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)

Although antiviral nucleoside analog therapy successfully delays progression of HIV infection to AIDS, these drugs cause unwelcome side-effects by inducing mitochondrial toxicity. We and others have demonstrated that the mitochondrial polymerase, DNA polymerase gamma (pol gamma), participates in mitochondrial toxicity by incorporating these chain-terminating antiviral nucleotide analogs into DNA. Here, we explore the role of three highly conserved amino acid residues in the active site of human pol gamma that modulate selection of nucleotide analogs as substrates for incorporation. Sequence alignments, crystal structures and mutagenesis studies of family A DNA polymerases led us to change Tyr951 and Tyr955 in polymerase motif B to Phe and Ala, and Glu895 in polymerase motif A was changed to Ala. The mutant polymerases were tested for their ability to incorporate natural nucleotides and the five antiviral nucleoside analogs currently approved for antiviral therapy: AZT, ddC, D4T, 3TC and carbovir. Steady-state kinetic analysis of the pol gamma derivatives with the normal and antiviral nucleotides demonstrated that Tyr951 is largely responsible for the ability of pol gamma to incorporate dideoxynucleotides and D4T-MP. Mutation of Tyr951 to Phe renders the enzyme resistant to dideoxynucleotides and D4T-TP without compromising the activity of the polymerase. Alteration of Glu895 and Tyr955 to Ala had the largest effect on overall polymerase activity with normal nucleotides, producing dramatic increases in K(m(dNTP)) and large decreases in k(cat). Mutation of Tyr955 in pol gamma causes the degenerative disease progressive external ophthalmoplegia in humans, and we show that this residue partially accounts for the ability of pol gamma to incorporate D4T-MP and carbovir. Alteration of Glu895 to Ala slightly increased discrimination against dideoxynucleotides and D4T-TP. The mechanisms by which pol gamma selects certain nucleotide analogs are discussed.
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PMID:Structural determinants in human DNA polymerase gamma account for mitochondrial toxicity from nucleoside analogs. 1274 17

Collier's sign is well known as unilateral or bilateral eyelid retraction due to midbrain lesions. This sign is usually caused by infarction, tumor, multiple sclerosis, neuro-degenerative disease, or encephalitis. We report a case of Miller Fisher syndrome (MFS) which demonstrated Collier's sign. A 54-year-old man developed ophthalmoplegia, ataxia, and areflexia two weeks after common cold-like symptoms. At the same time, bilateral upper eyelid retraction (Collier's sign) was remarkably observed. Serum anti-GQ1b antibody was positive. Albumino-cytologic dissociation was seen at two weeks after onset. We treated him with high dose intravenous immunogloblins (IVIg) for five days. There was remarkable improvement after the administration of IVIg, and there was a complete recovery from his eyelid retraction. All his symptoms of MFS also disappeared. The eyelid retraction of Collier's sign has been reported to occur with lesions in the rostral midbrain and posterior commissure. Therefore, Collier's sign in this patient suggested central nervous system involvement in the MFS. To our knowledge, this is the first report of MFS associated with Collier's sign.
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PMID:[Collier's sign in Miller Fisher syndrome]. 1732 81

Mitochondrial function degenerates with ageing and in ageing-related neuromuscular degenerative diseases, causing physiological decline of the cell. Factors that can delay the degenerative process are actively sought after. Here, we show that reduced cytosolic protein synthesis is a robust cellular strategy that suppresses ageing-related mitochondrial degeneration. We modelled autosomal dominant progressive external ophthalmoplegia (adPEO), an adult- or later-onset degenerative disease, by introducing the A128P mutation into the adenine nucleotide translocase Aac2p of Saccharomyces cerevisiae. The aac2(A128P) allele dominantly induces ageing-dependent mitochondrial degeneration and phenotypically tractable degenerative cell death, independently of its ADP/ATP exchange activity. Mitochondrial degeneration was suppressed by lifespan-extending nutritional interventions and by eight longevity mutations, which are all known to reduce cytosolic protein synthesis. These longevity interventions also independently suppressed ageing-related mitochondrial degeneration in the pro-ageing prohibitin mutants. The aac2(A128P) mutant has reduced mitochondrial membrane potential (delta psi(m)) and is synthetically lethal to low delta psi(m) conditions, including the loss of prohibitin. Mitochondrial degeneration was accelerated by defects in protein turnover on the inner membrane and was suppressed by cycloheximide, a specific inhibitor of cytosolic ribosomes. Reduced cytosolic protein synthesis suppressed membrane depolarization and defects in mitochondrial gene expression in aac(A128P) cells. Our finding thus establishes a link between protein homeostasis (proteostasis), cellular bioenergetics and mitochondrial maintenance during ageing.
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PMID:Reduced cytosolic protein synthesis suppresses mitochondrial degeneration. 1916 Apr 90

IOSCA is a difficult, progressive degenerative disease causing damage to the peripheral and central nervous system. All known 24 patients are Finnish. Initial symptoms include ataxia, athetosis, ophthalmoplegia, hearing disability and muscular hypotonia. Sensory axonal neuropathy and associated optic atrophy are typical of the disease, as well as primary hypergonadotropic hypogonadism in girls. The patients are progressively severely disabled from the age of approx. eighteen months. The pathogenesis is unknown and there is no curative treatment for the disease.
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PMID:[IOSCA - Infantile onset spinocerebellar ataxia]. 2188 47