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3 genes cause rare condition that leads to miscarriage

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Scientists have identified three genes responsible for recurrent molar pregnancies, a rare complication that occurs when a non-viable pregnancy with no embryo implants in the uterus.

The findings could have important implications, since until now very little has been known about the genetic causes of all forms of fetal loss.

In Quebec, molar pregnancy occurs in about one in every 600 pregnancies, and a total absence of maternal chromosomes characterizes half of these. Due to an imbalance in the number of chromosomes from the mother and the father, the placental tissue grows abnormally and forms a tumor, leading to a malignant cancer in approximately 15 to 20 percent of cases. Molar pregnancy is the most common form of all placental diseases (or trophoblastic diseases).

Long-standing mystery

“Our findings add three new genes to the list of mutations leading to fetal loss and will allow for more DNA testing for patients in order to prevent the recurrence of molar pregnancies and provide better genetic counseling and management for couples,” says lead author Rima Slim, an associate professor of human genetics and obstetrics and gynecology at McGill University and a researcher in the Child Health and Human Development Program at the Research Institute of the McGill University Health Centre.

However, clinicians and scientists still don’t fully understand why a molar pregnancy occurs.

“Human pregnancies with no embryos have fascinated and puzzled scientists in all civilizations since the time of Hippocrates,” Slim says. “Our findings uncover, for the first time, a mechanism for the genesis of this abnormality and link the causal factors involved in recurrent molar pregnancies, miscarriages, and male and female infertility to mutations in three genes.”

As reported in the American Journal of Human Genetics, researchers identified mutations in MEI1, TOP6BL/C11orf80, and REC114 in patients who had molar pregnancies without maternal chromosomes and recurrent miscarriages. They further investigated the impact of the Mei1 mutation in a mouse model to understand how the maternal chromosomes are lost.

The objective was to see whether Mei1-deficient mice produce oocytes (early eggs or ova) lacking maternal chromosomes, and to find out when and how these oocytes lose their chromosomes—questions that have remained unanswered since molar pregnancies were first described in 1977.

How do they happen?

The researchers followed the development of oocytes from mice in which the Mei1 gene had been deleted. In some of these mice, the absence of the gene caused conceptions with an abnormal number of maternal chromosomes, and the conceptions did not survive implantation in the uterus, leading to infertility. In others, some oocytes lost all their chromosomes before fertilization and were empty; fertilization of these eggs was still possible.

Jacek Majewski and his team oversaw sequencing of 68 patients and helped identify the new genes in eight patients.

“The mouse model was very important in producing new understanding of how these abnormal pregnancies occur without maternal chromosomes,” says coauthor Teruko Taketo, a researcher in the CHHD Program of the RI-MUHC, who enabled the team to look at the development of oocytes of Mei1-deficient mice as they matured in vitro.

Since 2010,  Slim has been collaborating on the identification of genetic causes of molar pregnancies with Philipe Sauthier, gyneco-oncologist at the University Hospital of Montreal, who founded the Quebec Trophoblastic Disease Network (RMTQ).

“The painful experience of a fetal loss associated with the discovery of an abnormal pregnancy is often destabilizing and stressful for women,” says Magali Breguet, nurse coordinator of the RMTQ. “This collaboration is a positive step forward for women who must undergo several months of medical monitoring and also live with the anxiety that their next pregnancy may also be a molar pregnancy.”

A grant from the Canadian Institute of Health Research supported the work.

Source: McGill University