Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report on a new maternally-inherited syndrome characterized by a combination of sensorineural hearing loss, ataxia and myoclonus in a large kindred from Sicily. Hearing loss was the most widespread and sometimes the only symptom found in family members. Sequence analysis of the mitochondrial DNA regions encompassing the tRNA genes revealed the presence of a heteroplasmic insertion at nucleotide position 7472. The insertion adds a seventh cytosine to a six-cytosine run that is part of the mitochondrial tRNASer(UCN) gene. Conformational analysis showed that this mutation is likely to alter the structure of the T psi C loop in the tRNASer(UCN) clover leaf secondary structure. Moreover, the degree of heteroplasmy in blood and muscle was correlated with the clinical phenotype, and homoplasmic mutant hybrids showed decreased complex I activity, low oxygen consumption and high lactic acid output, indicating faulty oxidative phosphorylation. Finally, mutation was absent in 381 unrelated maternal lineages, suggesting specific segregation with the disease. We propose that the C7472 insertion-mutation is pathogenic, and etiologically related to hearing loss and other symptoms that define a novel maternally-inherited clinical entity.
 ...
PMID:Maternally inherited hearing loss, ataxia and myoclonus associated with a novel point mutation in mitochondrial tRNASer(UCN) gene. 758 83

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.
 ...
PMID:Progressive myoclonus epilepsy and mitochondrial myopathy associated with mutations in the tRNA(Ser(UCN)) gene. 977 62

Epilepsia partialis continua (EPC) is a rare epileptic syndrome characterized by continuous focal seizures. We report on a 16-year-old girl who died of prolonged pharmacoresistant EPC in whom we identified a 7472insC mutation within the mitochondrial transfer ribonucleic acid (tRNA)(ser(UCN)). Additional symptoms included ataxia, lactic acidosis, myopathy, sensorineural hearing loss, severe headaches, and mental retardation. Quantification revealed 100% mutant mitochondrial DNA (mtDNA) in the patient, 4% in her mother, and none in her half-sister. This highly skewed mtDNA distribution is most improbable (approximately 3 x 10(-30)) if only explained by random genetic drift. Clustering of dysfunctional mitochondria and replicatory advantage of mutant mtDNA may play a role in the rapid segregation towards homoplasmy within one generation.
 ...
PMID:Epilepsia partialis continua associated with a homoplasmic mitochondrial tRNA(Ser(UCN)) mutation. 977 73

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.
 ...
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

We studied a large Dutch family with maternally inherited, progressive, sensorineural hearing loss in 27 patients. Only in a single family member was the hearing loss accompanied by neurological symptoms including ataxia and dysarthria. DNA analysis of the mitochondrial genome revealed the insertion of a C at nucleotide position 7472 in the tRNASer(UCN) gene (7472insC mutation). We determined the percentage of mutant DNA (heteroplasmy) in blood from all family members, and found no correlation between hearing loss and leucocyte heteroplasmy. The 7472insC mutation was previously identified in a smaller family from Sicily with sensorineural hearing loss in 9 family members, six of them also presenting neurologically with ataxia and myoclonus. The presence of the 7472insC mutation in two different pedigrees strongly supports its pathogenicity. However, the interfamilial difference in penetrance of the neurologic abnormalities is most likely to be strongly influenced by secondary factors different from the 7472insC mutation, as heteroplasmy or age of the patients were similar in both families. This mutation should therefore be analysed in families with maternally inherited hearing loss, irrespective of whether the hearing loss is non-syndromic or accompanied by neurologic abnormalities.
 ...
PMID:Hearing impairment and neurological dysfunction associated with a mutation in the mitochondrial tRNASer(UCN) gene. 1009 90

