Oocyte Maturation Arrest Research Articles

Exposure to perfluorooctane sulfonate in vitro perturbs the quality of porcine oocytes via induction of apoptosis

Perfluorooctane sulfonate (PFOS) is a widely used artificial surfactant with potential toxicity to humans and animals. However, little is known about the impact of PFOS on the female germ cell development. Here, we report that PFOS exposure weakens oocyte quality by disturbing oocyte meiotic competency and fertilization ability. Specifically, PFOS exposure impaired cytoskeleton assembly including spindle organization and actin polymerization to cause the oocyte maturation arrest. In addition, PFOS exposure also impaired the mitochondrial dynamics and function, resulting in the increased levels of reactive oxygen species (ROS) and DNA damage as well as generation of apoptosis. Lastly, PFOS exposure compromised the distribution of cortical granules (CGs) and their component ovastacin, leading to the failure of sperm binding and fertilization. Altogether, our study illustrates that oxidative stress-induced apoptosis is a major cause for the deteriorated quality of porcine oocytes exposed to PFOS.

Genetic factors as potential molecular markers of human oocyte and embryo quality.

Successful human reproduction requires gamete maturation, fertilization, and early embryonic development. Human oocyte maturation includes nuclear and cytoplasmic maturation, and abnormalities in the process will lead to infertility and recurrent failure of IVF/ICSI attempts. In addition, the quality of oocytes/embryos in the clinic can only be determined by morphological markers, and there is currently a lack of molecular markers for determining oocyte quality. As the number of patients undergoing IVF/ICSI has increased, many patients have been identified with recurrent IVF/ICSI failure. However, the genetic basis behind this phenotype remains largely unknown. In recent years, a few mutant genes have been identified by us and others, which provide potential molecular markers for determining the quality of oocytes/embryos. In this review, we outline the genetic determinants of abnormalities in the processes of oocyte maturation, fertilization, and early embryonic development. Currently, 16 genes (PATL2, TUBB8, TRIP13, ZP1, ZP2, ZP3, PANX1, TLE6, WEE2, CDC20, BTG4, PADI6, NLRP2, NLRP5, KHDC3L, and REC114) have been reported to be the causes of oocyte maturation arrest, fertilization failure, embryonic arrest, and preimplantation embryonic lethality. These abnormalities mainly have Mendelian inheritance patterns, including both dominant inheritance and recessive inheritance, although in some cases de novo mutations have also appeared. In this review, we will introduce the effects of each gene in the specific processes of human early reproduction and will summarize all known variants in these genes and their corresponding phenotypes. Variants in some genes have specific effects on certain steps in the early human reproductive processes, while other variants result in a spectrum of phenotypes. These variants and genetic markers will lay the foundation for individualized genetic counseling and potential treatments for patients and will be the target for precision treatments in reproductive medicine.

Identification of Novel Mutations in CDC20: Expanding the Mutational Spectrum for Female Infertility.

Oocyte maturation and fertilization are fundamental processes for successful human reproduction, and abnormalities in these processes will cause infertility. Recently, we identified biallelic mutations in CDC20 that are responsible for human oocyte maturation arrest, fertilization failure, and early embryonic development arrest. In this study, we screened for further CDC20 mutations in a new cohort of patients with abnormalities in oocyte maturation, fertilization, and early embryonic development. Through whole-exome sequencing, we identified the four novel mutations c.887G > A (p. Arg296Gln), c.964C > T (p.Arg322∗), c.1155G > C (p.Trp385Cys), and c.330 + 1G > A (p. Glu111Ilefs∗36) and one previously reported mutation c.965G > A (p.Arg322Gln) in CDC20 in four infertile individuals from three independent families. The patients had different phenotypes of oocyte maturation arrest and fertilization failure resulting from the different mutations. This study confirms our previous research and expands the spectrum of known mutations in CDC20, providing new evidence supporting the function of CDC20 in the genetic etiology of female infertility characterized by oocyte maturation arrest and fertilization failure.

Ethylene glycol butyl ether deteriorates oocyte quality via impairing mitochondrial function.

