title: NLRP7 mutations in women with diploid androgenetic and triploid moles: a proposed mechanism for mole formation.
abstract: Hydatidiform mole is an aberrant pregnancy with abnormal embryonic development and hydropic placental villi. Common moles are sporadic, not recurrent and affect one in every 1500 pregnancies in Western societies. Approximately, half of common moles are complete and mostly diploid androgenetic, whereas the remaining are partial and mostly triploid diandric. NLRP7 has been found to be responsible for a recurrent form of molar pregnancies. Recently, we showed that patients with NLRP7 mutations have an impaired inflammatory response to various stimuli. To date, molar tissues analyzed from patients with NLRP7 mutations have been found to be diploid and biparental. In this study, we report 10 new non-synonymous variants and one stop codon found in patients and not in controls. We demonstrate the presence of different types of moles, diploid biparental, diploid androgenetic, triploid and tetraploid conceptions, in patients with NLRP7 variants. We document in vitro and in vivo early embryo cleavage abnormalities in three patients. We propose a two-hit mechanism at the origin of androgenetic moles. This mechanism consists of variable degrees of early embryo cleavage abnormalities leading to chaotic mosaic aneuploidies, with haploid, diploid, triploid and tetraploid blastomeres. Surviving embryonic cells that reach implantation are then subject to the maternal immune response. Because of the patients' impaired inflammatory response, androgenetic cells, which are complete allograft, are able to grow and proliferate. In women with normal immune system, chaotic mosaic aneuploidies may also occur during early cleavage, however, androgenetic cells would die after implantation or stay undetected, confined to a small portion of the placenta.
authors.affiliation: Department of Human Genetics, McGill University Health Center, Montreal H3G 1A4, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Deveault
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Qian
authors.forename: Wafaa
authors.initials: W
authors.lastname: Chebaro
authors.forename: Asangla
authors.initials: A
authors.lastname: Ao
authors.forename: Lucy
authors.initials: L
authors.lastname: Gilbert
authors.forename: Amira
authors.initials: A
authors.lastname: Mehio
authors.forename: Rabia
authors.initials: R
authors.lastname: Khan
authors.forename: Seang Lin
authors.initials: SL
authors.lastname: Tan
authors.forename: Anita
authors.initials: A
authors.lastname: Wischmeijer
authors.forename: Philippe
authors.initials: P
authors.lastname: Coullin
authors.forename: Xing
authors.initials: X
authors.lastname: Xie
authors.forename: Rima
authors.initials: R
authors.lastname: Slim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D004171:Diploidy; D005260:Female; D006801:Humans; D006828:Hydatidiform Mole / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011123:Polyploidy; D011247:Pregnancy
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502448:NLRP7 protein, human