Maternal inheritance, mtDNA

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. 

Myoclonic epilepsy with ragged-red fibers (MERPF) is a rare syndrome which shows clear maternal inheritance and a variable clinical pattern including progressive myoclonus, cerebellar ataxia, dementia, and muscle weakness. It is associated with an A-to-G transition at position 8344 of the tRNA Lys gene in the mtDNA. The mutation is heteroplasmic and produces similar multicomplex deficiencies as are seen in KSS. 

In the formation of the zygote, all mitochondria are contributed by the ovum. Therefore, mtDNA is transmitted by maternal inheritance in a vertical, nonmendelian fashion. Strictly maternal transmission of mtDNA has been documented in humans by studies of restriction fragment length polymorphisms (RFLPs) in DNA from platelets. As exemplified by the disorders outlined above,... 

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. 

Transmission by Maternal Inheritance and Random Segregation of mtDNA during... 

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). 

In mammals, mtDNA is maternally inherited this is probably a result of the egg cell contributing much more cytoplasm to the zygote than to the sperm. 

Caused by a 5000 base deletion in mtDNA. It is not maternally inherited but rather occurs sporadically. Starts before the age of 20. 

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. ... 

The mtDNA is transmitted through the oocyte cytoplasm and is maternally inherited. 

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. 

The 16.6 kb human mtDNA codes for two ribo-somal ribonucleic acids, 22 transfer ribonucleic acids and 13 peptides, which are part of enzyme complexes of the respiratory chain in the inner mitochondrial membrane (Capaldi, 1988). Mitochondria are largely, but not entirely, maternally inherited (Gyllensten et al., 1991). They proliferate... 

Deficiencies of electron transport In cells, complete transfer of electrons from NADH and FAD(2H) through the chain to O2 is necessary for ATP generation. Impaired transfer through any complex can have pathologic consequences. Fatigue can result from iron-defeciency anemia, which decreases Fe for Fe-S centers and cytochromes Cytochrome Cj oxidase, which contains the O2 binding site, is inhibited by cyanide Mitochondrial DNA (mtDNA), which is maternally inherited, encodes some of the subunits of the electron transport chain complexes and ATP synthase. Oxphos diseases are caused by mutations in nuclear DNA or mtDNA that decrease mitochondrial capacity for oxidative phosphorylation. 

The genetics of mutations in mtDNA are defined by maternal inheritance, replicative segregation, threshold expression, a high mtDNA mutation rate, and the accumulation of somatic mutations with age. The maternal inheritance pattern reflects the exclusive transmission of mtDNA from the mother to her children. The egg contains approximately 300,000 molecules of mtDNA packaged into mitochondria. These are... 

Nuclear DNA mutations differ from mtDNA mutations in several important respects. These mutations do not show a pattern of maternal inheritance but are usually autosomal recessive. The mutations are uniformly distributed to daughter cells and therefore are expressed in all tissues containing the allele for a particular tissue-specific isoform. However, phenotypic expression still will be most apparent in tissues with high ATP requirements. 

There are several disorders of the respiratory chain. Many are transmitted by maternal inheritance as generally aU mitochondria in the ovum are of maternal origin. The thousands of mtDNA molecules in one cell are distributed randomly to the daughter cells, therefore different tissues may harbour a mixture of both normal and mutant mtDNA (heteroplasmy). Accordingly the clinical phenotype is highly variable. Mutations in nuclear genes encoding proteins for the respiratory chain are transmitted autosomally and usually cause a more severe disease. 

Unlike other cellular organelles, mitochondria have their own DNA. The human mitochondrial DNA (mtDNA), maternally transmitted, encodes 13 subunits of the respiratory chain enzyme complexes I, III, IV and complex V. In addition to structural genes, mtDNA also codes for 22 transfer RNAs and 2 ribosomal RNAs. This makes the oxidative phosphorylation system, which includes the respiratory chain (complexes I-IV) and complex V, unique as the different components are encoded by nuclear DNA (Mende-lian inheritence) and mtDNA (maternal inheritence) with the exception of complex II, which is entirely nuclear encoded. 

An important feamre of human mitochondrial mtDNA is that—because aU mitochondria are contributed by the ovum during zygote formation—it is transmitted by maternal nonmendefian inheritance. 

Mitochondrial DNA is inherited maternally. What makes mitochondrial diseases particularly interesting from a genetic point of view is that the mitochondrion has its own DNA (mtDNA) and its own transcription and translation processes. The mtDNA encodes only 13 polypeptides nuclear DNA (nDNA) controls the synthesis of 90-95% of all mitochondrial proteins. All known mito-chondrially encoded polypeptides are located in the inner mitochondrial membrane as subunits of the respiratory chain complexes (Fig. 42-3), including seven subunits of complex I the apoprotein of cytochrome b the three larger subunits of cytochrome c oxidase, also termed complex IV and two subunits of ATPase, also termed complex V. 

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... 

Mitochondrial DNA (mtDNA), which is clonally inherited through maternal lineages, has proved to be a powerful genetic marker for phyloge-... 

Mitochondrial DNA (mtDNA) Modern genetic material taken from the mitochondria, inherited only through the maternal line. 

Because most mtDNA is Inherited from egg cells rather than sperm, mutations in mtDNA exhibit a maternal cytoplasmic pattern of inheritance. 

In these situations, one approach has been to perform further testing using mtDNA sequencing. Since there are multiple copies of mitochondrion in each cell, the likelihood of obtaining a result is greatly increased when compared to nuclear DNA. However, mtDNA analysis involves difficult and expensive analytical procedures, and because it is inherited solely through the female fine, maternally related individuals will all have the same profile and statistical results are much less conclusive. 

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