Ethylene glycol butyl ether (EGBE) is a ubiquitous environmental pollutant that is commonly used in maquillage, industrial, and household products. EGBE has been shown to cause blood toxicity, carcinogenicity, and organ malformations. However, little is known about the impact of EGBE on the female reproductive system, especially oocyte quality. Here, we reported that EGBE influenced oocyte quality by showing the disturbed oocyte meiotic capacity, fertilization potential, and early embryonic development competency. Specifically, EGBE exposure impaired spindle/chromosome structure, microtubule stability, and actin polymerization to result in the oocyte maturation arrest and aneuploidy. In addition, EGBE exposure compromised the dynamics of cortical granules and their component ovastacin, leading to the failure of sperm binding and fertilization. Last, single-cell transcriptome analysis revealed that EGBE-induced oocyte deterioration was caused by mitochondrial dysfunction, which led to the accumulation of ROS and occurrence of apoptosis. Altogether, our study illustrates that mitochondrial dysfunction and redox perturbation is the major cause of the poor quality of oocytes exposed to EGBE.

Abnormal PIWI-interacting RNA profile and its association with the deformed extracellular matrix of oocytes from recurrent oocyte maturation arrest patients

To depict the PIWI-interacting RNA (piRNA) profile in oocytes from patients with recurrent oocyte maturation arrest (ROMA) and explore the piRNA candidates associated with the disease. An observational study. Academic research unit. Sixteen ROMA patients who provided 140 immature oocytes that arrested at metaphase I, and 146 control patients who provided 420 oocytes for invitro culture that were collected at the stages of germinal vesicle (GV), metaphase I (MI), and MII. None. Expression profiles of piRNA and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) validating data of piR-hsa-17139 and its target genes. After the piRNA profile was established using piRNA sequencing and hierarchical clustering, the target genes of the piRNA were predicted by bioinformatics databases and matched with mRNA sequencing data. The piRNA expression profiles showed a greater quantity of differentially expressed piRNAs in the older-stage oocytes compared with the early-stage oocytes. The piRNA and mRNA sequencing data indicated that the most affected genes were mainly concentrated in the extracellular matrix (ECM) pathway. Based on the comparison of the piRNA and mRNA sequencing data, four differentially expressed piRNAs were associated with modulation of those ECM pathway genes. The qRT-PCR validation confirmed that piR-hsa-17139 was the only up-regulated piRNA, and its target ECM genes were suppressed in ROMA oocytes. The expression level of piR-hsa-17139 declined slightly while the expression of its target ECM genes plunged dramatically during the development of normal oocytes. As the important genome monitors in gametogenesis, abnormally expressed piRNAs may affect the expression of ECM modulating genes, which subsequently contributes to ROMA.

The Recurrent Mutation in PATL2 Inhibits Its Degradation Thus Causing Female Infertility Characterized by Oocyte Maturation Defect Through Regulation of the Mos-MAPK Pathway

PAT1 homolog 2 (PATL2), encoding an RNA-binding protein, is a repressor involved in the translational regulation of maternal mRNAs during oocyte maturation. Previous studies have reported mutations in PATL2 those led to female infertility with oocyte maturation arrest; however, the mechanisms by which mutations affected meiotic maturation remained unclear. Here, we identified several novel and recurrent mutations of PATL2 in patients with similar phenotype, and chose the missense mutation c.649 T>A p.Tyr217Asn in PATL2 (PATL2Y217N) as a typical to investigate the underlying mechanisms. We confirmed that this mutation disturbed oocyte maturation and observed morphological defects of large polar body, symmetrical division and abnormal spindle after microinjection of corresponding mutated mRNA. We further evaluated the effect of the PATL2Y217N mutation in 293T cells, and found this mutation decreased the ubiquitination level and degradation of PATL2. Then, abnormally increased PATL2 bound mRNAs of Mos, an upstream activator of mitogen activated protein kinase (MAPK), to regulate its translational activity and subsequently impaired MAPK signaling pathway and oocyte meiosis. These results dissented from the previous view that PATL2 mutations reduced their expression and highlight the role of PATL2 in translational regulation of Mos and its association with MAPK signaling pathway during oocyte meiotic maturation.

Can in vitro maturation overcome cycles with repeated oocyte maturation arrest? A classification system for maturation arrest and a cohort study.

