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)

The clinical features and course of cardiac involvement in a patient with maternally inherited diabetes and deafness associated with the mitochondrial DNA 3243 mutation are reported. A 45-year-old woman with maternally transmitted diabetes mellitus and deafness presented with congestive heart failure. The patient showed a short P-R interval on electrocardiogram (ECG) and had developed progression from left ventricular hypertrophy to a hypokinetic cardiomyopathy pattern over the course of 10 months. Rapid cardiac change was accompanied by left ventricular remodeling, as shown by wall thinning on echocardiogram and decrease in QRS voltages on ECG. Coronary arteriography revealed no significant stenosis. In the endomyocardial biopsy specimens, light microscopy showed nonspecific cardiomyopathic changes. Genetic testing for mitochondrial DNA mutations in peripheral blood lymphocytes revealed an adenine (A)-to-guanine (G) substitution at nucleotide 3243 in the mitochondrial DNA encoding the transfer RNA for leucine (tRNA Leu (UUR)). The proportion of mutant mitochondrial DNA was 25%. Two of the patient's daughters, aged 13 and 21 years, who were symptom free, were found to carry the same point mutation. A short P-R interval on ECG in the younger of them was the sole manifestation of the mutation. Unfortunately, 6 months after diagnosis, the patient died suddenly at home. Accelerated cardiomyopathy can occur as a mitochondria-related complication in patients with maternally inherited diabetes and deafness associated with the 3243 mutation.
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PMID:Accelerated cardiomyopathy in maternally inherited diabetes and deafness. 1557 73

The deafness-associated A7445G mutation in the precursor of mitochondrial tRNA(Ser(UCN)) has been identified in several pedigrees from different ethnic backgrounds. To determine the role of nuclear background in the biochemical manifestation associated with the A7445G mutation, we performed a biochemical characterization of this mutation using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from a New Zealand family into human osteosarcoma mtDNA-less (rho(0)) cells. Compared with three control cybrids, three cybrids derived from an affected matrilineal relative carrying the homoplasmic A7445G mutation exhibited approximately 38-57% decrease in the steady-state level of tRNA(Ser(UCN)), which is less reduced levels than in lymphoblastoid cells in the previous study. Furthermore, approximately 22% reduction in the level of aminoacylation of tRNA(Ser(UCN)) was observed in the mutant cybrid cells. Interestingly, approximately 60-63% decrease of steady-state level of ND6 gene, which belongs to the same precursor as that of tRNA(Ser(UCN)), in cybrid cell lines carrying the A7445G mutation, is more than that observed in lymphoblastoid cells. These observations strongly point out a mechanistic link between the processing defect of the tRNA(Ser(UCN)) precursor and decreased stability of ND6 mRNA precursor. These results also imply the influence of nuclear background on the biochemical phenotype associated with the A7445G mutation.
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PMID:Biochemical characterization of the deafness-associated mitochondrial tRNASer(UCN) A7445G mutation in osteosarcoma cell cybrids. 1569 74

The A3243G mutation within the human mitochondrial (hs mt) tRNALeuUUR gene is associated with maternally inherited deafness and diabetes (MIDD) and other mitochondrial encephalopathies. One of the most pronounced structural effects of this mutation is the disruption of the native structure through stabilization of a high-affinity dimeric complex. We conducted a series of studies that address the structural properties of this tRNA dimer, and we assessed its formation under physiological conditions. Enzymatic probing was used to directly define the dimeric interface for the complex, and a discrete region of the D-stem and loop of hs mt tRNALeuUUR was identified. The dependence of dimerization on magnesium ions and temperature was also tested. The formation of the tRNA dimer is influenced by temperature, with dimerization becoming more efficient at physiological temperature. Complexation of the mutant tRNA is also affected by the amount of magnesium present, and occurs at concentrations present intracellularly. Terbium probing experiments revealed a specific metal ion-binding site localized at the site of the A3243G mutation that is unique to the dimer structure. This metal ion-binding site presents a striking parallel to dimeric complexes of viral RNAs, which use the same hexanucleotide sequence for complexation and feature a similarly positioned metal ion-binding site within the dimeric structure. Taken together, these results indicate that the unique dimeric complex formed by the hs mt tRNALeuUUR A3243G mutant exhibits interesting similarities to biological RNA dimers, and may play a role in the loss of function caused by this mutation in vivo.
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PMID:Structural probing of a pathogenic tRNA dimer. 1570 31

