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NLRP7 | Novel Genes for female Reproductive Failure | Novel genes for fetal loss

NLRP7

In 2006, our group discovered that bi-allelic mutations in NLRP7 are responsible for recurrent molar pregnancies. NLRP7 is a maternal-effect gene that is required primarily in the oocyte. Oocytes from patients with recessive mutations in NLRP7 fertilize normally and the resulting molar conceptions have diploid biparental genomes. However, in these molar tissues, all imprinted genes lack maternal methylation marks that are normally established during oogenesis. In these molar conceptions, tissues differentiation is impaired and trophoblastic proliferation exacerbated. In addition, the patients have compromised inflammatory response; consequently, they retain these defective pregnancies, in which embryonic development had arrested earlier, until ~12 weeks of gestation. It is the delayed retention of these pregnancies, in which fetal vessels did not differentiate, that contributes to the molar phenotype. We are currently investigating more precisely the role of NLRP7 in cellular differentiation and proliferation in collaboration with Dr. Brian Cox (University of Toronto).

Novel Genes for female Reproductive Failure

In collaboration with several clinicians from various countries and with Dr. Jacek Majewski鈥檚 group, we have identified biallelic deleterious mutations in nine genes, MEI1, TOP6BL, REC114, FOXL2, KASH5, MAJIN, SYCP2, HFM1, and MEIOB, in patients with androgenetic hydatidiform moles. Some of these patients had recurrent androgenetic moles and others had only one mole with miscarriages and/or infertility, which highlight the roles of these genes in various forms of reproductive failure. In addition, five of these genes have been shown to be responsible for premature ovarian failure, which links molar pregnancies to ovarian ageing. These findings explain the increased frequency of moles with advanced maternal age, which is the strongest risk factor for common sporadic androgenetic HM, affecting 1 in every 600 pregnancies.

With the collaboration with Dr. Teruko Taketo, we investigated the mechanisms of androgenetic mole formation in Mei1^-/- and Hfm1^-/- females and found that some of their oocytes lose all their chromosomes with the entire spindle into the first polar body. The occurrence of the same mechanism in two mouse models argues in favor of its plausibility at the origin of androgenetic mole formation in humans.

Novel genes for fetal loss

We are also working on the identification of more genes causing recurrent hydatidiform moles, miscarriages, and infertility, with the collaboration of many clinicians. To achieve this goal, we recruit patients with any of the following conditions:

1. at least two molar pregnancies (all histological and genotypic types),
2. at least five miscarriages and no live birth,
3. women with at least 5 years of infertility and no live birth.

If you had had any of the above conditions and you wish to participate in our study, please contact us at rrw [at] muhc.mcgill.ca.