Causative Mutations and Mechanism of Androgenetic Hydatidiform Moles

Nguyen, Ngoc Minh; Ge, Zhao‐Jia; Reddy, Ramesh; Fahiminiya, Somayyeh; Sauthier, Philippe; Bagga, Rashmi; Şahin, Feride İffet; Mahadevan, Sangeetha; Osmond, Matthew; Bréguet, Magali; Rahimi, Kurosh; Lapensée, Louise; Hovanes, Karine; Srinivasan, Radhika; Veyver, Ignatia B. Van den; Sahoo, Trilochan; Akhigbe, AO; Majewski, Jacek; Taketo, Teruko; Slim, Rima

doi:10.1016/j.ajhg.2018.10.007

Cited by 78 publications

(52 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…(A) The distribution of variants in REC114 exons and the protein structure of REC114. Red arrows indicate new mutations found in our research and the purple arrow indicates the mutation reported previously 22. All variants lie in or around exon 4.…”

Section: Resultsmentioning

confidence: 67%

“…Null mutations and overexpression of REC114 both prevent DSB formation in S. cerevisiae , resulting in inviable spores,15 and Rec114 -null mutant mice are defective in both spermatogenesis and oogenesis 14. Recently, Nguyen et al reported that a homozygous splicing mutation in REC114 , which is located directly before exon 4 in the splicing region (purple arrowhead, figure 2A), might cause complete hydatidiform moles (CHMs) in humans, and the patient with the mutation in their paper was reported to have had one miscarriage, two spontaneous CHMs and one CHM after intrauterine sperm injection 22. She had not tried IVF or ICSI technologies, thus the state of fertilisation and embryo development were unknown.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Homozygous mutations in REC114 cause female infertility characterised by multiple pronuclei formation and early embryonic arrest

et al. 2019

View full text Add to dashboard Cite

BackgroundAbnormal pronuclear formation during fertilisation and subsequent early embryonic arrest results in female infertility. In recent years, with the prevalence of assisted reproductive technology, a few genes have been identified that are involved in female infertility caused by abnormalities in oocyte development, fertilisation and embryonic development. However, the genetic factors responsible for multiple pronuclei formation during fertilisation and early embryonic arrest remain largely unknown.ObjectiveWe aim to identify genetic factors responsible for multiple pronuclei formation during fertilisation or early embryonic arrest.MethodsWhole-exome sequencing was performed in a cohort of 580 patients with abnormal fertilisation and early embryonic arrest. Effects of mutations were investigated in HEK293T cells by western blotting and immunoprecipitation, as well as minigene assay.ResultsWe identified a novel homozygous missense mutation (c.397T>G, p.C133G) and a novel homozygous donor splice-site mutation (c.546+5G>A) in the meiotic gene REC114. REC114 is involved in the formation of double strand breaks (DSBs), which initiate homologous chromosome recombination. We demonstrated that the splice-site mutation affected the normal alternative splicing of REC114, while the missense mutation reduced the protein level of REC114 in vitro and resulted in the loss of its function to protect its partner protein MEI4 from degradation.ConclusionsOur study has identified mutations in REC114 responsible for human multiple pronuclei formation and early embryonic arrest, and these findings expand our knowledge of genetic factors that are responsible for normal human female meiosis and fertility.

show abstract

Section: Resultsmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Homozygous mutations in REC114 cause female infertility characterised by multiple pronuclei formation and early embryonic arrest

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Hydatidiform moles are known to affect approximately 1 in 600 pregnancies, half of which are triploid dispermic (two paternal and one maternal set of chromosomes) and half of which are diploid androgenetic (two paternal sets of chromosomes). An estimated 85% of the latter type are monospermic, and may arise via the extrusion of maternal chromosomes to the first polar body, followed by "diploidization" of the paternal chromosomes (Nguyen et al 2018) . The mosaic near-haploid constitution of embryo E7.5 is theoretically consistent with a dispermic origin, as a result of postzygotic diploidization of a triploid zygote (Golubovsky 2003) .…”