Nuclear gene(s) have been shown to modulate the phenotypic expression of mitochondrial DNA mutations. We report here the identification and characterization of the yeast nuclear gene MTO2 encoding an evolutionarily conserved protein involved in mitochondrial tRNA modification. Interestingly, mto2 null mutants expressed a respiratory-deficient phenotype when coexisting with the C1409G mutation of mitochondrial 15 S rRNA at the very conservative site for human deafness-associated 12 S rRNA A1491G and C1409T mutations. Furthermore, the overall rate of mitochondrial translation was markedly reduced in a yeast mto2 strain in the wild type mitochondrial background, whereas mitochondrial protein synthesis was almost abolished in a yeast mto2 strain carrying the C1409G allele. The other interesting feature of mto2 mutants is the defective expression of mitochondrial genes, especially CYTB and COX1, but only when coexisting with the C1409G allele. These data strongly indicate that a product of MTO2 functionally interacts with the decoding region of 15 S rRNA, particularly at the site of the C1409G or A1491G mutation. In addition, we showed that yeast and human Mto2p localize in mitochondria. The isolated human MTO2 cDNA can partially restore the respiratory-deficient phenotype of yeast mto2 cells carrying the C1409G mutation. These functional conservations imply that human MTO2 may act as a modifier gene, modulating the phenotypic expression of the deafness-associated A1491G or C1409T mutation in mitochondrial 12 S rRNA.
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PMID:Mutations in MTO2 related to tRNA modification impair mitochondrial gene expression and protein synthesis in the presence of a paromomycin resistance mutation in mitochondrial 15 S rRNA. 1594 50

We report herein the case of a 28-year-old man presenting with hyperglycemic chorea-ballism (HCB) in addition to mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). He was admitted to a local hospital due to weight loss, general fatigue and thirst. The patient had diabetes mellitus, with a blood glucose level of 738 mg/dl and HbA1c of 19.8%. Although insulin therapy improved hyperglycemia, he noticed involuntary movements in the right upper and lower limbs, which subsequently extended to the left side. The patient was thus transferred to our hospital. He displayed short stature (154 cm) and emaciation, and a maternal family history of diabetes mellitus was elicited. He had no history of stroke-like episode, headache, vomiting and seizure. Neurological examination revealed low intelligence (IQ 57), mild sensorineural deafness, and chorea-ballism in the extremities and head without ptosis or eye movement disturbance. Brain computed tomography (CT) demonstrated areas of high density, while T1-weighted magnetic resonance imaging (MRI) revealed extreme hyperintensity and T2-weighted MRI showed hyperintensity in bilateral caudate nuclei, putamina and globi pallidus. HCB was diagnosed. In, CSF, lactate level was increased to 43.9 mg/dl (n, 4-16), pyruvate level was 1.65 mg/dl (n, 0.3-0.9) and total protein concentration was 59 mg/dl. Histological examination of a biopsy sample from the biceps brachii muscle demonstrated ragged-red fibers. An A3243G point mutation in the tRNA(Leu(UUR)) gene was detected, indicating the presence of MELAS. Involuntary movements improved on treatment with haloperidol up to 4.5 mg/day. HCB usually appears in elderly individuals, and cases less than 40-years-old are very rare. The mitochondrial dysfunction in MELAS may accelerate development of HCB.
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PMID:[A case of MELAS presenting juvenile-onset hyperglycemic chorea-ballism]. 1611 32

We report here on the characterization of a three-generation Chinese family with aminoglycoside-induced and nonsyndromic hearing impairment. Ten of 17 matrilineal relatives exhibited bilateral and sensorineural hearing impairment. Of these, nine matrilineal relatives, who had a history of exposure to aminoglycosides, exhibited variable severity and audiometric configuration of hearing loss. The dose and age at the time of drug administration seemed to be correlated with the severity of the hearing loss experienced by affected individuals. Sequence analysis of the complete mitochondrial genome in the pedigree showed the presence of homoplasmic A1555G mutation and 37 variants belonging to haplogroup D4a. Of those variants, the G7444A mutation is of special interest as the mutation at this position results in a read-through of the stop condon AGA of the COI message, thereby adding three amino acids (Lys-Gln-Lys) to the C-terminal of the polypeptide. Alternatively, the G7444A mutation is adjacent to the site of 3' end endonucleolytic processing of L-strand RNA precursor, spanning tRNA(Ser(UCN)) and ND6 mRNA. Thus, the G7444A mutation, similar to the deafness-associated A7445G mutation, may lead to a defect in the processing of the L-strand RNA precursor, thus influencing the phenotypic expression of the A1555G mutation. These data also imply that nuclear background plays a role in the aminoglycoside ototoxicity associated with the A1555G mutation in this Chinese pedigree.
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PMID:Cosegregation of the G7444A mutation in the mitochondrial COI/tRNA(Ser(UCN)) genes with the 12S rRNA A1555G mutation in a Chinese family with aminoglycoside-induced and nonsyndromic hearing loss. 1615 38

