Causative Mutations and Mechanism of Androgenetic Hydatidiform Moles

Am J Hum Genet. 2018 Nov 1;103(5):740-751. doi: 10.1016/j.ajhg.2018.10.007.

Ngoc Minh Phuong Nguyen ¹, Zhao-Jia Ge ¹, Ramesh Reddy ¹, Somayyeh Fahiminiya ², Philippe Sauthier ³, Rashmi Bagga ⁴, Feride Iffet Sahin ⁵, Sangeetha Mahadevan ⁶, Matthew Osmond ², Magali Breguet ³, Kurosh Rahimi ⁷, Louise Lapensee ⁸, Karine Hovanes ⁹, Radhika Srinivasan ¹⁰, Ignatia B Van den Veyver ⁶, Trilochan Sahoo ⁹, Asangla Ao ¹¹, Jacek Majewski ², Teruko Taketo ¹², Rima Slim ¹³

Affiliations

1 Department of Human Genetics, McGill University Health Centre, Montréal, QC H4A 3J1, Canada.
2 Department of Human Genetics, McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Genome Québec Innovation Center, Montréal, QC H3A 0G1, Canada.
3 Department of Obstetrics and Gynecology, Gynecologic Oncology Division, Centre Hospitalier de l'Université de Montréal, Réseau des Maladies Trophoblastiques du Québec, Montréal, QC H2X 0C1, Canada.
4 Department of Obstetrics & Gynecology, Post Graduate Institute of Medical, Education and Research, PGIMER, Chandigarh 160012, India.
5 Department of Medical Genetics, Faculty of Medicine, Baskent University, 06810 Ankara, Turkey.
6 Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, USA.
7 Department of Pathology, Centre Hospitalier de l'Université de Montréal, Montréal, QC H2X 0C1, Canada.
8 Ovo Clinic, Montréal, QC H4P 2S4, Canada; Department of Obstetrics and Gynecology, Centre Hospitalier de l'Université de Montréal, Montréal, QC H2X 0C1, Canada.
9 Invitae, Irvine, CA 92618, USA.
10 Cytology & Gynecological Pathology, Post Graduate Institute of Medical Education and Research PGIMER, Chandigarh 160012, India.
11 Department of Human Genetics, McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Obstetrics and Gynecology, McGill University Health Centre, Montréal, QC H4A 3J1, Canada.
12 Department of Obstetrics and Gynecology, McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Surgery, McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Biology, McGill University, Montréal, QC H3A 0G4, Canada.
13 Department of Human Genetics, McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Obstetrics and Gynecology, McGill University Health Centre, Montréal, QC H4A 3J1, Canada. Electronic address: [email protected].

PMID: 30388401 DOI: 10.1016/j.ajhg.2018.10.007

Abstract

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.

Keywords

MEI1; REC114; TOP6BL; female infertility; male infertility; recurrent hydatidiform moles; recurrent miscarriages.

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