Abstract
Familial recurrent hydatidiform mole (RHM) is a maternal-effect autosomal recessive disorder usually associated with mutations of the NLRP7 gene. It is characterized by HM with excessive trophoblastic proliferation, which mimics the appearance of androgenetic molar conceptuses despite their diploid biparental constitution. It has been proposed that the phenotypes of both types of mole are associated with aberrant genomic imprinting. However no systematic analyses for imprinting defects have been reported. Here, we present the genome-wide methylation profiles of both spontaneous androgenetic and biparental NLRP7 defective molar tissues. We observe total paternalization of all ubiquitous and placenta-specific differentially methylated regions (DMRs) in four androgenetic moles; namely gain of methylation at paternally methylated loci and absence of methylation at maternally methylated regions. The methylation defects observed in five RHM biopsies from NLRP7 defective patients are restricted to lack-of-methylation at maternal DMRs. Surprisingly RHMs from two sisters with the same missense mutations, as well as consecutive RHMs from one affected female show subtle allelic methylation differences, suggesting inter-RHM variation. These epigenotypes are consistent with NLRP7 being a maternal-effect gene and involved in imprint acquisition in the oocyte. In addition, bioinformatic screening of the resulting methylation datasets identified over sixty loci with methylation profiles consistent with imprinting in the placenta, of which we confirm 22 as novel maternally methylated loci. These observations strongly suggest that the molar phenotypes are due to defective placenta-specific imprinting and over-expression of paternally expressed transcripts, highlighting that maternal-effect mutations of NLRP7 are associated with the most severe form of multi-locus imprinting defects in humans.
Highlights
The most common form of complete hydatidiform mole (CHM) is sporadic and androgenetic diploid in origin
Complete hydatidiform moles (CHMs) are abnormal human conceptsus characterized by excessive trophoblast proliferation that commonly result from the absence of a maternal genetic contribution compensated by two copies of the paternal genome
70% of women affected by familial recurrent HM (RHM) are associated with recessive mutations of NLRP7 [5, 6], whereas genetic aberrations of KHDC3L are much less frequent, and present in only ~10% of patients without an NLRP7 involvement [7, 8]
Summary
The most common form of complete hydatidiform mole (CHM) is sporadic and androgenetic diploid in origin. 70% of women affected by familial recurrent HM (RHM) are associated with recessive mutations of NLRP7 [5, 6], whereas genetic aberrations of KHDC3L are much less frequent, and present in only ~10% of patients without an NLRP7 involvement [7, 8] In both cases the mutations cause the RHM by maternal-effect. Definitive evidence that a defective oocyte is responsible for the pathophysiology of RHM comes from the observations that assisted reproductive cycles using donated oocytes in three patients with recessive NLRP7 mutations resulted in normal offspring [8, 9] This maternal-effect model is consistent with transcript abundance of both NLRP7 and KHDC3L, which accumulate in the developing oocytes and are present in early pre-implantation embryos [10, 11]. Paternal transmission of NLRP7 mutations does not interfere with spermatogenesis, since males homozygous for NLRP7 mutations can father children [5, 12]
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