15 October 2012

The mechanism of inheritance of mitochondrial diseases has been deciphered

Genetic information about a living organism is mainly contained in the nucleus in the form of DNA. However, the energy centers of the cell – mitochondria – are also carriers of their own genetic information encrypted in the so-called mitochondrial DNA (mtDNA). Mutations of mtDNA can lead to malfunctions of these organelles, manifested by muscle weakness, neurodegenerative diseases, heart disease and diabetes. They are also involved in the aging process.

Mutant genes, and, accordingly, diseases can be transmitted to the next generations, however, in this case, only the maternal mtDNA is inherited. mtDNA inheritance does not obey the classical laws of Mendelian genetics, and until now experts have not been able to reach consensus on the mechanisms underlying this process.

A new mouse model developed by Christoph Freyer from the Institute of Aging Biology. Max Planck (Cologne), together with an international group of researchers, allowed us to partially get an answer to this question. It turned out that intrafamilial variations in the relative number of mutated mtDNAs are determined even before the human mother is born.

A key component of the model is a pathogenic, that is, a mutation in the mitochondrial gene known as "tRNA methionine", which is the cause of the development of the disease. Genes encoding transport RNAs make up only a fraction of the total number of mtDNAs, but their mutations underlie most of the known mitochondrial diseases. This contradiction has never had a satisfactory explanation.

Using the gene encoding tRNA methionine, Freyer analyzed the mutation level – the ratio of mutant and normal copies of the gene – at three different phases of the reproductive process. First, he studied the germ cells of mouse embryos and found that the mutation level varies from cell to cell. After the birth of the mice, he analyzed the mutation levels in the immature eggs of the females. Subsequently, these data were compared with the levels of mutations in the mtDNA of their children.

The main result of the work was the demonstration of the fact that, unlike genes encoding proteins, which, according to recently obtained data, are subject to prenatal selection, tRNA genes in female germ cells do not undergo selection. Therefore, whether mutant genes will be passed on to the next generation, and if so, in what quantity, is determined at the stage of embryonic development of the future mother, during the formation of her eggs.

Mutant genes often coexist with normal ones in affected eggs. This condition is called heteroplasmia. In other words, each egg contains normal and mutant genes in a certain ratio. Therefore, the mutation may or may not be transmitted to the next generation. This mechanism also explains intra-family differences.

The results obtained can form the basis of new methods of genetic diagnosis. In the future, Freyer plans to use his mouse model to test the effectiveness of treatments that could potentially prevent the transmission of mtDNA mutations to the next generations.

Article by Christoph Freyer et al. Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission is published in the journal Nature Genetics.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Max Planck Institute for Biology of Aging:
Whether mitochondrial diseases will be inherited is largely decided when the mother herself is still an embryo.


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