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.

Authors

Ngoc Minh Phuong Nguyen¹, Zhao-Jia Ge¹, Ramesh Reddy¹, Somayyeh Fahiminiya², Philippe Sauthier³, Rashmi Bagga⁴, Feride Iffet Sahin⁵, Sangeetha Mahadevan⁶, Matthew Osmond², Magali Breguet³, Kurosh Rahimi⁷, Louise Lapensee⁸, Karine Hovanes⁹, Radhika Srinivasan¹⁰, Ignatia B Van den Veyver⁶, Trilochan Sahoo⁹, Asangla Ao¹¹, Jacek Majewski², Teruko Taketo¹², Rima Slim¹³

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: rima.slim@muhc.mcgill.ca.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Androgens / genetics*
Animals
Chromosomes / genetics
Female
Humans
Hydatidiform Mole / genetics*
Male
Mammals / genetics
Mice
Mice, Inbred C57BL
Mutation / genetics*
Oocytes / pathology
Pregnancy
Zygote / pathology

Substances

Androgens

Grants and funding

MOP-130364/CIHR/Canada