Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029089 (ophthalmoplegia)
 3,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in mitochondrial genes encoded by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes have been implicated in a wide range of neuromuscular diseases. MtDNA base substitution and rearrangement mutations generally inactivate one or more tRNA or rRNA genes and can cause myopathy, cardiomyopathy, cataracts, growth retardation, diabetes, etc. nDNA mutations can cause Leigh syndrome, cardiomyopathy, and nephropathy, due to defects in oxidative phosphorylation (OXPHOS) enzyme complexes; cartilage-hair hypoplasia (CHH) and mtDNA depletion syndrome, through defects in mitochondrial nucleic acid metabolism; and ophthalmoplegia with multiple mtDNA deletions, caused by adenine nucleotide translocator-1 (ANT1) mutations. Mouse models have been prepared that recapitulate a number of these diseases. The mtDNA 16S rRNA chloramphenicol (CAP) resistance mutation was introduced into the mouse female germline and caused cataracts and rod and cone abnormalities in chimeras and neonatal lethal myopathy and cardiomyopathy in mutant animals. A mtDNA deletion was introduced into the mouse germline and caused myopathy, cardiomyopathy, and nephropathy. Conditional inactivation of the nDNA mitochondrial transcription factor (Tfam) gene in the heart resulted in neonatal lethal cardiomyopathy, while its inactivation in the pancreatic beta-cells caused diabetes. The ATP/ADP ratio was implicated in mitochondrial diabetes through transgenic modification of the beta-cell ATP-sensitive K(+) channel (K(ATP)). Mutational inactivation of the mouse Ant1 gene resulted in myopathy, cardiomyopathy, and multiple mtDNA deletions in association with elevated reactive oxygen species (ROS) production. Inactivation of uncoupler proteins (Ucp) 1-3 revealed that mitochondrial Delta Psi regulated ROS production. The role of mitochondrial ROS toxicity in disease and aging was confirmed by inactivating glutathione peroxidase (GPx1), resulting in growth retardation, and by total and partial inactivation of Mn superoxide dismutase (MnSOD; Sod2), resulting in neonatal lethal dilated cardiomyopathy and accelerated apoptosis in aging, respectively. The importance of mitochondrial ROS in degenerative diseases and aging was confirmed by treating Sod2 -/- mice and C. elegans with catalytic antioxidant drugs.
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PMID:Mouse models for mitochondrial disease. 1157 27

To determine the relationship between myoglobin (Mb) and the defense system against reactive oxygen species in various myopathies, we performed immunohistochemical analyses of Mb and various antioxidant enzymes, including manganese superoxide dismutase (Mn-SOD), copper zinc SOD (CuZn-SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Biopsied muscle specimens were obtained from patients with chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), Duchenne muscular dystrophy (DMD), and polymyositis (PM). In patients with CPEO/KSS, stainings of Mb, SOD, CAT, and GSH-Px in nonatrophic ragged-red fibers (RRFs) were more intense than those in non-RRFs. These pronounced stainings corresponded to ragged-red lesions. The staining intensities of these antioxidant enzymes were significantly correlated with that of Mb (P < 0.001). Atrophic RRFs in specimens from patients with CPEO/KSS showed intense stainings of these antioxidant enzymes but not intense staining of Mb. In specimens from patients with DMD/PM, the antioxidant enzymes but not Mb were overexpressed in degenerative fibers. These results suggest that oxidative stress is associated with Mb expression specifically in mitochondrial diseases. The antioxidant enzymes seem to be upregulated to protect against muscle damage in nonatrophic RRFs. However, the Mb-mediated oxidative damage may become more extensive and result in further mitochondrial dysfunction and progressive atrophy of RRF with impaired upregulation of Mb.
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PMID:Overexpressions of myoglobin and antioxidant enzymes in ragged-red fibers of skeletal muscle from patients with mitochondrial encephalomyopathy. 1450 21

Alterations in the expression of free radical scavenging enzymes and production of reactive oxygen species (ROS) in tissue cells may contribute to the pathogenesis of mitochondrial diseases such as chronic progressive external ophthalmoplegia (CPEO) syndrome. Since the mitochondria with impaired respiratory function in affected tissues generate more ROS via electron leakage, we examined the expression levels of free radical scavenging enzymes in primary culture of muscle fibroblasts of eight patients with CPEO syndrome. The results showed that the enzyme activity and protein levels of Mn-SOD of the fibroblasts from CPEO patients were significantly increased but those of Cu,Zn-SOD, catalase and glutathione peroxidase (GPx) were not increased compared with controls. A similar pattern was observed in the mRNA levels of Mn-SOD and GPx in muscle fibroblasts of all CPEO patients. The activity ratios of Mn-SOD/catalase and Mn-SOD/GPx in muscle fibroblasts of the CPEO patients were increased 1.7-3.4 and 1.8- to 5.3-fold, respectively, compared to those of the controls. Moreover, by using flow cytometry we found that the production of O2(*-) and H2O2 in the fibroblasts was about 2 times higher than those of controls. The 8-OHdG/dG ratios in total DNA of muscle biopsies from three CPEO patients were much higher than those of age-matched controls as determined by high performance liquid chromatography (HPLC). In the light of these findings, we suggest that the increase in expression of Mn-SOD, ROS production and oxidative damage in affected tissues may play an important role in the pathogenesis and progression of the CPEO syndrome.
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PMID:Increased expression of manganese-superoxide dismutase in fibroblasts of patients with CPEO syndrome. 1468 Sep 79