Human Molecular Genetics Advance Access originally published online on December 9, 2008
Human Molecular Genetics 2009 18(5):888-897; doi:10.1093/hmg/ddn418
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NLRP7 mutations in women with diploid androgenetic and triploid moles: a proposed mechanism for mole formation
1 Department of Human Genetics 2 Department of Obstetrics and Gynecology 3 Department Pathology, McGill University Health Center, Montreal H3G 1A4, Canada 4 Women's Reproductive Health Laboratory, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Peoples' Republic of China 5 Department of Medical Genetics, Policlinico Sant'Orsola-Malpighi-University of Bologna, Bologna, Italy 6 INSERM U 782, Endocrinologie et Génétique de la Reproduction et du Développement, 32 rue des carnets, F 92140 Clamart, France
* To whom correspondence should be addressed at: Montreal General Hospital Research Institute, L3-121, 1650 Cedar Avenue, Montreal P.Q. H3G 1A4, Canada. Tel: +1 5149341934 (ext. 44550); Fax: +1 5149348261; Email: rima.slim{at}muhc.mcgill.ca
Received August 4, 2008; Revised November 5, 2008; Accepted December 5, 2008
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.