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Mutations in a tubulin gene caused infertility due to oocyte arrest in about a third of families tested. The investigators found that the mutant tubulins wreak havoc on microtubule assembly in the oocyte. Successful human reproduction starts when a metaphase II oocyte fuses with a sperm cell to form a fertilized egg. In human oocytes, the meiotic cell cycle begins in the neonatal ovary and pauses at prophase I of meiosis until puberty, when a surge of luteinizing hormone stimulates the resumption of meiosis and ovulation. This leads to progression of the oocyte from metaphase I to metaphase II. 1 – 3 Oocytes arrested in prophase I have an intact nucleus, termed the germinal vesicle, whereas oocytes that have resumed meiosis are characterized by the breakdown of the germinal vesicle. After germinal-vesicle breakdown, metaphase I . . .

Background Previous work demonstrated that there are numerous miRNAs in human follicular fluids, some of which are associated with reproductive diseases. In the current study, we sought to determine whether microRNAs (miRNAs) in the follicular fluid (FF) are differentially expressed between women with and without endometriosis and to uncover the association of miRNAs with the oocyte and embryonic development potential. Methods FF was harvested from 30 women with endometriosis and 30 women without who underwent in vitro fertilization treatment at the University Hospital between February and December 2016. The FF samples were subjected to miRNA profiling and validation via quantitative reverse transcription polymerase chain reaction analysis. Mouse/human metaphase-I (MI) oocytes were harvested and micro-injected with an miR-451 inhibitor, and the effects of miR-451 knockdown on Wnt/WNT signalling genes were investigated. Results Oocyte number, fertilization rate, and number of available embryos were decreased significantly in women with endometriosis relative to those without endometriosis. Hsa-miR-451 in FF was downregulated in endometriosis patients relative to control subjects ( P  < 0.01). Moreover, the proportions of mouse/human MI oocytes that developed into 2-pronuclei (2PN), 2-cell, 8–10-cell and blastocyst-stage embryos were affected by miR-451 knockdown in mouse/human oocytes. Components of the Wnt signalling pathway were aberrantly expressed in the mouse/human oocytes and embryos in the miR-451 inhibitor-injected group. Conclusions miR-451 was downregulated in FF samples from endometriosis patients and was modestly effective in distinguishing endometriosis patients from non-endometriosis patients. miR-451 downregulation in mouse and human oocytes affected pre-implantation embryogenesis by suppressing the Wnt signalling pathway. This miRNA might serve as a novel biomarker of oocyte and embryo quality in assisted reproductive treatment.

PANX1, one of the members of the pannexin family, is a highly glycosylated channel-forming protein. Recently, we identified heterozygous variants in PANX1 that follow an autosomal dominant inheritance pattern and cause female infertility characterized by oocyte death. In this study, we screened for novel PANX1 variants in patients with the phenotype of oocyte death and discovered a new type of inheritance pattern accompanying PANX1 variants. We identified two novel homozygous missense variants in PANX1 [NM_015368.4 c.712T>C (p.(Ser238Pro) and c.899G>A (p.(Arg300Gln))] associated with the oocyte death phenotype in two families. Both of the homozygous variants altered the PANX1 glycosylation pattern in cultured cells, led to aberrant PANX1 channel activation, and resulted in mouse oocyte death after fertilization in vitro. It is worth noting that the destructive effect of the two homozygous variants on PANX1 function was weaker than that caused by the recently reported heterozygous variants. Our findings enrich the variational spectrum of PANX1 and expand the inheritance pattern of PANX1 variants to an autosomal recessive mode. This highlights the critical role of PANX1 in human oocyte development and helps us to better understand the genetic basis of female infertility due to oocyte death.