Maternally-inherited diabetes and deafness (MIDD) has been related to an A to G transition in the mitochondrial tRNA Leu (UUR) gene at the base pair 3243. Although some previous articles have reported that this mutation may be a cause of cardiomyopathy in diabetes, the degree of cardiac involvement and a specific treatment has not been established. Here, we reported a case of a patient with MIDD who developed congestive heart failure and the therapeutic usefulness of Coenzyme Q10 (CoQ10). In our patient, after the introduction of Coenzyme Q10 150 mg/day, there was a gradual improvement on left ventricular function evaluated by echocardiography. The fractional shortening (FS) and ejection fraction (EF) increased from 26 to 34% and from 49 to 64%, respectively. No side effects were noted. Three months after CoQ10 discontinuation, the parameters of systolic function evaluated by echocardiography decreased, suggesting that CoQ10 had a beneficial effect. Identification of diabetes and cardiomyopathy due to mitochondrial gene mutation may have therapeutic implications and Coenzyme Q10 is a possible adjunctive treatment in such patients.
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PMID:Myocardial dysfunction in mitochondrial diabetes treated with Coenzyme Q10. 1625 79

Maternal diabetes associated with neural deafness is designated as MIDD (maternal inherited diabetes and deafness); it is linked to a A3243G tRNA leucine gene mutation. The disease course is progressive and involvement of other systems is frequent. In most cases, macular pattern dystrophy is present. Muscular lesions are characteristic of mitochondrial myopathies. Mitochondrial abnormalities have also been observed in pancreas, heart, kidney, smooth muscle of the digestive tract with variable heteroplasmy levels. MIDD may present as a single syndrome or is part of MELAS or Kearns-Sayre syndrome.
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PMID:[Diabetes and mitochondrial cytopathies: pathological studies]. 1632 55

Nuclear modifier genes have been proposed to modulate the phenotypic manifestation of human mitochondrial 12S rRNA A1491G mutation associated with deafness in many families world-wide. Here we identified and characterized the putative nuclear modifier gene TRMU encoding a highly conserved mitochondrial protein related to tRNA modification. A 1937bp TRMU cDNA has been isolated and the genomic organization of TRMU has been elucidated. The human TRMU gene containing 11 exons encodes a 421 residue protein with a strong homology to the TRMU-like proteins of bacteria and other homologs. TRMU is ubiquitously expressed in various tissues, but abundantly in tissues with high metabolic rates including heart, liver, kidney, and brain. Immunofluorescence analysis of human 143B cells expressing TRMU-GFP fusion protein demonstrated that the human Trmu localizes and functions in mitochondrion. Furthermore, we show that in families with the deafness-associated 12S rRNA A1491G mutation there is highly suggestive linkage and linkage disequilibrium between microsatellite markers adjacent to TRMU and the presence of deafness. These observations suggest that human TRMU may modulate the phenotypic manifestation of the deafness-associated mitochondrial 12S rRNA mutations.
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PMID:Human TRMU encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase is a putative nuclear modifier gene for the phenotypic expression of the deafness-associated 12S rRNA mutations. 1651 84

We have identified two locations with novel multiplasmic length variants in the mitochondrial DNA of a family with diabetes and deafness. At nt568 in the D-loop, the 6-bp polycytidine tract was found to be variable in length up to a total of 12 residues. A second region with length variants was found at nt8281 in the intergenic COII-tRNA(Lys) region, which consists of two copies of the 9-bp repeat CCCCCTCTA. Only the second repeat occurs in a heteroplasmic C(9-14)A form with both T residues largely deleted. In addition, the mtDNA contained a number of new homoplasmic point mutations. Both length variants are stably inherited in a maternal way with no major changes in their length distribution. In contrast, during culture of fibroblasts from the proband the average length of the polycytidine tracts is increased at both locations indicating a fibroblast-specific genetic instability. Cybrid cells containing mtDNA from the proband proliferate less efficient than cybrids with wild-type mtDNA in co-culture experiments, suggesting functional consequences of the mtDNA length variants or the additional homoplasmic point mutations. Since oxygen consumption was not severely affected, these mutation seem less detrimental for mitochondrial function than the A3243G diabetogenic mutation and most other pathogenic mtDNA mutations. The contribution of mtDNA length variants to the phenotype of members of this family is discussed.
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PMID:Novel mitochondrial DNA length variants and genetic instability in a family with diabetes and deafness. 1670 48


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