Researchers find gene
that causes miscarriages
By Rebecca Lau

OTTAWA — As an obstetrician, Dr. Andrée Gruslin is repeatedly discouraged by the lack of scientific advancement that can help patients with high risk pregnancies. As a researcher with the Ottawa Health Research Institute, she's developing the very studies that may one day prevent miscarriages and stillbirths.

Scientists may soon be able to predict whether a woman will have a high risk pregnancy.

"I only see those with complications and it's very frustrating for the parents and for us that look after these mothers to not be able to identify that there's going to be a problem ahead of time," she says.

"And more importantly, not be able to treat them," she adds.

Gruslin and her colleagues published a highly publicized study this past summer that indicated a malfunctioning enzyme may cause women to carry small fetuses. Abnormally small fetuses, which can cause fetal death, are caused by a condition known as fetal growth restriction. In these cases, the placentas don't develop normally and the fetus is unable to properly receive nutrients and oxygen. Gruslin says if the fetuses do survive, the babies often have "a slew of complications" for life.

"They were programmed differently when they were fetuses and that makes them more prone to be diabetic, hypertensive and have heart disease."

Searching for an answer

Gruslin says very little is known about the placenta and its mechanisms for growth. Her research team hoped to answer the mystery of fetal growth restriction by targeting the molecule IGF-II, which acts as a growth factor for the placenta.

Scientists knew that in order for IGF-II to make tissues grow, it had to be cut into three small pieces. What they didn't know was - what cut it?

"We didn't know the [enzyme] that does the last cut at the end that result in the activation of the growth factor."

Gruslin and her colleagues reasoned that the correct enzyme might be PC4 because the amino acids that constitute the structure of IGF2 can be recognized by this enzyme However, previous research concentrated only on the presence of PC4 in the ovaries and testes. By looking at a sample of human placentas, the researchers were able to locate PC4 in the placenta as well. Even more significantly, it was shown in test tubes that PC4 did indeed cut IGF-II.

The team then set up an artificial invasion assay with IGF-II, PC4 and an inhibitor of PC4 to test the significance of the enzyme in the placenta's development. Invasion happens when placenta cells invade the uterus penetrate the muscle to bring blood and oxygen to the embryo. IGF-II is the growth factor that aids invasion. When the process is hampered by inactive IGF-II, the placenta is improperly developed and the fetuses become small.

The artificial invasion model showed a decrease of invaded cells when the PC4 was not allowed to act properly because of the addition of an inhibitor. By testing blood from fifteen women in the later stages of pregnancy, the team saw that women with small babies had less cut pieces of IGF-II and presumably had malfunctioning PC4. On the other hand, expectant mothers with normal fetuses had a large number of cut IGF-II pieces.

"So all of that put together allowed us to say that probably this enzyme in this gene is important in ensuring the placenta grows normally," Gruslin says.

Looking to the future

Due to their findings, researchers hope that they might be able to create a test to predict whether women will have fetal growth restriction. The team is now verifying their results with lab mice that have no PC4. They will also test a larger sample of pregnant women.

"Perhaps in five to 10 years from now, we'll be able to use gene therapy. So, if you knew that your PC4 was not working well, then maybe we could put in or drive the PC4 gene to make it work better."

But currently, Gruslin says testing is a more realistic goal. She says women who are flagged as risks can then be watched closely for complications or have their babies delivered early to prevent fetal deaths.

Gruslin says fetal growth restriction is not a highly researched area and can be overlooked when it comes to grants and funding.

She says a major driving force in her research is her patients, one of whom suffered eight consecutive miscarriages.

"It really motivates you to keep going because it's just horrible. It’s really dreadful," she says. "You feel so helpless to not be able to do anything about it. It stimulates you a lot to keep going back in the lab."