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New genetic clue to ectopic pregnancies found by Wellcome Sanger Institute

A gene that could play a key role in ectopic pregnancy has been pinpointed by researchers at the Wellcome Sanger Institute.

The study, in mice, offers a promising target for further study in humans to search for genetic mutations or anomalies underlying the condition.

A micrograph of an ectopic pregnancy, also known as eccyesis or tubal pregnancy, is a complication of pregnancy in which the embryo attaches outside the uterus
A micrograph of an ectopic pregnancy, also known as eccyesis or tubal pregnancy, is a complication of pregnancy in which the embryo attaches outside the uterus

Ectopic pregnancy occurs when a fertilised egg implants and develops outside the uterus, usually in one of the fallopian tubes.

It is not possible to save a ‘tubal pregnancy’ when this occurs - medicine or an operation is usually required to protect the health of the mother.

The NHS says about one in every 90 pregnancies is ectopic, which amounts to about 11,000 pregnancies a year. Across Europe and the US, it affects one to two per cent of all conceptions and is the most common cause of pregnancy-related death in the first trimester, yet the cause is unknown.

Sanger researchers have discovered that the gene Adgrd1 is important in the journey of the egg from the ovary to the uterus, along the fallopian tubes, which are also known as oviducts.

When this gene was deleted, female mice became infertile, as all their eggs remained stuck in the fallopian tubes.

This was the first evidence of gene regulation in the transit of eggs from the ovaries to the uterus in mammals.

In the normal process, the egg ‘pauses’ for several days at a certain location in the fallopian tubes, called the ampullary-isthmic junction. This is where fertilisation occurs if sperm are present, before the egg then continues its journey.

If fertilised, the egg should implant into the wall of the uterus.

The egg’s movement is controlled by factors including tiny hairs, or cilia, on the surface of the fallopian tubes, which ‘wave’ the egg towards the uterus. Muscle contractions and the flow of oviductal fluid also aid the egg’s journey, but the biology of this process is not yet fully understood.

In particular, scientists have not known how the ‘pause’ at the ampullary-isthmic junction is regulated.

In their study, Sanger scientists aimed to identify genes required for female fertility whose function was not fully understood.

Analysing the International Mouse Phenotyping Consortium database, which has data on mice that have had certain genes suppressed or ‘switched off’, they identified Adgrd1 as a gene of interest.

An ultrasound scan
An ultrasound scan

Examining female mice lacking a functional Adgrd1 gene, they found the ovulated normally and fertilisation took place. But the eggs could not move past the ampullary-isthmic junction and implanted outside of the uterus.

The mechanism was the same as ectopic pregnancy in humans, although that condition does not occur in mice - instead, they are simply infertile.

Investigating the movement of cilia in the fallopian tubes, muscle contractions and the flow of oviductal fluid, they sought to understand why, and scientists at US-based biomedical company Genentech conducted a genetic screen to determine the molecular mechanisms involved.

They concluded that the suppression of Adgrd1 activity was affecting the flow of oviductal fluid, which prevented the egg continuing its journey to the uterus after pausing at the ampullary-isthmic junction

Dr Enrica Bianchi, first author of the study from the Wellcome Sanger Institute, said: “The flow of oviductal fluid in mammals is somewhat counterintuitive, in that it flows in the opposite direction to the egg’s direction of travel. What we’ve discovered in this study is that the strength of this flow is normally downregulated by the Adgrd1 gene. But when Adgrd1 is suppressed, the flow is not reduced and the egg cannot seem to move past the ampullary-isthmic junction.”

Nadia Martinez-Martin, a senior author of the paper from biotechnology company Genentech, suggested the work “opens new avenues for the treatment of ectopic pregnancy”.

Further studies are required in humans, which share a similar reproductive biology to mice and many other mammals, to see if the role of Adgrd1 is the same and whether there is a connection between the mutation or loss of function of the gene and ectopic pregnancy.

Dr Gavin Wright, senior author of the study from the Wellcome Sanger Institute, said: “Though several risk factors of ectopic pregnancy are known, the precise genetic and molecular mechanisms behind the condition have remained unclear. The discovery of the function of Adrgd1 in oviductal fluid regulation, and the consequences of its absence, provides an important clue for researchers studying the causes of ectopic pregnancy in future.”

The research was published in Nature Communications.

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