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Comprehensive genotype–phenotype correlations between NLRP7 mutations and the balance between embryonic tissue differentiation and trophoblastic proliferation
  1. Ngoc Minh Phuong Nguyen1,2,
  2. Li Zhang2,
  3. Ramesh Reddy1,2,
  4. Christine Déry1,2,
  5. Jocelyne Arseneau3,
  6. Annie Cheung4,
  7. Urvashi Surti5,
  8. Lori Hoffner5,
  9. Muhieddine Seoud6,
  10. Ghazi Zaatari7,
  11. Rashmi Bagga8,
  12. Radhika Srinivasan9,
  13. Philippe Coullin10,
  14. Asangla Ao1,2,
  15. Rima Slim1,2
  1. 1Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada
  2. 2Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada
  3. 3Department of Pathology, McGill University Health Centre, Montreal, Quebec, Canada
  4. 4Department of Pathology, University of Hong Kong, Queen Mary Hospital, Hong Kong, China
  5. 5Department of Pathology, University of Pittsburgh, Magee-Womens Hospital, Pittsburgh, Pennsylvania, USA
  6. 6Department of Obstetrics and Gynecology, American University of Beirut, Beirut, Lebanon
  7. 7Department of Pathology, American University of Beirut, Beirut, Lebanon
  8. 8Department of Obstetrics & Gynecology, Post Graduate Institute of Medical Education and Research, PGIMER, Chandigarh, India
  9. 9Cytology & Gynecological Pathology, Post Graduate Institute of Medical Education and Research, PGIMER, Chandigarh, India
  10. 10INSERM U782, Endocrinologie et Génétique de la Reproduction et du Développement, Clamart, France
  1. Correspondence to Dr Rima Slim, Human Genetics, McGill University Health Centre Research Institute, L3-121, 1650 Cedar Ave., Montreal, Quebec, Canada H3G 1A4; rima.slim{at}muhc.mcgill.ca

Abstract

Background Hydatidiform mole (HM) is a human pregnancy with excessive trophoblastic proliferation and abnormal embryonic development that may be sporadic or recurrent. In the sporadic form, the HM phenotype is driven by an abnormal ratio of paternal to maternal genomes, whereas in the recurrent form, the HM phenotype is caused by maternal-recessive mutations, mostly in NLRP7, despite the diploid biparental origin of the HM tissues. In this study, we characterised the expression of the imprinted, maternally expressed gene, CDKN1C (p57KIP2), the genotype, and the histopathology of 36 products of conception (POC) from patients with two defective alleles in NLRP7 and looked for potential correlations between the nature of the mutations in the patients and the various HM features.

Methods/results We found that all the 36 POCs are diploid biparental and have the same parental contribution to their genomes. However, some of them expressed variable levels of p57KIP2 and this expression was strongly associated with the presence of embryonic tissues of inner cell mass origin and mild trophoblastic proliferation, which are features of triploid partial HMs, and were associated with missense mutations. Negative p57KIP2 expression was associated with the absence of embryonic tissues and excessive trophoblastic proliferation, which are features of androgenetic complete HMs and were associated with protein-truncating mutations.

Conclusions Our data suggest that NLRP7, depending on the severity of its mutations, regulates the imprinted expression of p57KIP2 and consequently the balance between tissue differentiation and proliferation during early human development. This role is novel and could not have been revealed by any other approach on somatic cells.

  • NLRP7
  • hydatidiform mole
  • trophoblastic proliferation
  • tissue differentiation
  • CDKN1C (p57KIP2)

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