Mitochondrial 'bottleneck' cracked - New hope for disease prediction

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Mitochondrial 'bottleneck' cracked - New hope for disease prediction

http://medicalnewscenter.com/recent/eurekalert-medical-news.shtml

Scientists have shown for the first time how a particular family of

diseases are passed down from mother to child and how this can lead

to the severity of the disease differing widely. The research, funded

by the Wellcome Trust, offers hope of being able to predict a child's

risk of developing a mitochondrial disease which can cause muscle

weakness, diabetes, strokes, heart failure and epilepsy.

All human and animal cells contain many mitochondria, which are

involved in energy production within the body. Mitochondria have

their own genetic information, known as mitochondrial DNA, or mtDNA,

which is inherited. However, whereas a child inherits one copy of DNA

from each parent, a child may inherit many copies of mtDNA, which are

only passed down from the mother.

Mutations in mtDNA can affect energy production within cells and

therefore lead to disease. However, mitochondrial diseases differ

both in location and severity depending on where and at what levels

the mutations are distributed. Defective mitochondria cause most

damage in muscles, nerves and the brain, the parts of the body which

consume the most energy.

" Inheritance of mitochondrial diseases within families has proved

incredibly difficult to predict, " says Professor Chinnery, a

Wellcome Trust Senior Clinical Research Fellow at Newcastle

University. " A mother can pass on a small proportion of mutant mtDNA,

or a very high proportion, and this can make the difference between a

child being born without disease and another having a very severe

form of the disease. "

A woman's eggs are formed at a very early stage in her development.

As a precursor cell divides into a number of eggs, so the

mitochondria from that cell are distributed randomly throughout these

eggs. Hence different eggs can contain very different amounts of

mutant mtDNA, which determine the amount of mutant genetic material

that is passed on to the next generation. This difference is thought

to explain the variation in the severity of the disease between

siblings however the mechanism responsible for this variation was not

understood for many years.

Now this research has proven that there is a " mitochondrial genetic

bottleneck " , where only a small number of mtDNA molecules in the

mother are passed on to the next generation.

" In essence, it's a game of chance, " explains Professor Chinnery. " If

you have a mixture of red and white balls and pick handfuls at

random, then some of those handfuls will contain very few red balls

and other very few white ones. We have shown this is the reason for

the different amounts of mutant mtDNA in different eggs. "

Now, in research published online today in the journal Nature

Genetics, Professor Chinnery and an international team of

collaborators have shown in mice that this bottleneck does in fact

exist and causes the dramatic reduction in the number of mtDNA

molecules in the cells that eventually form the eggs. This leads to

the wide variation in the severity of disease. Depending on which egg

is fertilised, a high proportion of abnormal mitochondria may be

passed on to the child. In this case, the child will be more severely

affected than the mother.

Whilst once considered rare, mitochondrial diseases are now thought

to affect as many as one person in 5,000. However, even when the

precise proportion of abnormal mtDNA carried by the mother is known,

scientists have been unable to predict whether and how a child will

be affected. Professor Chinnery hopes that this new research will

open up opportunities for predicting disease risk.

" With conventional genetics, we're able to say, for example, that if

you carry a certain gene, your child has a one in ten chance of

developing a particular disease, " he says. " Now that we understand

how different levels of abnormal mtDNA are inherited, we may soon be

able to predict a child's risk of disease and the level of severity. "

[Guest guest]

Wow - now this is interesting, and important! Thanks Gretchen.