Oocyte maturation arrest is one of the important causes of female infertility, but the genetic factors remain largely unknown. PABPC1L , a predominant poly(A)‐binding protein in Xenopus , mouse, and human oocytes and early embryos prior to zygotic genome activation, plays a key role in translational activation of maternal mRNAs. Here, we identified compound heterozygous and homozygous variants in PABPC1L that are responsible for female infertility mainly characterized by oocyte maturation arrest in five individuals. In vitro studies demonstrated that these variants resulted in truncated proteins, reduced protein abundance, altered cytoplasmic localization, and reduced mRNA translational activation by affecting the binding of PABPC1L to mRNA. In vivo , three strains of Pabpc1l knock‐in (KI) female mice were infertile. RNA‐sequencing analysis showed abnormal activation of the Mos‐MAPK pathway in the zygotes of KI mice. Finally, we activated this pathway in mouse zygotes by injecting human MOS mRNA, and this mimicked the phenotype of KI mice. Our findings reveal the important roles of PABPC1L in human oocyte maturation and add a genetic potential candidate gene to be screened for causes of infertility. Synopsis Seven rare variants in PABPC1L were identified in five infertile females mainly characterized by oocyte maturation arrest followed recessive inheritance pattern. In vitro and in vivo functional studies confirmed the destructive effects and pathogenicity of PABPC1L variants. In vitro , truncating variants resulted in truncated proteins, reduced protein abundance, and altered cytoplasmic localization. Missense variants impaired the ability of RNA‐binding and mRNA translational activation of PABPC1L protein. In vivo , three strains of Pabpc1l KI mice corresponding to patient‐derived variants showed early embryonic arrest and female infertility. Mos‐MAPK pathway was abnormally activated in KI zygotes and the phenotype of KI mice was mimicked by injecting MOS mRNA into the zygotes. Graphical Abstract Seven rare variants in PABPC1L were identified in five infertile females mainly characterized by oocyte maturation arrest followed a recessive inheritance pattern. In vitro and in vivo functional studies confirmed the destructive effects and pathogenicity of PABPC1L variants.

Previous work indicated that the implantation and pregnancy rates of women with endometriosis are lower than those of healthy women during in-vitro fertilisation and embryonic transfer. And there are numerous microRNAs (miRNAs) in human uterine luminal fluid (ULF), some of which are associated with early preimplantation development of embryos. In our study, we sought to determine whether miRNAs in the ULF are differentially expressed between women with and without endometriosis and to uncover the association of miRNAs with the development potential of blastocysts. The implantation and clinical pregnancy rates significantly decreased in women with endometriosis than in those without endometriosis. Notably, hsa-miR-145-5p was upregulated in ULF samples from women with endometriosis (fold change > 2, false discovery rate < 0.001). Moreover, the ratios of mouse/human early embryos that developed into blastocyst-staged embryos ( P  = 0.0065 and P  = 0.0098, respectively) were significantly affected via miR-145-5p upregulation in mouse/human early embryos. Notch signalling pathway components had abnormal expression levels in the mouse/human blastocyst-stage embryos in the miR-145-5p mimic-enriched extracellular vesicles (EVs) group. In conclusions, our study revealed that human extracellular vesicle-derived miRNAs in ULF impacted the developmental potential of blastocysts in women with endometriosis. Moreover, the upregulation of miR-145-5p-enriched EVs in mouse and human embryos negatively affected blastocyst development by suppressing the expression of components of the NOTCH signalling pathway, which may contribute to elucidate the cause of infertility in women with endometriosis.

Immunoglobulin-like domain containing receptor 1 (ILDR1) is a poorly characterized gene that was first identified in lymphoma cells. Mutations in ILDR1 are responsible for DFNB42, but the pathogenesis of hearing loss caused by ILDR1 mutations remains to be elucidated. To explore the role of ILDR1 in hearing, we created Ildr1 knockout mice. In heterozygous mice, ILDR1 expression was found in outer hair cells (OHCs) and inner hair cells (IHCs) of the organ of Corti. ILDR1-deficient mice are profoundly deaf by postnatal day 21 (P21). No significant difference was observed in the supporting cells and IHCs of ILDR1-deficient mice, but progressive degeneration of OHCs occurred at P15 and disruption of the tunnel running through the organ of Corti was noticeable at P21. By P28, there were no OHCs visible in any of the turns of the organ of Corti, and the tunnel of the organ of Corti was entirely destroyed. ILDR1 deficiency affects expression of tricellulin in vivo, and this provides a possible explanation to hearing loss. To further elucidate the mechanism of deafness related to ILDR1 deficiency, we pursued a differential proteomic approach to comprehensively assess differential protein expression in the cochleae of Ildr1+/− and Ildr1−/− mice at P21. Altogether, 708 proteins were up-regulated (fold change >1.5) and 114 proteins were down-regulated (fold change <0.5) in the Ildr1−/− mice compared with Ildr1+/− mice. Gene ontology classification indicated that a number of differentially expressed proteins are involved in cell adhesion, protein and vesicle-mediated transport, cell death, membrane organization, and cellular homeostasis. A few of these proteins are closely related to hearing development. Taken together, our data suggest that ILDR1 is important for the survival of OHCs and provide novel insights into the pathogenesis of human deafness DFNB42 deafness.

