title: Comprehensive genotype-phenotype correlations between NLRP7 mutations and the balance between embryonic tissue differentiation and trophoblastic proliferation.
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 (p57(KIP2)), 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.
  
  
  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 p57(KIP2) 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 p57(KIP2) 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 p57(KIP2) 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.
authors.affiliation: Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Ngoc Minh Phuong
authors.initials: NM
authors.lastname: Nguyen
authors.affiliation: Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Reddy
authors.affiliation: Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Déry
authors.affiliation: Department of Pathology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Arseneau
authors.affiliation: Department of Pathology, University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
authors.forename: Annie
authors.initials: A
authors.lastname: Cheung
authors.affiliation: Department of Pathology, University of Pittsburgh, Magee-Womens Hospital, Pittsburgh, Pennsylvania, USA.
authors.forename: Urvashi
authors.initials: U
authors.lastname: Surti
authors.affiliation: Department of Pathology, University of Pittsburgh, Magee-Womens Hospital, Pittsburgh, Pennsylvania, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Hoffner
authors.affiliation: Department of Obstetrics and Gynecology, American University of Beirut, Beirut, Lebanon.
authors.forename: Muhieddine
authors.initials: M
authors.lastname: Seoud
authors.affiliation: Department of Pathology, American University of Beirut, Beirut, Lebanon.
authors.forename: Ghazi
authors.initials: G
authors.lastname: Zaatari
authors.affiliation: Department of Obstetrics & Gynecology, Post Graduate Institute of Medical Education and Research, PGIMER, Chandigarh, India.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Bagga
authors.affiliation: Cytology & Gynecological Pathology, Post Graduate Institute of Medical Education and Research, PGIMER, Chandigarh, India.
authors.forename: Radhika
authors.initials: R
authors.lastname: Srinivasan
authors.affiliation: INSERM U782, Endocrinologie et Génétique de la Reproduction et du Développement, Clamart, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Coullin
authors.affiliation: Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Asangla
authors.initials: A
authors.lastname: Ao
authors.affiliation: Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Rima
authors.initials: R
authors.lastname: Slim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005260:Female; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D018392:Genomic Imprinting / Q000235:genetics; D005838:Genotype; D006801:Humans; D006828:Hydatidiform Mole / Q000235:genetics*; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D018895:Microsatellite Repeats / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D011247:Pregnancy; D014327:Trophoblasts / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; C502448:NLRP7 protein, human
keywords: CDKN1C (p57KIP2); NLRP7; hydatidiform mole; tissue differentiation; trophoblastic proliferation