Early embryonic arrest is a challenge for in vitro fertilization (IVF). No genetic factors were previously revealed in the sperm-derived arrest of embryonic development. Here, we reported two infertile brothers presenting normal in conventional semen analysis, but both couples had no embryos for transfer after several IVF and intracytoplasmic sperm injection (ICSI). Whole-exome sequencing identified a homozygous missense mutation of ACTL7A in both brothers. This mutation is deleterious and causes sperm acrosomal ultrastructural defects. The Actl7a knock-in mouse model was generated, and male mutated mice showed sperm acrosomal defects, which were completely consistent with the observations in patients. Furthermore, the sperm from ACTL7A/Actl7a-mutated men and mice showed reduced expression and abnormal localization of PLCζ as a potential cause of embryonic arrest and failure of fertilization. Artificial oocyte activation could successfully overcome the Actl7a-mutated sperm-derived infertility, which is meaningful in the future practice of IVF/ICSI for the ACTL7A-associated male infertility.

Human oocyte maturation is a precondition for fertilization and ensuing embryonic development. Previously, we identified TUBB8 variants as a genetic determinant of human oocyte maturation arrest and showed that these variants cause variable and mixed phenotypes in oocyte maturation and early embryo development. We also estimated that rare inherited or de novo variants in the TUBB8 gene accounted for 30% of individuals in a small cohort of patients affected by oocyte maturation arrest. In the present study, we recruited a further 87 patients from unrelated families diagnosed with oocyte maturation or early embryonic arrest and identified 30 patients carrying TUBB8 variants. The corresponding phenotypes not only include oocyte maturation arrest, failure of fertilization, and early embryonic arrest, but also extend to the new phenotype of failure of embryo implantation. These observations provide the most detailed mutational and phenotypic spectrum of TUBB8, further extend the spectrum of variants and dysfunctional oocyte and embryo phenotypes caused by TUBB8 variants, and confirm previous findings for a critical role of TUBB8 during oocyte maturation and early embryonic development. Thus, TUBB8 mutation screening might not only be a genetic diagnostic marker for patients with oocyte maturation arrest, but might also have clinical implications for evaluating the competence of patients' functional oocytes with first polar body (PB1).

Problem Resident memory T (TRM) cells reside in the uterus during pregnancy may play an important role in balancing maternal‐fetal tolerance with anti‐infectious immunity. Although CD8+TRM and decidual CD8+T cells have been extensively characterized, the properties of decidual CD8+TRM (dTRM) cells remain poorly defined. Method of study We investigated the heterogeneity, phenotypes, and functions of dTRM cells, and compared the proportion of dTRM cells between normal pregnancy and recurrent spontaneous abortion (RSA) using flow cytometry. Moreover, we cocultured peripheral CD8+T (CD8+pT) cells with trophoblast, or decidual stomal cells (DSCs) in the presence or absence of anti‐TGF‐β antibody or TGF‐β type I receptor inhibitor to explore the effects of maternal‐fetal environment on decidual CD8+TRM cell formation. Results We found that CD69+CD103+TRM cells were abundant in CD8+dT cells but not in CD4+dT cells with effector‐memory (EM, CD45RA−CCR7−) phenotypes. The percentage of dTRM cells from RSA patients was significantly higher than that from normal pregnancy. Furthermore, dTRM cells showed increased expressions of chemokine receptors, T‐cell exhaustion‐related molecules, and produced more anti‐inflammatory cytokines and effector cytokines upon stimulation. Moreover, DSCs produced a considerable level of TGF‐β and upregulated CD103 expression on CD69+CD8+pT cells, which can be significantly reversed by blocking TGF‐β receptor. Conclusion Our findings demonstrate that TRM cells with unique properties are present in the decidua during human early pregnancy. They possess an enhanced capacity to produce effector cytokines and regulatory molecules, which might be important in the balance between maternal‐fetal immune tolerance and the capacity to aggressively respond to infections.

BackgroundClinical ovulation induction induces blood estrogen (E2) in excess of physiological levels, which can hinder uterine receptivity. In contrast, progesterone produces the opposite clinical effect, suggesting that it might be capable of recovering the lost receptivity resulting from exposure to high estrogen levels. Integrins are the most widely used biological markers for monitoring uterine conditions. We studied progesterone-induced changes in integrin β expression patterns as biomarkers for changes in uterine receptivity in response to increased estrogen levels.MethodsEndometrial biopsy samples from patients were screened for their estrogen (E2) and progesterone (P4) content and expressing levels of integrin β1 and β3. Uterine receptivity was evaluated using human endometrial adenocarcinoma cells in an embryo attachment model. The respective and concatenated effects of embryo attachment and changes in the integrin β1 and β3 expression patterns on the adenocarcinoma cell plasma membranes in response to 100 nM concentrations of E2 and P4 were evaluated.ResultsIncreased blood E2 concentrations were associated with significantly decreased the levels of integrin β3 expression in uterine biopsy samples. In vitro experiments revealed that a 100 nM E2 concentration inhibited the distribution of integrin β3 on the plasma membranes of human endometrial adenocarcinoma cells used in the embryo attachment model, and resulted in decreased rates of embryo attachment. In contrast, P4 enhanced the expression of integrin β1 and promoted its distribution on the plasma membranes. Furthermore, P4 recovered the embryo attachment efficiency that was lost by exposure to 100 nM E2.ConclusionsBlood E2 and P4 levels and integrin β3 and β1 expression levels in uterine biopsy samples should be considered as biomarkers for evaluating uterine receptivity and determining the optimal time for embryo transfer. Trial registration Trial number: ChiCTR-TRC-13003777; Name of registry: Chinese Clinical Trial Registry; Date of registration: 4 September 2013; Date of enrollment of the first study participant: 15 October 2013Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1052-0) contains supplementary material, which is available to authorized users.