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.