Section: Discussionmentioning

confidence: 99%

Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism

Starostik

Sosina

McCoy

2020

Preprint

View full text Add to dashboard Cite

Less than half of human zygotes survive to live birth, primarily due to aneuploidies of meiotic or mitotic origin. Mitotic errors lead to chromosomal mosaicism, defined by multiple cell lineages with distinct chromosome complements. The incidence and fitness consequences of chromosomal mosaicism in human embryos remain controversial, with most previous studies based on bulk DNA assays or comparisons of multiple biopsies of a few embryonic cells. Single-cell genomic data provide an opportunity to quantify mosaicism on an embryo-wide scale. To this end, we extended an approach to infer aneuploidies based on chromosome dosage-associated changes in gene expression by integrating signatures of allelic imbalance. We applied this method to published single-cell RNA sequencing data from 74 disaggregated human embryos, spanning the morula to blastocyst stages. Our analysis revealed widespread mosaic aneuploidies across preimplantation development, with 59 of 74 (80%) embryos harboring at least one aneuploid cell (1% FDR). By clustering copy number calls, we reconstructed histories of chromosome mis-segregation, distinguishing meiotic and early mitotic errors from those occurring after lineage differentiation. We observed no significant enrichment of aneuploid cells in the trophectoderm compared to the inner cell mass, though we do detect such an enrichment in published data from later post-implantation stages. Finally, we observed that aneuploid cells exhibit upregulation of immune response genes, as well as downregulation of genes involved in proliferation, metabolism, and protein processing, consistent with stress responses previously documented in other stages and systems. Together, our work provides a high-resolution view of aneuploidy in preimplantation embryos and supports the conclusion that low-level mosaicism is a common feature of early human development.

show abstract

“…The mechanism of androgenetic CHM development, and maternal nucleus loss, has been known for a long time. Recently, MEI1, TOP6BL/ C11orf80, and REC114 were reported as candidate causative genes by screening patients with recurrent androgenetic CHMs 24 . In Mei1-deficient female mice, 8% of the oocytes lose all their chromosomes by extruding them with the spindles into the first polar body.…”

Section: Discussionmentioning

confidence: 99%

Parental contribution to trisomy in heterozygous androgenetic complete moles

Usui

Sato

Shozu

2020

Sci Rep

View full text Add to dashboard Cite

Complete hydatidiform moles (CHMs) comprise a proliferative trophoblastic disorder and are known to be androgenetic and diploid. Androgenetic CHMs are classified as having monospermic and dispermic origins. Rarely, some CHMs have other genetic constitutions, such as biparental diploid or tetraploid. Previous studies have shown the possibility that androgenetic heterozygous CHMs have an additional chromosome with high frequency. This study aimed to comprehensively analyse the molecular karyotyping of androgenetic dispermic CHMs and the parental contribution of their additional chromosomes. Single-nucleotide polymorphism arrays were performed with the genomic DNA of CHMs and patients. The B allele frequency and selected B allele frequency plotting of CHM were visualised. Among the 31 dispermic CHMs, eight showed trisomy and one showed double trisomy; of the 10 additional chromosomes, seven were of maternal original and three were of paternal origin. In addition, three disomic chromosomes comprised one maternal and one paternal chromosome, although these should theoretically have had two paternal chromosomes in the case of androgenetic CHMs. The subclassification of heterozygous CHMs, with or without maternal contribution, is a new approach and could be a candidate indicator of gestational trophoblastic neoplasia risk.

show abstract

Causative Mutations and Mechanism of Androgenetic Hydatidiform Moles

Cited by 78 publications

References 54 publications

Homozygous mutations in REC114 cause female infertility characterised by multiple pronuclei formation and early embryonic arrest

Homozygous mutations in REC114 cause female infertility characterised by multiple pronuclei formation and early embryonic arrest

Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism

Parental contribution to trisomy in heterozygous androgenetic complete moles

Contact Info

Product

Resources

About