deafness and maternal inherited diabetes are the clues to suspect this subtype of diabetes.
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PMID:[Diabetes mellitus associated with the A3243G mutation of mitochondrial DNA. Apropos a case]. 1007 17


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