Project 451206

Reproductive failure manifests as infertility, recurrent miscarriages and molar pregnancies (pregnancies with no embryos). These conditions affect up to 10% of couples. Little is known about genes responsible for them because of their genetic complexity and heterogeneity. My group has so far identified four genes responsible responsible for recurrent moles, including three for a specific subtype that contain only paternal chromosomes (called androgenetic). With Dr. Taketo, we modeled this disease in mutant mice and found that some of their oocytes, during their intimate preparation to meet with the sperm, instead of losing half of their chromosomes, they lose them all, and some lead to androgenetic embryos. Mutations in the three identified genes in 2018 cause also recurrent miscarriages and female and male infertility. Recently, we identified four additional novel candidate genes that have similar roles in oocytes and again their mutations were found in patients with recurrent androgenetic moles, recurrent miscarriages, and infertility. We believe that androgenetic moles has homogenized a subgroup of patients enriched for mutations in genes with the same role in oocytes. Therefore, studying recurrent androgenetic moles is an opportunity to advance and speed up the genetics of reproductive failure. The goals of this proposal are to (1) complete the identification of the 4 novel genes by finding more patients with mutations in them and identifying other novel genes with similar roles; (2) model some features of this condition in the mouse and determine whether all mouse models lose their maternal chromosomes by the same mechanism; and (3) delineate the nature of the oocyte defects that lead to androgenetic embryos in mice. This will translate into DNA tests, accurate genetic counselling based on the defective gene, and will help reproductive biologists rationalizing assisted reproductive technology services and tailoring them to the need of each patient.