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VBI Study Finds Mitochondrial Mutations More Common Than Expected

NEW YORK (GenomeWeb News) – Mutations in mitochondrial DNA are more common in the general population than previously imagined, according to new research.
In a paper appearing in the latest issue of the American Journal of Human Genetics, researchers from the UK and the US looked at the prevalence of ten potentially pathogenic mitochondrial mutations in some three thousand British babies. Their work revealed a larger than anticipated pool of mitochondrial mutations — at least one in every 200 European infants tested carried disease-linked mutations. Now, researchers say, more needs to be done to understand and prevent the transmission of mitochondrial disease.
Mitochondrial diseases, caused by mutations in mitochondrial DNA, can lead to muscle weakness, diabetes, heart disease, stroke, or epilepsy. The symptoms and severity of these diseases vary widely from one individual to the next. Even individuals from the same family, who presumably share mutations, can have different forms of the disease. In addition, the amount of mutated mitochondrial DNA can differ from one cell to the next.
“There’s a lot of variation in how these diseases show up,” co-author David Samuels, a researcher at Virginia Tech’s Virginia Bioinformatics Institute, told GenomeWeb Daily News.
Based on epidemiology and pedigree analyses, researchers previously estimated that roughly one in every 5,000 people has mitochondrial disease. However, this is likely an under-estimate, Samuels explained, because the diseases can manifest themselves in so many different ways and the link to mitochondria may not be detected.
The difficulty in tracking the inheritance of mitochondrial diseases is exacerbated by the fact that the consequences of certain mutations can change from one generation to the next. For instance, an asymptomatic mother may pass on a mutation that causes clinical disease in her child.
In an effort to understand just how common these mitochondrial mutations are, the researchers looked at the prevalence of pathogenic point mutations in infants from north Cumbria, England. They focused on ten mutations that are most often seen in patients with mitochondrial disease. Newborns were selected for the study mitochondrial mutations are sometimes cleared from the blood of older individuals, Samuels said.
The team analyzed umbilical cord blood samples from 3,168 infants and used Sequenom's MassArray genotyping to look at the frequency of the mutations of interest. They then verified their results with DNA cloning and sequencing.  
The researchers detected only five of the ten mutations that were the focus of the study, but these mutations were much more common than expected. At least one in every 200 infants carried potentially pathogenic mitochondrial mutations. “That surprised me when you consider the [estimated] rate of people with diseases is one in five thousand,” Samuels said. That suggests that an awful lot of people are carrying silent mitochondrial mutations, he added.
The mutation patterns also provided some clues about the nature of mitochondrial changes, Samuels noted. For instance, a mutation called m.14484T to C was only detected amongst individuals who belonged to mitochondrial haplogroup J. Although this needs to be tested further, the finding suggests that mitochondrial haplogroup could influence the formation of pathogenic mitochondrial DNA mutations.
As expected, Samuels said, some, but not all, mothers tested carried the same mutations as their children. Those that didn’t may have lost the mutation from their blood, Samuels said. But it’s also possible that the mutation arose spontaneously in some of the children.
In addition, Samuels said, the likelihood of mutations manifesting themselves as disease depends not only on the particular mutation present, but also the amount of mutated mitochondrial DNA in an individual’s cells. That means more research needs to be done on how mutations are passed from a mother to her child before this research can be applied to genetic counseling.
More research is also needed to understand the nature of mitochondrial mutations in non-European populations, Samuels said. For instance, he said, it’s known that there is generally larger variation in mitochondrial DNA in African populations, which are older than European populations. How that relates to potentially pathogenic mitochondrial mutations, if at all, remains to be seen. “I definitely think that that experiment should be done,” Samuels said.

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