CAN WE IDENTIFY MORE GENES WITH LINKS TO MISCARRIAGE?

Around 1 in 4 pregnancies ends in miscarriage, but in many cases a definite cause cannot be found. It’s an all-too-common situation that is heart breaking for parents, and incredibly frustrating for the clinicians involved.

Miscarriage can happen for many reasons, including infection and hormonal imbalances. But around half of all miscarriages that occur before 12 weeks of pregnancy are thought to be caused by a gene mutation or chromosomal abnormality that prevents the baby from developing as it should. One approach to understanding, and potentially preventing, pregnancy loss is to identify gene mutations that have an adverse effect on embryo development. This is an area in which mouse embryo screening programmes such as DMDD and the IMPC can make an important contribution.


EMBRYONIC LETHAL GENES AND MISCARRIAGE

Recurrent miscarriage, the loss of 3 or more consecutive pregnancies, affects around 1% of couples who are trying to conceive. The condition has already been linked to mutations in several genes, including F2, F5 and ANXA5, which are all involved in blood clotting. This suggests that there may be other genes linked to miscarriage that have not yet been discovered.

The DMDD programme studies the effect of inactivating single genes in mouse embryos. For each inactivated gene, we record any abnormalities in the embryo’s development – from brain and heart defects down to tiny problems at the level of individual nerves and blood vessels. Our study is limited to a set of genes called ‘embryonic lethal’. By definition, inactivating any one of these genes causes developmental abnormalities so serious that the embryo is not able to survive past birth. These genes have clear relevance to miscarriage research, and the data we are gathering could be key to understanding more about the genetic causes of pregnancy loss.

 

Click to view larger image.
Detailed imaging of embryos allows us to identify abnormalities down to the level of individual nerves and blood vessels.

CANDIDATE GENES FOR VERY EARLY PREGNANCY LOSS

Around a third of the genes studied by DMDD, if inactivated, cause mouse embryos to die in the very early stages of development. We call these genes ‘early lethal’, and if a mouse embryo is missing any one of them it cannot survive to 9.5 days of gestation. In the mouse, 9.5 days is mid-gestation, but this stage of development is actually comparable with week 4 for a human embryo.

To date we have found more than 60 genes that are lethal in the first 9.5 days of gestation. This data could be a starting point for identifying genes whose mutations might be responsible for miscarriage in the first few weeks of pregnancy.


MISCARRIAGE LATER IN PREGNANCY

DMDD also studies genes that cause mouse embryos to die around 14.5 days of gestation, which is roughly equivalent to week 8 of a human pregnancy. By 14.5 days’ gestation, mouse embryos have grown to around 1cm in length and are big enough for us to look in detail for abnormalities in their development. We see a wide range of problems, but very common abnormalities include abnormalities of the hypoglossal nerve, which controls tongue movement, and a range of different heart defects.

Many of the embryonic lethal genes we have studied at 14.5 days’ gestation have not yet been associated with human disease or miscarriage. The data is available to explore at dmdd.org.uk, and these genes may be interesting candidates for those researching the genetic basis of miscarriage.

THE ZIKA VIRUS AND DMDD

The Zika virus has raised global awareness of birth defects more than at any time in the last 50 years [1]. A recent Nature Editorial explores the opportunities this presents to increase support for vaccination programmes, compulsory fortification of food staples and investment in population-scale databases to mine information on the causes of birth defects. But what does it mean for research into the genetic basis of developmental disorders and rare diseases?


HOW RARE IS RARE?

Some birth defects, such as Zika-linked microcephaly, are infectious in origin. But many are related to genetic mutations, which can also prevent an embryo from developing as it should. The rare diseases resulting from genetic mutations can be chronic and life threatening, and 30% of rare disease patients die before their fifth birthday [2]. Many mutations can also lead to miscarriage. Genetic cardiac conditions affect around 1% of newborn babies [3], but it’s estimated that these defects prevent around ten times as many foetuses from surviving until birth.

A rare disease is difficult to study, because of the relatively small group of patients – by definition less than 1 in 2000 of the general population are affected. But with more than 6000 known rare diseases, 80% of these with a genetic component, it’s likely you or someone you know has a rare disease. 7% of the population will be affected at some point in their lives, which equates to around 3.5 million people in the UK alone [3].


CLUES FROM SYSTEMATIC SCREENS

We have a huge challenge to find and prevent the causes of rare diseases. For those diseases linked to genetic mutations it’s vital that we understand their genetic basis, and basic research in developmental biology is fundamental to this.

Mouse research in particular offers a wealth of information, thanks to systematic studies that would not be possible in human patients. The mouse genome can be manipulated to delete (knock out) a specific gene. The resulting embryos and adult mice can then be studied to look for abnormalities in the way they develop. It’s a unique way to understand the role that a specific gene plays in development from embryo through to adult, and the developmental abnormalities that may arise from a fault with the gene. Around 30% of gene deletions cause abnormalities so severe that the embryo does not survive until birth, so study of these genes also provides clues about the genetic basis of miscarriage.

Systematic screens by the DMDD and IMPC are working to study the effects of individually knocking out every gene in the mouse genome. With all data freely available online, they are a rich resource for those researching human birth defects, miscarriage and developmental disorders.

The Zika virus has put birth defects back on the political agenda, and scientists have a challenge to find and prevent their causes. In this context, systematic screens of mouse gene knockouts and other gene mutations are more important than ever.


REFERENCES

[1] Use Zika to renew focus on birth-defect research, Nature Editorial, Nature 535, 8 (7 July 2016)

[2] About Rare Diseases, Rare Disease UK

[3] Congenital Heart Disease, Centres for Disease Control and Prevention