To investigate the role of gonadotropin-stimulated and human chorionic gonadotropin (hCG) -primed in vitro oocyte maturation (IVM) in cases of repeated in vitro fertilization (IVF) failure due to various forms of oocyte maturation arrest (OMA). Retrospective cohort study. In all, 63 women with IVF failure due to OMA were evaluated in this study. According to the Hatirnaz & Dahan classification, 11 (17.5%) women were OMA type 1, 22 (34.9%) were OMA type 2, 0 were OMA type 3, 11 (17.5%) were OMA type 4, and 19 women were OMA type 5 (30.1%). Fewer oocytes were retrieved in the IVM than in the IVF cycles. No embryos were produced from oocytes collected in the IVM cycles of women with OMA types 1, 2, and 4. In the OMA type 5 group, 9 (47.4%) day 2 embryos and 6 (31.6%) day 3 embryos were obtained. The difference between the groups was statistically significant (P= 0.001, P= 0.002, respectively). Single day 3 embryo transfer was performed for the six patients with OMA type 5 but no clinical pregnancies occurred. Follicle-stimulating hormone-stimulated and hCG-primed IVM does not improve oocyte maturation, developmental potential, or pregnancy rates of women with OMA. Future studies directed to re-establishing normal cytoskeletal architecture and machinery, and resumption of meiosis may be beneficial for obtaining mature oocytes.

Molecular genetics of infertility: loss-of-function mutations in humans and corresponding knockout/mutated mice.

Infertility is a major issue in human reproductive health, affecting an estimated 15% of couples worldwide. Infertility can result from disorders of sex development (DSD) or from reproductive endocrine disorders (REDs) with onset in infancy, early childhood or adolescence. Male infertility, accounting for roughly half of all infertility cases, generally manifests as decreased sperm count (azoospermia or oligozoospermia), attenuated sperm motility (asthenozoospermia) or a higher proportion of morphologically abnormal sperm (teratozoospermia). Female infertility can be divided into several classical types, including, but not limited to, oocyte maturation arrest, premature ovarian insufficiency (POI), fertilization failure and early embryonic arrest. An estimated one half of infertility cases have a genetic component; however, most genetic causes of human infertility are currently uncharacterized. The advent of high-throughput sequencing technologies has greatly facilitated the identification of infertility-associated gene mutations in patients over the past 20 years. This review aims to conduct a narrative review of the genetic causes of human infertility. Loss-of-function mutation discoveries related to human infertility are summarized and further illustrated in tables. Corresponding knockout/mutated animal models of causative genes for infertility are also introduced. A search of the PubMed database was performed to identify relevant studies published in English. The term 'mutation' was combined with a range of search terms related to the core focus of the review: infertility, DSD, REDs, azoospermia or oligozoospermia, asthenozoospermia, multiple morphological abnormalities of the sperm flagella (MMAF), primary ciliary dyskinesia (PCD), acephalic spermatozoa syndrome (ASS), globozoospermia, teratozoospermia, acrosome, oocyte maturation arrest, POI, zona pellucida, fertilization defects and early embryonic arrest. Our search generated ∼2000 records. Overall, 350 articles were included in the final review. For genetic investigation of human infertility, the traditional candidate gene approach is proceeding slowly, whereas high-throughput sequencing technologies in larger cohorts of individuals is identifying an increasing number of causative genes linked to human infertility. This review provides a wide panel of gene mutations in several typical forms of human infertility, including DSD, REDs, male infertility (oligozoospermia, MMAF, PCD, ASS and globozoospermia) and female infertility (oocyte maturation arrest, POI, fertilization failure and early embryonic arrest). The causative genes, their identified mutations, mutation rate, studied population and their corresponding knockout/mutated mice of non-obstructive azoospermia, MMAF, ASS, globozoospermia, oocyte maturation arrest, POI, fertilization failure and early embryonic arrest are further illustrated by tables. In this review, we suggest that (i) our current knowledge of infertility is largely obtained from knockout mouse models; (ii) larger cohorts of clinical cases with distinct clinical characteristics need to be recruited in future studies; (iii) the whole picture of genetic causes of human infertility relies on both the identification of more mutations for distinct types of infertility and the integration of known mutation information; (iv) knockout/mutated animal models are needed to show whether the phenotypes of genetically altered animals are consistent with findings in human infertile patients carrying a deleterious mutation of the homologous gene; and (v) the molecular mechanisms underlying human infertility caused by pathogenic mutations are largely unclear in most current studies. It is important to use our current understanding to identify avenues and priorities for future research in the field of genetic causes of infertility as well as to apply mutation knowledge to risk prediction, genetic diagnosis and potential treatment for human infertility.

