Homozygous Mutations in WEE2 Cause Fertilization Failure and Female Infertility Qing Sang, Bin Li, Yanping Kuang, Xueqian Wang, Zhihua Zhang, Biaobang.

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Homozygous Mutations in WEE2 Cause Fertilization Failure and Female Infertility Qing Sang, Bin Li, Yanping Kuang, Xueqian Wang, Zhihua Zhang, Biaobang Chen, Ling Wu, Qifeng Lyu, Yonglun Fu, Zheng Yan, Xiaoyan Mao, Yao Xu, Jian Mu, Qiaoli Li, Li Jin, Lin He, Lei Wang The American Journal of Human Genetics Volume 102, Issue 4, Pages 649-657 (April 2018) DOI: 10.1016/j.ajhg.2018.02.015 Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 1 Identification of Mutations in WEE2 (A) Four pedigrees presented with the fertilization failure phenotype. Families 1, 2, and 3 were consanguineous families with a recessive inheritance pattern. Sanger sequencing confirmation is shown below the pedigrees. Affected individuals undergoing whole-exome sequencing and homozygosity mapping are labeled with an asterisk. The equal sign indicates infertility. Black circles represent the affected individuals. (B) Locations and conservation of mutations in the WEE2 gene. The positions of all mutations are indicated in the genomic structure of WEE2, and the conservation of the mutated amino acids is indicated by the alignment of seven mammalian species. The American Journal of Human Genetics 2018 102, 649-657DOI: (10.1016/j.ajhg.2018.02.015) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 2 Morphology of Normal Zygotes and Retrieved Oocytes after ICSI and the Effects of the Mutations on WEE2 Protein Levels in Oocytes and HeLa Cells (A) The morphologies of a normal zygote and affected individual oocytes on day 1 after ICSI. The white arrow indicates the pronuclei, and the black arrow indicates the zona pellucida. The white arrowhead indicates the first polar body, and the black arrowhead indicates the second polar body. Scale bar = 40 μm. (B) Immunofluorescence of healthy control and affected individual oocytes with the p.Glu75Valfs∗6 or p.His337Tyrfs∗24 mutation. Abbreviations: MI, metaphase I; PB1, first polar body; PN, pronuclei. Scale bar = 40 μm. (C) Protein level and localization of WT and mutant WEE2 in HeLa cells. Scale bar = 10 μm. (D) Protein level and localization of WT and mutant WEE2 in mouse GV oocytes. Images were captured by confocal microscopy (Leica). Scale bar = 20 μm. The American Journal of Human Genetics 2018 102, 649-657DOI: (10.1016/j.ajhg.2018.02.015) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 3 Effects of the Mutations on WEE2 and Cdc2 Phosphorylation and Pronuclei Formation (A) The effects of the mutations on WEE2 protein level by western blotting in HeLa cells transfected with WT or mutant constructs. (B) The effects of the mutations on serine phosphorylation of WEE2 in HeLa cells. WEE2 was immunoprecipitated by FLAG beads, and western blotting was performed using a phospho-serine antibody. (C) The effects of the mutations on tyrosine 15 phosphorylation of Cdc2 in HeLa cells. HeLa cells were transfected with WT or mutant constructs, and 20 μg whole-cell lysate was used for western blotting. (D) The effects of the mutations on pronuclei formation. A total of 10 pl of the 500 ng/μL WEE2 cRNA solution was injected into mouse MII oocytes, and the pronuclei formation rate was calculated 10 hr after WEE2 cRNA injection. The total number of oocytes used is listed on top of the column. Significance was compared between WT and mutant groups. Three independent experiments were performed, and results are shown as the mean ± SEM. ∗∗∗p < 0.001. The American Journal of Human Genetics 2018 102, 649-657DOI: (10.1016/j.ajhg.2018.02.015) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 4 Phenotypic Rescue by WEE2 cRNA Injection into Oocytes from the Proband from Family 4 (A) In the control group, two retrieved PB1 oocytes underwent ICSI without WEE2 cRNA injection. Day 0 indicates the time point at 4 hr after ICSI. The white arrowhead indicates the first polar body, and the black arrowhead indicates the second polar body. Scale bar = 40 μm. (B) In the experimental group, four retrieved PB1 oocytes were injected with WEE2 cRNA and cultured for 4 hr and then used for ICSI. Day 0 indicates the time point at 4 hr after cRNA injection and just before ICSI. Oocytes were monitored for 6 days after ICSI. White arrows indicate the pronuclei. Scale bar = 40 μm. The American Journal of Human Genetics 2018 102, 649-657DOI: (10.1016/j.ajhg.2018.02.015) Copyright © 2018 American Society of Human Genetics Terms and Conditions