Point mutations, mtDNA

As described above, maternal inheritance has been documented in diseases due to point mutations of mtDNA, while most diseases due to mtDNA deletions or duplications are sporadic. 

Some OXPHOS disorders, including Luft disease, result from mutations in nuclear DNA. A second group arise from point mutations in mtDNA and a third group involve deletions, often very large, in mtDNA. Persons with these deletions survive because they have both mutated and normal mtDNA, a condition of heteroplasmy of mtDNA. As these persons age their disease may become more severe because they lose many normal mitochondria.d,e... 

Point Mutations in Protein-Coding Genes of mtDNA. 94... 

Large-scale deletions, insertions, and tandem duplications of mtDNA are usually not found in blood cells, and the proportions of mtDNA with point mutations in blood cells are generally lower than those in muscle of patients with mitochondrial disease (PI, W5). Thus, the absence of mtDNA mutation in blood samples cannot be used to exclude mitochondrial disease (L7, PI). On the other hand, higher levels of mutant mtDNA are usually found in postmitotic tissues such as cardiac and skeletal muscles and skin tissue of patients. Large-scale deletions or point mutations of mtDNA are generally detectable in muscle biopsies of about 70% of patients with mitochondrial disease (L7, PI). Some of these patients are affected by mutations in nuclear DNA. Other, unknown mutations in mtDNA or nuclear DNA are present in the rest of the patients. 

Although DNA mutations in nuclear DNA may cause mitochondrial dysfunction, the majority of genetically defined mitochondrial diseases are caused by mutations in mtDNA (M15, PI, S4). Point mutations and deletions of mtDNA have been reported to be associated with or responsible for mitochondrial myopathies and/or encephalomyopathies (M15, PI, S4). Patients with such diseases usually manifest major clinical symptoms early in life and at a later stage may develop additional multisystem disorders such as encephalopathy and/or peripheral neuropathy. Most of the mitochondrial myopathies occur sporadically and are often caused by large-scale mtDNA deletions (PI). However, there are several reports on maternally inherited mitochondrial myopathy and familial mitochondrial myopathy. These patients usually harbor a specific mtDNA mutation and often exhibit defects in NADH-CoQ reductase and/or cytochrome c oxidase. 

Point Mutations in rRNA/tRNA Genes of mtDNA Associated with Mitochondrial Diseases 2... 

A number of distinctive syndromes have been shown to be associated with specific point mutations of mtDNA (Table 1) (M15, S4, S14). Several point mutations have been reported to occur at tRNA genes in the mitochondrial genome. For example, the A8344G mutation is present in patients with MERRF syndrome (S9), whereas the A3243G mutation of mtDNA was first identified in a subgroup of patients with MELAS syndrome (G4). MERRF syndrome was the first... 

Although point mutations and large-scale deletions of mtDNA have been established to be closely associated with mitochondrial diseases (C9, LI, L7, Ml5, S4),... 

ATP synthesis in cybrids harboring homoplasmic mtDNA with the T8993G point mutation. 

Cl. Casali, C., Santorelli, F. M., D Amati, G., Bemucci, P., DeBiase, L., and DiMauro, S., A novel mtDNA point mutation in maternally inherited mitochondrial myopathy. Biochem. Biophys. Res. Common. 213, 588-593 (1995). 

M12. Michikawa, Y., Mazzucchelli, F., Bresolin, N., Scarlato, G., and Attardi, G., Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science 286, 774-779 (1999). 

SI 1. Shoubridge, E. A., Johns, T., and Karpati, G., Complete restoration of a wild-type mtDNA genotype in regenerating muscle fibres in a patient with a tRNA point mutation and mitochondrial... 

Til. Trounce, I., Neill, S., and Wallace, D. C., Cytoplasmic transfer of the mtDNA nt 8993 T-G (ATP 6) point mutation associated with Leigh syndrome into mtDNA-less cells demonstrates co-segregation with a decrease in state III respiration and ADP/O ratio. Proc. Natl. Acad. Sci. USA 91, 8334-8338 (1994). 

Molecular analysis of mtDNA from muscle biopsies often provides a definitive diagnosis of MELAS. Individuals with more severe clinical manifestations of MELAS generally have greater than 80% mutant mtDNA in postmitotic tissues such as muscle. In approximately 80% of MELAS cases, the responsible mutation is an A —> G base substitution at nucleotide position 3243. A smaller subset of MELAS patients (7.5%) possesses a different point mutation, aT C transition at nucleotide position 3271. At least eight additional point mutations and one four-base pair deletion mutation also have been described. 

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