Mutation analysis of tubulin beta 8 class VIII in infertile females with oocyte or embryonic defects.

Variants of tubulin beta 8 class VIII (TUBB8) have been shown to be associated with female infertility characterized by oocyte or embryonic defects. To further investigate the mutational spectrum of TUBB8 and the prevalence of variants, we performed Sanger sequencing of TUBB8 on a total of 115 infertile females who had undergone repeated in vitro fertilization cycles with oocyte or embryonic defects and 200 healthy controls. A total of 31 variants which were absent from the controls were identified in 36 unrelated individuals, accounting for a large proportion of this cohort (31.3%). All of the variants including heterozygous/homozygous missense variants and a heterozygous frameshift insertion variant were at conserved sites and predicted to be deleterious. Besides, these variants had diverse phenotypic effects, including not only oocyte maturation arrest, fertilization failure, and early embryonic arrest, but also multi-pronuclei (MPN) formation, which is a new phenotype associated with TUBB8 variants. Overall, this study reveals a large number of variants of the TUBB8 gene in infertile females with oocyte or embryonic defects. Our results not only broaden the mutational and phenotypic spectra of TUBB8 variants, but also further confirm the critical role of TUBB8 in oocyte maturation, fertilization, and early embryonic development.

THE OOCYTE MATURATION FAILURE AND EMBRYO ARREST: A RETROSPECTIVE STUDY IN THE THIRTEEN-YEAR PERIOD

Oocyte maturation and embryo arrest are well-known cases in clinical practice but this issue is still not sufficiently analyzed. According to investigations on animal models more than 35 genes have been found to be associated with abnormal early embryonic development. It has already been confirmed that five human genes, such as TUBB8, TLE6, PATL2, PADI6 and KHDC3L, have the similar functions. According to the Istanbul consensus, arrested embryos are those that have not cleaved during a 24-h period. There is a group of patients for whom the embryo arrest is a stable problem and recurs in subsequent IVF cycles. Patients with inability to obtain mature, morphologically normal egg that can be fertilized are rarer.The aim of the study was to evaluate the frequency of embryo arrest and oocyte maturation arrest within patients under 37 years of age. Retrospective study. Cycles of 6015 patients in the thirteen-year period (2006-2018) were analyzed in this retrospective study. Only patients under 37 years of age, who underwent routine stimulation protocols, were included in the investigation. The embryo and oocyte maturation arrest group included patients who did not receive any blastocysts during all their stimulations. The analysis showed that the group with embryo and oocyte maturation arrest reached to 3.34 % (n =201). Additionally two groups of poor (n=851) and good responders (n=5164) were assessed. It was shown that the percentage of patients with embryo and oocyte maturation arrest in the group of good responders was 1.8% (n=92) compared with the poor responders group – 12.8% (n=109). This study included a group of patients from only one IVF clinic. For clearer understanding of this issue there is a need of similar analysis among different groups within different populations. According to our assumptions, the results may be the same. It is important to analyze other populations for more accurate evaluation of embryo and oocyte maturation arrest frequency. Moreover, it is crucial to assess the genetic background of such conditions. The identification of new genes that play a key role in early embryonic development will allow to create a new genetic screening panel.

PROOF OF CONCEPT OF A TREATMENT FOR HUMAN OOCYTE MATURATION ARREST;TRANSVAGINAL OVARIAN NEEDLE INJURY PRECEEDING LETROZOLE PRIMING IN VITRO MATURATION

We aim to present the proof of concept of a novel targeted treatment strategy; transvaginal ovarian needle injury (TVOI) preceeding letrozole priming in vitro oocyte maturation (Letrozole IVM) for women suffering from repeated in vitro fertilization failures due to oocyte maturation arrest (OMA).

