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Mitochondrial DNA depletion syndrome
Mitochondrial DNA depletion syndrome (MDS) refers to a group of autosomal recessive disorders which cause the affected tissues to suffer from a significant drop in mitochondrial DNA. Symptoms may manifest as myopathic, hepatopathic, and/or encephalomyopathic.〔(Elpeleg, Orly. Inherited Mitochondrial DNA Depletion. Pediatric Research (2003) 54, 153–159)〕 These syndromes affect tissue found in the muscle, liver, or both the muscle and brain, respectively. The condition is typically fatal in infancy and early childhood, though some have survived to their teenage years with the myopathic variant and some have survived into adulthood with the SUCLA2 encephalimyopathic variant 〔Tritschler, H.-J. Mitochondrial myopathy of childhood associated with depletion of mitochondrial DNA. Neurology Volume 42, Issue 1, January 1992, Pages 209-217〕 There is currently no curative treatment for any form of MDSs, though some preliminary treatments have shown a reduction in symptoms.〔Saito, K. Pyruvate therapy for mitochondrial DNA depletion syndrome. Biochimica et Biophysica Acta (BBA) - General Subjects Volume 1820, Issue 5, May 2012, Pages 632–636〕
==Causes==
The myopathic form of MDS manifests symptoms within the first year of life, and is diagnosed by higher levels of serum creatine kinase, which is atypical in other mitochondrial myopathies.〔Moraes, C.T. mtDNA depletion with variable tissue expression: A novel genetic abnormality in mitochondrial diseases. American Journal of Human Genetics Volume 48, Issue 3, March 1991, Pages 492-501〕 Myopathic MDSs is strongly correlated to a variety of mutations in the gene TK2, seeing a reduction of TK2 activity to less than 32% in MDS patients found with the mutation. Because TK2 plays a key role in the mitochondrial salvage pathways of several deoxyribonucleoside triphosphates (dNTPs), a lowered activity would lead to less cycling of nucleotides. This lack of nucleotide recycling is detrimental since the mitochondria cannot synthesize entirely new deoxynucleotides, and the inner membrane of the mitochondria prevents the negatively charged nucleotides of the cytosol from entering.〔Saada, A. Deoxyribonucleotides and disorders of mitochondrial DNA integrity. DNA and Cell Biology Volume 23, Issue 12, December 2004, Pages 797-806〕
The encephalomyopathic form of MDS is commonly characterized by psychomotor retardation, muscle hypotonia, hearing impairment, and generalized seizures. A common mutation in this form of MDSs involves a mutation in the SUCLA2 gene, which codes for the beta-subunit of SCS-A. This enzyme catalyzes the synthesis of succinate and coenzyme A into succinyl-CoA, but is also associated with the complex formed by nucleoside diphosphate kinase (NDPK) in the last step of the dNTP salvage pathway.〔Elpeleg, Orly. Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. The American Journal of Human Genetics, Volume 76, Issue 6, 2005, Pages 1081–1086〕 Other encephalomyopathic forms of MDS have been associated with mutations in the RRM2B gene.〔El-Hattab and Scaglia, 2013 Apr; 10(2): 186–198. Published online 2013 Feb 6. doi: 10.1007/s13311-013-0177-6〕
The hepatopathic form of MDS involves the onset of symptoms including hypotonia, hypoglycemia, persistent vomiting, and failure to thrive within the first year of life.〔Mazziotta, M.R.M. Fatal infantile liver failure associated with mitochondrial DNA depletion. The Journal of Pediatrics Volume 121, Issue 6, December 1992, Pages 896–901〕 Mutations in three genes have been linked to hepatopathic MDS: DGUOK, POLG, and MPV17. DGUOK encodes for mitochondrial deoxyguanosine kinase (dGK), which catalyzes the phosphorylation of deoxyribonucleosides into nucleotides.〔Wang, L. Molecular insight into mitochondrial DNA depletion syndrome in two patients with novel mutations in the deoxyguanosine kinase and thymidine kinase 2 genes. Molecular Genetics and Metabolism Volume 84, Issue 1, January 2005, Pages 75–82〕 POLG encodes for the catalytic subunit pol γA, which is part of mitochondrial DNA polymerase.〔Van Goethem, G. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nature Genetics Volume 28, Issue 3, 2001, Pages 211-212〕
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