Causative Mutations and Mechanism of Androgenetic Hydatidiform Moles

• Published in: American journal of human genetics Vol. 103; no. 5; pp. 740 - 751
• Main Authors: Nguyen, Ngoc Minh Phuong, Ge, Zhao-Jia, Reddy, Ramesh, Fahiminiya, Somayyeh, Sauthier, Philippe, Bagga, Rashmi, Sahin, Feride Iffet, Mahadevan, Sangeetha, Osmond, Matthew, Breguet, Magali, Rahimi, Kurosh, Lapensee, Louise, Hovanes, Karine, Srinivasan, Radhika, Van den Veyver, Ignatia B., Sahoo, Trilochan, Ao, Asangla, Majewski, Jacek, Taketo, Teruko, Slim, Rima
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2018; Elsevier
• Subjects: female infertility; male infertility; MEI1; REC114; recurrent hydatidiform moles; recurrent miscarriages; TOP6BL; recurrent hydatidiform moles; MEI1; recurrent miscarriages; female infertility; REC114; male infertility; TOP6BL
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2018.10.007

Androgenetic complete hydatidiform moles are human pregnancies with no embryos and affect 1 in every 1,400 pregnancies. They have mostly androgenetic monospermic genomes with all the chromosomes originating from a haploid sperm and no maternal chromosomes. Androgenetic complete hydatidiform moles were described in 1977, but how they occur has remained an open question. We identified bi-allelic deleterious mutations in MEI1, TOP6BL/C11orf80, and REC114, with roles in meiotic double-strand breaks formation in women with recurrent androgenetic complete hydatidiform moles. We investigated the occurrence of androgenesis in Mei1-deficient female mice and discovered that 8% of their oocytes lose all their chromosomes by extruding them with the spindles into the first polar body. We demonstrate that Mei1−/− oocytes are capable of fertilization and 5% produce androgenetic zygotes. Thus, we uncover a meiotic abnormality in mammals and a mechanism for the genesis of androgenetic zygotes that is the extrusion of all maternal chromosomes and their spindles into the first polar body.