Causative Mutations and Mechanism of Androgenetic Hydatidiform Moles

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Causative Mutations and Mechanism of Androgenetic Hydatidiform Moles Ngoc Minh Phuong Nguyen, Zhao-Jia Ge, Ramesh Reddy, Somayyeh Fahiminiya, Philippe Sauthier, Rashmi Bagga, Feride Iffet Sahin, Sangeetha Mahadevan, Matthew Osmond, Magali Breguet, Kurosh Rahimi, Louise Lapensee, Karine Hovanes, Radhika Srinivasan, Ignatia B. Van den Veyver, Trilochan Sahoo, Asangla Ao, Jacek Majewski, Teruko Taketo, Rima Slim The American Journal of Human Genetics Volume 103, Issue 5, Pages 740-751 (November 2018) DOI: 10.1016/j.ajhg.2018.10.007 Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree Structure, Reproductive Outcomes, and Mutation Analysis of Two Families with Bi-allelic MEI1 Mutations (A) Sanger sequencing and segregation of the mutation identified in MEI1 in the family of proband 1333 (indicated by an arrow). (B) RT-PCR demonstrating abnormal splicing caused by the nonsense mutation (c.3452G>A) and the generation of three cDNA fragments, the normal fragment indicated by a black arrow and two abnormal fragments indicated by dashed red lines (a larger fragment that includes intron 27 and a smaller fragment that skips exon 28). (C) Sanger sequencing and segregation of the mutations identified in MEI1 in the family of proband 880 (indicated by an arrow). (D) Abnormal splicing in affected individual 880 showing the amplification of a smaller cDNA fragment that corresponds to the skipping of exon 11 (red arrow) and another cDNA fragment corresponding to the normal splicing isoform (black arrow). RNA was from lymphoblastoid cell lines (LCL) of the affected women. (E) Schematic presentation of the domains of human and mouse MEI1. The positions of the mutations are indicated by arrows. The mutations identified in this study are shown in red. In black is a recently reported mutation in two infertile brothers with non-obstructive azoospermia. The mutation in the Mei1 knockout is shown on the mouse protein. The American Journal of Human Genetics 2018 103, 740-751DOI: (10.1016/j.ajhg.2018.10.007) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 2 Pedigree Structure, Reproductive Outcomes, and Mutation Analyses of TOP6BL/ C11orf80 and REC114 in Three Affected Women with Bi-allelic Mutations (A) Pedigree of proband 1031 showing the segregation of TOP6BL/C11orf80 mutations and the chromatograms. (B) Pedigree of proband HM74 showing the chromatogram of her mutation in TOP6BL/C11orf80 and the conservation of the changed amino acid in different species by multiple alignment from NCBI. (C) Pedigree of proband 978 with REC114 mutation and the chromatograms. The American Journal of Human Genetics 2018 103, 740-751DOI: (10.1016/j.ajhg.2018.10.007) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 3 Meiosis I Abnormalities in Oocytes from Wild-Type, Heterozygous, and Homozygous Mice (A) Fully grown oocytes from Mei1+/+ and Mei1−/− mice were cultured in vitro and the frequency of various stages at different time point were recorded by phase contrast microscopy. The absence of polar body (PB) 17–19 hr after germinal vesicle (GV) breakdown was our criterion for arrest before metaphase I stage (MI) and the presence of at least one PB was our criterion for progression to metaphase II arrest (MII). (B) Percentages of oocytes with or without abnormalities observed after in vitro maturation. (C) Numbers (N) of oocytes with various PB abnormalities observed after in vitro maturation. (D) Examples of oocytes with abnormal polar bodies after in vitro or in vivo maturation. The American Journal of Human Genetics 2018 103, 740-751DOI: (10.1016/j.ajhg.2018.10.007) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 4 Various Spindle and Chromosome Congression Abnormalities after In Vitro Maturation (A) Oocyte from wild-type at MII displaying two normal spindles, one in the oocyte with aligned chromosomes and another in the polar body (PB). (B) An oocyte from Mei1−/− with tripolar spindles within the oocyte and misaligned chromosomes. (C) An oocyte from Mei1−/− with tripolar spindles that had extruded DNA at two poles into the PB (arrows). (D) An empty oocyte from Mei1−/− that had extruded the spindles and the chromosomes at their two poles into two PB (arrows). (E) Another empty oocyte from Mei1−/− that had extruded all its DNA with the spindles into the PB (arrows). (F) An oocyte that extruded one large (large arrow) and two normal-size PB (small arrows). The American Journal of Human Genetics 2018 103, 740-751DOI: (10.1016/j.ajhg.2018.10.007) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 5 H3K9me2 Staining of Maternal Chromosomes in Oocytes and Zygotes from Wild-Type and Mei1−/− (A) H3K9me2 immunofluorescence of GV and MII oocytes from wild-type and Mei1−/− females, demonstrating that H3 methylase is not impaired in Mei1-deficient oocytes. (B) H3K9me2 immunofluorescence on zygotes showing the staining of maternal but not paternal chromosomes in a zygote from Mei1−/− females. GV stands for germinal vesicle; MII, metaphase II; PB, polar body; ZP, zona pellucida; ♀, maternal chromosomes; ♂, paternal chromosomes; and DIC, differential interference contrast. The American Journal of Human Genetics 2018 103, 740-751DOI: (10.1016/j.ajhg.2018.10.007) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 6 Preimplantation Development of Mei1−/− Oocytes in Culture Zygotes were collected from wild-type or Mei1−/− females 20 hr after hCG injection and mating with wild-type males and cultured in vitro. Embryonic development was analyzed daily using phase contrast microscopy. The embryos that failed to develop by the next day were removed for further analysis. Embryos derived from Mei1−/− oocytes were arrested mainly at the 2- to 4-cell stage. A few reached the morula or blastocyst stages but appeared disorganized and none hatched. The American Journal of Human Genetics 2018 103, 740-751DOI: (10.1016/j.ajhg.2018.10.007) Copyright © 2018 American Society of Human Genetics Terms and Conditions