Major advances made at the RI-MUHC could help improve counselling for individuals suffering from infertility, premature ovarian insufficiency, recurrent miscarriages and androgenetic hydatidiform mole.
A molar pregnancy, also known as a hydatidiform mole, is an abnormal human pregnancy with no embryo and an overgrowth of the cells that form the placenta. The common form of molar pregnancies affects one in every 600 pregnancies in Quebec. Half of these moles are androgenetic, that is, they contain only the father鈥檚 chromosomes with no chromosomes from the mother, and their frequency increases 10 times with advanced maternal age. Because of the hyperproliferation of their cells, androgenetic moles may become malignant and lead to a placental cancer in up to 15 per cent of cases.
Scientists at the Research Institute of the 9I制作厂免费 Health Centre (RI-MUHC) recently discovered six new genes 鈥撀�FOXL2, MAJIN, KASH5, SYCP2, HFM1聽and听惭贰滨翱叠聽鈥� that cause recurrent androgenetic moles, recurrent miscarriages and infertility when mutated on both alleles (copies of the same gene) in the patients. Five of these genes are essential for Meiosis I, the process of cell division necessary for the production of sperm and eggs in humans. Previous studies have linked defects in some of the six genes to premature ovarian failure, a well-known cause of female infertility. In addition, five of these genes have been linked to male infertility.
These findings, just published in聽, will improve the molecular diagnosis of recurrent molar pregnancies, premature ovarian failure and infertile women and men.
鈥淥ur findings suggest that recurrent androgenetic moles are a sign of ovarian ageing. They will change current clinical practice by introducing the evaluation of ovarian reserve for patients with recurrent moles,鈥� says聽, corresponding and co-senior author of the study, Senior Scientist in the聽聽(CHHD) at the RI-MUHC and Professor in the Department of Human Genetics at 9I制作厂免费.
The six new genes add to four other genes that are also responsible for recurrent molar pregnancies and that were previously discovered by the same team (NLRP7, discovered in 2006, and聽MEI1, TOP6BL听补苍诲听REC114,听).
A broad international investigation
In collaboration with the team led by聽, Investigator at the RI-MUHC and Professor of Human Genetics at 9I制作厂免费, the researchers performed exome sequencing on 75 unrelated patients referred by physicians from around the world. These patients had at least two hydatidiform moles and did not have mutations in the previously described genes associated with the condition.
The researchers then checked whether the patients who were negative for biallelic mutations (on both alleles of a gene), had only one defective allele in genes with roles in Meiosis I and ovarian functions. They added 240 patients with other forms of reproductive failure 鈥� referred primarily from the MUHC Repeated Pregnancy Loss clinic, founded by Dr. William Buckett, and the R茅seau des Maladies Trophoblastiques du Qu茅bec, founded by Dr. Philippe Sauthier. This second group of patients had either a molar pregnancy and at least one miscarriage, or at least two miscarriages without a molar pregnancy.
They found that 14 per cent to 28 per cent of these patients had one defective allele that appeared to be most frequent in patients with at least two molar pregnancies.
鈥淥ur data suggest that these monoallelic variants could be contributing, with other factors, to the genetic susceptibility of these patients for reproductive failure. Our study provides an explanation of the increased frequency of androgenetic moles with advanced maternal age,鈥� explains Prof. Slim.
The authors of the study explain that 鈥減atients with monoallelic variants in these genes can conceive and have healthy children; however, they are at higher risk for infertility, premature ovarian insufficiency and reproductive loss than women from the general population.鈥�
Modelling the genesis of moles
To better elucidate the mechanisms underlying this health and reproductive problem, the researchers modelled the disease in mice with deficiency in the聽HFM1听驳别苍别.
鈥淲e observed several defects that affect the meiotic progression, some of which were previously observed by our team in mice with deficiency in the Mei1 gene, another gene responsible for the causation of recurrent androgenetic moles,鈥� explains聽, co-senior author of the study, Senior Scientist in the CHHD Program at the RI-MUHC and Professor in the Department of Surgery at 9I制作厂免费. 鈥淚n this study, using live-cell imaging, we were able to visualize and understand for the first time how the eggs from聽Hfm1聽deficient mice lose all their chromosomes.鈥�
The authors emphasize that the identification of the same mechanism in two mouse models supports its plausibility at the origin of androgenetic mole formation in humans.
鈥淎ndrogenetic moles have been described in 1977. Today, we can better explain to the patients the formation of these aberrant conceptions and the genesis of androgenetic moles,鈥� says Prof. Slim.
About the study
The study聽Defects in meiosis I contribute to the genesis of androgenetic hydatidiform moles聽was conducted by Maryam Rezaei, Manqi Liang, Zeynep Yalcin, Jacinta H. Martin, Parinaz Kazemi, Eric Bareke, Zhao-Jia Ge, Majid Fardaei, Claudio Benadiva, Reda Hemida, Adnan Hassan, Geoffrey J. Maher, Ebtesam Abdalla, William Buckett, Pierre-Adrien Bolze, Iqbaljit Sandhu, Onur Duman, Suraksha Agrawal, JianHua Qian, Jalal Vallian Broojeni, Lavi Bhati, Pierre Miron, Fabienne Allias, Amal Selim, Rosemary A. Fisher, Michael J. Seckl, Philippe Sauthier, Isabelle Touitou, Seang Lin Tan, Jacek Majewski, Teruko Taketo and Rima Slim.
This work was primarily supported by the Canadian Institutes of Health Research and also benefited from funding from Mitacs Accelerate in partnership with Originelle Inc., 9I制作厂免费鈥檚 Centre for Research in Reproduction and Development, the RI-MUHC Desjardins Studentship and the Faculty of Medicine and Health Sciences of 9I制作厂免费.
The investigators would like to thank all the researchers and clinicians who contributed to the study, as well as the patients and families who participated.