Maternal inheritance, mitochondrial

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. 

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). 

Very weak patterns of family substmcturing have been observed in jack pine stands (Cheliak et al, 1985 Xie and Knowles, 1991 Saenz-Romero et al, 2001). Dong and Wagner (1994) found that maternally inherited mitochondrial DNA showed higher levels of population subdivision than paternally inherited cWoroplast DNA. No differences in isozyme variation were detected between natural and plantation stands (Knowles, 1985). 

Dong, J., and D.B. Wagner. 1994. Paternally inherited chloroplast polymorphism in Pinus Estimation of diversity and population subdivision, and tests of disequilibrium with a maternally inherited mitochondrial polymorphism. Genetics 36 1187-1194. 

WooDWAM), D. O., and Munkres, K. D. (1966). Alterations of a maternally inherited mitochondrial structural protein in respiratory-deficient strains (rf Neurospora. Proc. Natl. Acad. Sci. U.S. 55, 872-880. 

Mitochondria are unique organelles in that they contain their own DNA (mtDNA), which, in addition to ribosomal RN A (rRNA) and transfer RN A (tRNA)-coding sequences, also encodes 13 polypeptides which are components of complexes I, III, IV, and V (Anderson et al., 1981). This fact has important implications for both the genetics and the etiology of the respiratory chain disorders. Since mtDNA is maternally-inherited, a defect of a respiratory complex due to a mtDNA deletion would be expected to show a pattern of maternal transmission. However the situation is complicated by the fact that the majority of the polypeptide subunits of complexes I, III, IV, and V, and all subunits of complex II, are encoded by nuclear DNA. A defect in a nuclear-coded subunit of one of the respiratory complexes would be expected to show classic Mendelian inheritance. A further complication exists in that it is now established that some respiratory chain disorders result from defects of communication between nuclear and mitochondrial genomes (Zeviani et al., 1989). Since many mitochondrial proteins are synthesized in the cytosol and require a sophisticated system of posttranslational processing for transport and assembly, it is apparent that a diversity of genetic errors is to be expected. 

This type of inheritance, also known as maternal inheritance, applies to genes in mitochondrial DNA. Mitochondria, which are structures in each cell that convert molecules into energy, each contain a small amount of DNA. Because only egg cells contribute mitochondria to the developing embryo, only females can pass on mitochondrial conditions to their children. Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children. 

The circular mitochondrial chromosome encodes 13 of the more than 80 proteins that comprise the major complexes of oxidative phosphorylation as well as 22 tRNAs and 2 rRNAs. Mutations in these genes affect highly aerobic tissues (nerves, muscle), and the diseases exhibit characteristic mitochondrial pedigrees (maternal inheritance). 

F. Mitochondrial disorders exhibit a maternal inheritance pattern. 

A mutation in any of the 13 protein subunits, the 22 tRNAs, or the two rRNAs whose genes are carried in mitochondrial DNA may possibly cause disease. The 13 protein subunits are all involved in electron transport or oxidative phosphorylation. The syndromes resulting from mutations in mtDNA frequently affect oxidative phosphorylation (OXPHOS) causing what are often called "OXPHOS diseases."3-6 Mitochondrial oxidative phosphorylation also depends upon 100 proteins encoded in the nucleus. Therefore, OXPHOS diseases may result from defects in either mitochondrial or nuclear genes. The former are distinguished by the fact that they are inherited almost exclusively maternally. Most mitochondrial diseases are rare. However, mtDNA is subject to rapid mutation, and it is possible that accumulating mutants in mtDNA may be an important component of aging.h k... 

Rapid rearrangement of a polymorphic minisatellite within the D-loop/control region of the 5. mansoni mitochondrial genome has also been reported by various authors (Minchella et al., 1994 Bieberich and Minchella, 2001 Jannolti-Passos et al., 2001). These observations are discussed in detail in the section entitled Maternal Inheritance. ... 

Zl. Zeviani, M., Gellera, C., Antozzi, C., Rimoldi, M., Morandi, L., Villani, E, Tiranti, V., and DiDonato, S., Maternally inherited myopathy and mitochondrial myopathy Association with mutation in mitochondrial DNA tRNALeu(UUR). Lancet 338,143-147 (1991). 

LHON is a distinct form of optic atrophy. LHON is a point mutation in the mitochondrial genome.These mutations occur at nucleotide sites 3,460,11,778, and l4,484.These DNA mitochondrial mutations are transmitted with the cytoplasm, making this disease maternally inherited. Environmental epigenetic triggers (smoking, alcohol) have been identified. 

The A1555G mutation in the human mitochondrial 12S RNA, which has been associated with hearing loss after aminoglycoside administration (63) and has been rmph-cated in maternally inherited hearing loss in the absence of aminoglycoside exposure in some families, can be identified by a simple and rapid method for large-scale screening that uses one-step multiplex allele-specific PCR (64). 

Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disease and the first linked to maternal inheritance through a mutation in the mtDNA. LHON is characterized by bilateral subacute loss of central vision caused by focal degeneration of the retinal ganglion cell layer and of the optic nerve. After initial symptoms, both eyes are usually affected within 6 months. Approximately 50% to 60% of males and only 8% to 32% of females who possess the mtDNA mutation will actually develop this optic neuropathy. Nuclear-encoded factors that affect mtDNA expression, mtDNA products, or mitochondrial metabolism may modify the phenotypic expression of LHON. Genetic coimseling in LHON is complicated in that the amount of mutant mtDNA transmitted by heteroplasmic females cannot be predicted, and testing cannot predict which individuals will develop visual symptoms. ... 

Fourteen mtDNA tRNA mutations have been associated with maternally inherited disease. Such mutations are typically associated with severe mitochondrial myopathies, characterized by ragged red skeletal muscle fibers upon Gomori trichrome staining and the accumulation of structurally abnormal mitochondria in muscle. Mutations in tRNAs exemplify the threshold effect whereby (due to replicative segragation) individuals may not exhibit clinical signs until the proportion of mutant mtDNA exceeds 80-90%. Myoclonic epilepsy and ragged red fiber (MERRF) disease, mitochondrial encephalomyo-pathy tactic acidosis (MELAS), as well as maternally inherited myopathy and cardiomyopathy (MMC) are well-characterized mitochondrial diseases. 

A human egg harbors several hundred thousand molecules of mitochondrial DNA, whereas a sperm contributes only a few hundred and thus has little effect on the mitochondrial genotype. Because the maternally inherited mitochondria are present in large numbers and not all of the mitochondria may be affected, the pathologies of mitochondrial mutants can be quite complex. Even within a single family carrying an identical mutation, chance fluctuations in the percentage of mitochondria with the mutation lead to large... 

Mt5178A is not the only mitochondrial variant to be linked with ageing and disease in people. Several others have been identified, although their effects are less pervasive. We get a sense of their overall importance from a looser relationship the maternal inheritance of longevity. Mitochondria, as we have seen, are only passed on in the egg, so all 13 mitochondrial genes come from our mothers. If these genes really do influence lifespan, and we can only inherit them from our mothers, then our own... 

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