Critical roles of the ddx5 gene in zebrafish sex differentiation and oocyte maturation

DEAD-box helicase 5 (Ddx5) functions as an ATP-dependent RNA helicase and as a transcriptional coactivator for several transcription factors; however, the developmental function of the ddx5 gene in vertebrates is not fully understood. We found that the zebrafish ddx5 gene was expressed in developing gonads. Using the genome editing technology transcription activator-like effector nuclease, we established a ddx5-disrupted zebrafish and examined the morphological phenotypes of the mutant. We found that the majority of ddx5-deficient mutants developed as fertile males with normal testes and a small number of ddx5-deficient mutants developed as infertile females with small ovaries. Apoptotic cell death at 31 days post fertilization was increased in thick immature gonads (presumptive developing ovaries) of the ddx5-deficient mutant compared to those of heterozygous wild-type fish, while the number of apoptotic cells in thin immature gonads (presumptive developing testes) was comparable between the mutant and wild-type animals. Histological analysis revealed that ovaries of adult ddx5-deficient females had fewer vitellogenic oocytes and a larger number of stage I and II oocytes. The amount of cyclic adenosine monophosphate in the ddx5-deficient ovaries was high compared to that of wild-type ovaries, presumably leading to the mitotic arrest of oocyte maturation. Therefore, the ddx5 gene is dispensable for testis development, but it is essential for female sex differentiation and oocyte maturation in zebrafish.

Identification novel mutations in TUBB8 in female infertility and a novel phenotype of large polar body in oocytes with TUBB8 mutations

We aimed to identify novel variants in TUBB8 and corresponding new abnormal phenotypes in oocytes/fertilization/ embryonic development responsible for female infertility. Sanger sequencing of TUBB8 was performed in infertile women with abnormalities in oocyte maturation or embryonic development. The effects of the variants were evaluated in patients' oocytes by morphological observations and immunofluorescence. We identified 34 novel variants of TUBB8 in 51 patients who were diagnosed with abnormalities in oocyte maturation or early embryonic development. We found a novel phenotype in which large polar bodies were present in three independent patients possibly associated with a recurrent variant. Moreover, we identified a novel type of TUBB8 variant consisting of an in-frame deletion-insertion, which has not been previously reported. Our present study identified 34 novel variants in TUBB8 in 51 patients. These patients show oocyte maturation arrest, oocytes with large polar body, fertilization failure, early embryonic arrest or embryonic implantation failure. These results expand the kinds of variants and phenotypic spectrum of TUBB8 variants with regard to female infertility.

Human follicular fluid proteome reveals association between overweight status and oocyte maturation abnormality

BackgroundHuman follicular fluid (HFF), which is composed by essential proteins required for the follicle development, provides an important microenvironment for oocyte maturation. Recently, overweight status has been considered as a detrimental impact factor on oocyte maturation, but whether HFF proteome could provide protein markers for assessing overweight-based oocyte maturation deficiency is still unknown.MethodsTo reveal the HFF-based molecular characteristics associated with abnormal oocyte maturation, an iTRAQ-based comparative proteomic analysis was performed to investigate different HFF protein expression profiles from normal weight women and overweight status women.ResultsTwo hundred HFF proteins were quantified in our data, of which 43% have not been overlapped by two previous publications. Compared with the HFF proteins of normal weight women, 22 up-regulated HFF proteins and 21 down-regulated HFF proteins were found in the overweight status women. PANTHER database showed these altered HFF proteins participated in development, metabolism, immunity, and coagulation, and STRING database demonstrated their complicated interaction networks. The confidence of proteomic outcome was verified by Western blot analysis of WAP four-disulfide core domain protein 2 (WFDC2), lactotransferrin (LTF), prostate-specific antigen (KLK3), fibronectin (FN1), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Further, ELISA assay indicated WFDC2 might be a potentially useful candidate HFF marker for the diagnosis of oocyte maturation arrest caused by overweight status.ConclusionsOur work provided a new complementary high-confidence HFF dataset involved in oocyte maturation, and these altered HFF proteins might have clinical relevance and diagnostic and prognostic value for abnormal oocyte maturation in overweight status women.

