The “faulty gatekeeper” that causes increased miscarriage and birth defects

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It is well known that the risk of miscarriage and the risk of having a baby with chromosomal abnormalities increases significantly with maternal age. This age-related decrease in fertility and increase in miscarriage is almost all caused by problems in the oocyte (also known as an egg cell).

Monash researchers have, for the first time, discovered that eggs from older mothers can bypass the gatekeeper that normally prevents the final development of eggs that have damage in their DNA. The data, published today in the prestigious journal Nature Communications, means that scientists may be able to develop new approaches to prevent the DNA errors occurring in older mothers, reducing the number of miscarriages and births of babies with chromosomal problems.

One of the lead researchers, Professor John Carroll, Director of Monash’s new Biomedicine Discovery Institute said “More Australian women over 40 are having babies than ever before with a record 12,800 babies born to women over 40 in 2011, compared to just over 7000 in 2001.”

The research is a collaboration between scientists at Monash University, University College London and the University of Ionnina in Greece. Petros Marangos and John Carroll have been studying reproduction in animal models at an age equivalent to women in their late 30s and early 40s. The researchers have shown that eggs from older models fail to arrest development when there is chromosomal damage. These damaged eggs may then be able to undergo fertilisation, which would result in embryos with increased risk of miscarriage or offspring with chromosomal abnormalities. In younger models, there is a more robust gatekeeping mechanism that recognises eggs that are “faulty”, stopping their development and preventing normal fertilisation.

It is known that older oocytes, or egg cells, have a number of problems including a decrease in the amount of a protein called Rec8. Rec8 is responsible for holding chromosomes together for the lifespan of the egg and is therefore necessary for the normal separation of chromosomes when the egg-cells divide. Mistakes in this process can create chromosomal abnormalities like Down’s syndrome. The work by Professors Carroll and Marangos and their teams have revealed the actual point in older eggs when these chromosomes segregate – called the spindle assembly checkpoint – that is the tipping point for when damaged eggs go on to be fertilised, or not.

“In the eggs of younger models, and likely younger women, this is the actual point when DNA damage causes the egg to arrest its development,” Professor Marangos said.

“In older models, and women, the process isn’t as stringent and more damaged eggs get through the gatekeeper and may go on to be fertilised,” he added.

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According to Professor Carroll, the discovery of the exact time when damaged eggs “slip through the gatekeeper” in older women opens the way to develop mechanisms that can prevent damaged eggs being fertilised, raising the likelihood of more viable eggs going on to be fertilised.

(Source: Monash University, Nature Communications)

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Date Created: December 3, 2015