Mature spermatozoa with normal morphology and motility are essential for male reproduction. The epididymis has an important role in the proper maturation and function of spermatozoa for fertilization. However, factors related to the processes involved in spermatozoa modifications are still unclear. Here we demonstrated that CCDC28A, a member of the CCDC family proteins, is highly expressed in testes and the CCDC28A deletion leads to male infertility. We found CCDC28A deletion had a mild effect on spermatogenesis. And epididymal sperm collected from Ccdc28a −/− mice showed bent sperm heads, acrosomal defects, reduced motility and decreased in vitro fertilization competence whereas their axoneme, outer dense fibers, and fibrous sheath were all normal. Furthermore, we found that CCDC28A interacted with sperm acrosome membrane-associated protein 1 (SPACA1) and glycogen synthase kinase 3a (GSK3A), and deficiencies in both proteins in mice led to bent heads and abnormal acrosomes, respectively. Altogether, our results reveal the essential role of CCDC28A in regulating sperm morphology and motility and suggesting a potential marker for male infertility.

BackgroundTUBB8 is a primate-specific β-tubulin isotype whose expression is confined to oocytes and the early embryo. We previously found that mutations in TUBB8 caused oocyte maturation arrest. The objective was to describe newly discovered mutations in TUBB8 and to characterise the accompanying spectrum of phenotypes and modes of inheritance.Methods and resultsPatients with oocyte maturation arrest were sequenced with respect to TUBB8. We investigated the effects of identified mutations in vitro, in cultured cells and in mouse oocytes. Seven heterozygous missense and two homozygous mutations were identified. These mutations cause a range of folding defects in vitro, different degrees of microtubule disruption upon expression in cultured cells and interfere to varying extents in the proper assembly of the meiotic spindle in mouse oocytes. Several of the newly discovered TUBB8 mutations result in phenotypic variability. For example, oocytes harbouring any of three missense mutations (I210V, T238M and N348S) could extrude the first polar body. Moreover, they could be fertilised, although the ensuing embryos became developmentally arrested. Surprisingly, oocytes from patients harbouring homozygous TUBB8 mutations that in either case preclude the expression of a functional TUBB8 polypeptide nonetheless contained identifiable spindles.ConclusionsOur data substantially expand the range of dysfunctional oocyte phenotypes incurred by mutation in TUBB8, underscore the independent nature of human oocyte meiosis and differentiation, extend the class of genetic diseases known as the tubulinopathies and provide new criteria for the qualitative evaluation of meiosis II (MII) oocytes for in vitro fertilization (IVF).

Asthenozoospermia is one of the main factors leading to male infertility, but the genetic mechanisms have not been fully elucidated. Variants in the androglobin (ADGB) gene were identified in an infertile male characterized by asthenozoospermia. The variants disrupted the binding of ADGB to calmodulin. Adgb–/– male mice were infertile due to reduced sperm concentration (< 1 × 106 /mL) and motility. Spermatogenesis was also abnormal, with malformation of both elongating and elongated spermatids, and there was an approximately twofold increase in apoptotic cells in the cauda epididymis. These exacerbated the decline in sperm motility. It is surprising that ICSI with testicular spermatids allows fertilization and eventually develops into blastocyst. Through mass spectrometry, we identified 42 candidate proteins that are involved in sperm assembly, flagella formation, and sperm motility interacting with ADGB. In particular, CFAP69 and SPEF2 were confirmed to bind to ADGB. Collectively, our study suggests the potential important role of ADGB in human fertility, revealing its relevance to spermatogenesis and infertility. This expands our knowledge of the genetic causes of asthenozoospermia and provides a theoretical basis for using ADGB as an underlying genetic marker for infertile males.