When cells are exposed to ionizing radiation, they initiate a complex response that includes the arrest of cell cycle progression in G1 and G2, apoptosis and DNA repair. DNA is an important subcellular target of ionizing radiation, but oxydative damage to plasma membrane lipids initiates signal transduction pathways that activate apoptosis and that may play a role in cell cycle regulation. How is DNA damage converted into intracellular signals for cell cycle arrest? The ataxia telangectasia mutant (ATM) protein and/or the DNA-dependent protein kinase (DNA-PK), that are both activated by DNA damage, may initiate cell cycle arrest by activating the p53 tumor suppressor protein. The p53 protein acts as a transcription factor and regulates expression of several components implicated in pathways that regulate cell cycle progression. The best known, p21WAF1/CIP1 protein, is an inhibitor of cyclin-dependent kinases (CDK), a family of protein kinases known as key regulators of cell cycle progression. p21WAF1/CIP1 was shown to be able to inhibit several CDK, but is most effective toward G1/S cyclins. Other CDK inhibitors, p27KIP1 and p15INK4b are activated by irradiation and contribute to the G1 arrest. Moreover, radiation-induced G2 arrest was shown to require inhibitory phosphorylation of the kinase cdc2 via an ATM-dependent pathway. Mutations in cell cycle regulatory genes are common in human cancer and cell cycle regulatory deficiency can lead to increase resistance to ionizing radiation in cancer cells. The major function of p53-dependent G1 arrest may be elimination of cells containing DNA damage whereas G2 arrest following radiation has been shown to be important in protecting cells from death. Cell cycle checkpoints offer a new set of potential targets for chemotherapeutic compounds, especially the G2 checkpoint. Thus, abrogation of the G2 checkpoint with methylxanthines such as caffeine or protein kinase inhibitors such as staurosporine and UCN-01 (7-hydroxystaurosporine) was found to sensitize cells to ionizing radiation. These data did not lead to clinical applications, but confirm targeting of the G2 checkpoint may be an important strategy for cancer therapy.
 ...
PMID:[Cell cycle regulation after exposure to ionizing radiation]. 1034 40

The nucleotide pair (np) 7472 insC mitochondrial DNA mutation in the tRNA(Ser)(UCN) gene is associated with sensorineural deafness, combined in some individuals with a wider syndrome including ataxia and myo-clonus. Previous studies in osteosarcoma cell cybrids revealed only a mild respiratory defect linked to the mutation. We have investigated the biochemical and molecular consequences of the mutation, using a panel of seven osteosarcoma cell cybrids containing 100% mutant mtDNA, plus two cybrids carrying 100% wild-type mtDNA from the same patient. The mutation is associated with a mild growth deficit in selective (galactose) medium that is only significant in combination with a reduced mtDNA copy number, suggesting a mechanism that might modulate clinical phenotype. The mutation results in a 65% drop in the steady-state level of tRNA(Ser)(UCN), but causes at most only a very mild and quantitative abnormality of mitochondrial protein synthesis, associated with modest hypersensitivity to doxycyclin. No evidence for a specific defect in aminoacylation was obtained, and unlike the case with the np 7445 mutation, the pattern of RNA processing of light strand transcripts of the ND6 region was not systematically altered. Comparing the np 7472 and np 7445 mutant phenotypes in cultured cells suggests that sensorineural deafness can result from a functional insufficiency of mitochondrial tRNA(Ser)(UCN), to which some cells of the auditory system are especially vulnerable.
 ...
PMID:Molecular phenotype of the np 7472 deafness-associated mitochondrial mutation in osteosarcoma cell cybrids. 1054 8

Interactions between the checkpoint abrogator UCN-01 and several pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK pathway have been examined in a variety of human leukemia cell lines. Exposure of U937 monocytic leukemia cells to a marginally toxic concentration of UCN-01 (e.g., 150 nM) for 18 h resulted in phosphorylation/activation of p42/44 MAPK. Coadministration of the MEK inhibitor PD184352 (10 microM) blocked UCN-01-induced MAPK activation and was accompanied by marked mitochondrial damage (e.g., cytochrome c release and loss of DeltaPsi(m)), caspase activation, DNA fragmentation, and apoptosis. Similar interactions were noted in the case of other MEK inhibitors (e.g., PD98059; U0126) as well as in multiple other leukemia cell types (e.g., HL-60, Jurkat, CCRF-CEM, and Raji). Coadministration of PD184352 and UCN-01 resulted in reduced binding of the cdc25C phosphatase to 14-3-3 proteins, enhanced dephosphorylation/activation of p34(cdc2), and diminished phosphorylation of cyclic AMP-responsive element binding protein. The ability of UCN-01, when combined with PD184352, to antagonize cdc25C/14-3-3 protein binding, promote dephosphorylation of p34(cdc2), and potentiate apoptosis was mimicked by the ataxia telangectasia mutation inhibitor caffeine. In contrast, cotreatment of cells with UCN-01 and PD184352 did not substantially increase c-Jun-NH(2)-terminal kinase activation nor did it alter expression of Bcl-2, Bcl-x(L), Bax, or X-inhibitor of apoptosis. However, coexposure of U937 cells to UCN-01 and PD184352 induced a marked increase in p38 MAPK activation. Moreover, SB203580, which inhibits multiple kinases including p38 MAPK, partially antagonized cell death. Lastly, although UCN-01 +/- PD184352 did not induce p21(CIP1), stable expression of a p21(CIP1) antisense construct significantly increased susceptibility to this drug combination. Together, these findings indicate that exposure of leukemic cells to UCN-01 leads to activation of the MAPK cascade and that interruption of this process by MEK inhibition triggers perturbations in several signaling and cell cycle regulatory pathways that culminate in mitochondrial injury, caspase activation, and apoptosis. They also raise the possibility that disrupting multiple signaling pathways, e.g., by combining UCN-01 with MEK inhibitors, may represent a novel antileukemic strategy.
 ...
PMID:Pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) kinase/MAPK cascade interact synergistically with UCN-01 to induce mitochondrial dysfunction and apoptosis in human leukemia cells. 1143 48

Camptothecin (CPT) that targets DNA topoisomerase I is one of the most promising broad-spectrum anticancer drugs in development today. The cytotoxicity of CPT is S phase (S)-specific because the collision of advancing replication forks with CPT-topoisomerase I-DNA complexes results in DNA damage. After DNA damage, proliferating cells could actively slow down the DNA replication through an S checkpoint to provide time for repair. We report now that there is an activated S checkpoint response in CPT-treated mammalian cells. This response is regulated by Ataxia and Rad3-related (ATR)/CHK1 pathway. Compared with their wild-type counterparts, CPT-treated Ku80-/- cells showed stronger inhibition of DNA replication. This stronger inhibition had no relationship with DNA-dependent protein kinase (DNA-PK) activity but correlated with the higher activities of ATR and the higher activities of CHK1 in such cells. Not only caffeine, the nonspecific inhibitor of ATR, or UCN-01, the nonspecific inhibitor of CHK1, but also the specific CHK1 antisense oligonucleotide abolished the stronger inhibition of DNA replication in CPT-treated Ku80-/- cells. These results in aggregate indicated that the stronger S checkpoint in CPT-treated Ku80-/- cells is regulated through the highly activated ATR/CHK1 pathway.
 ...
PMID:Ku affects the ataxia and Rad 3-related/CHK1-dependent S phase checkpoint response after camptothecin treatment. 1198 Jun 37

We describe a young woman with a progressive mitochondrial myopathy that started with muscle weakness and went on to include deafness, dementia and ataxia. Skeletal muscle showed the histological and biochemical features of mitochondrial respiratory chain dysfunction. Genetic analysis identified a novel, heteroplasmic, A to G transition in tRNA(Ser(UCN)) at position 7480 affecting a highly conserved base in the anticodon loop. Single-fibre PCR showed highest levels of mutation in cytochrome c-oxidase-deficient fibres and quantification in two biopsies taken 5 years apart showed no change in percentage heteroplasmy. The mutation was present at lower levels in the patient's blood, but was not found in either her mother's or sister's blood and skeletal muscle, suggesting a sporadic occurrence. This is the eighth disease-causing mutation in this tRNA gene and confirms serine (UCN) as one of the most common sites for mtDNA mutation.
 ...
PMID:Sporadic mitochondrial myopathy due to a new mutation in the mitochondrial tRNASer(UCN) gene. 1521 Jan 64


1 2 Next >>