Bi-allelic Missense Pathogenic Variants in TRIP13 Cause Female Infertility Characterized by Oocyte Maturation Arrest

Normal oocyte meiosis is a prerequisite for successful human reproduction, and abnormalities in the process will result in infertility. In 2016, we identified mutations in TUBB8 as responsible for human oocyte meiotic arrest. However, the underlying genetic factors for most affected individuals remain unknown. TRIP13, encoding an AAA-ATPase, is a key component of the spindle assembly checkpoint, and recurrent homozygous nonsense variants and a splicing variant in TRIP13 are reported to cause Wilms tumors in children. In this study, we identified homozygous and compound heterozygous missense pathogenic variants in TRIP13 responsible for female infertility mainly characterized by oocyte meiotic arrest in five individuals from four independent families. Individuals from three families suffered from oocyte maturation arrest, whereas the individual from the fourth family had abnormal zygote cleavage. All displayed only the infertility phenotype without Wilms tumors or any other abnormalities. Invitro and invivo studies showed that the identified variants reduced the protein abundance of TRIP13 and caused its downstream molecule, HORMAD2, to accumulate in HeLa cells and in proband-derived lymphoblastoid cells. The chromosome mis-segregation assay showed that variants did not have any effects on mitosis. Injecting TRIP13 cRNA into oocytes from one affected individual was able to rescue the phenotype, which has implications for future therapeutic treatments. This study reports pathogenic variants in TRIP13 responsible for oocyte meiotic arrest, and it highlights the pivotal but different roles of TRIP13 in meiosis and mitosis. These findings also indicate that different dosage effects of mutant TRIP13 might result in two distinct human diseases.

Rare homozygous mutation in TUBB8 associated with oocyte maturation defect-2 in a consanguineous mating family

PurposeVariations in many genes may lead to the occurrence of oocyte maturation defects. To investigate the genetic basis of oocyte maturation defects, we performed clinical and genetic analysis of a pedigree.MethodsThe proband with oocyte maturation defect-2 receiving ovulation induction therapy and her parents were selected for clinical detection, whole exome sequencing and Sanger sequencing. One unrelated healthy woman received ovulation induction therapy as control. Mutations were assessed after frequency screening of public exome databases. Then homozygous variants shared by the proband and her parents were selected.ResultsArrest of oocytes maturation was observed. A new missense mutation in TUBB8 (TUBB8: NM_177,987: exon 2: c. C161T: p. A54V) was identified, which was shown to be rare compared with public databases. The variant was highly conserved among primates, and was suggested to be deleterious by online software prediction.ConclusionsThe homozygote of this variant (TUBB8: NM_ 177,987: exon 2:c.C161T: p.A54V) might affect spindle assembly, cause arrest of oocyte maturation and lead to oocyte maturation defect-2.

Novel homozygous mutations in PATL2 lead to female infertility with oocyte maturation arrest.

To identify the disease gene in 40 patients with female infertility due to oocyte maturation arrest. Genomic DNA was extracted from peripheral blood of 40 patients and their family members. Whole-exome sequencing was performed on the patients, and the PATL2 mutations were identified and confirmed by Sanger sequencing. Harmfulness of the mutations was analyzed by SIFT, Polyphen-2, Mutation Taster, and M-CAP software, and we used western immunoblotting analysis to check the effect of mutations on PATL2 protein expression in vitro. Two novel missense mutations c.1528C>A (p.Pro510Thr) and c.1376C>A (p.Ser459Tyr) in PATL2 were identified in three patients (7.5%) from two consanguineous families in our cohort. We found that mutations in PATL2 resulted in variable oocyte phenotypes, including GV arrest, MI arrest, and morphologic abnormalities. Western immunoblotting analysis showed that the expression levels of the two novel mutant PATL2 proteins decreased significantly. We identified two novel PATL2 mutations that caused oocyte maturation arrest and abnormal morphology, and variable phenotypes in patients.

Novel mutations in PATL2: expanding the mutational spectrum and corresponding phenotypic variability associated with female infertility.

Oocyte maturation arrest results in primary female infertility, but the genetic etiology of this phenotype remains largely unknown. Previously, we and other groups have reported that biallelic mutations in PATL2 are mainly responsible for human oocyte germinal vesicle-stage arrest and that the specific phenotype varies for different mutations. Here, we identified four novel missense mutations (p.V260M, p.Q300*, p.T425P, and p.D293Y), a novel frameshift mutation (p.N239Tfs*9), and a reported splicing mutation (p.R75Vfs*21) in PATL2 in seven affected individuals from five unrelated families, showing a multiplicity of phenotypes in oocyte maturation arrest, fertilization failure, or embryonic developmental arrest, which further expands the mutational and phenotypic spectrum in patients with PALTL2 mutations. This work further indicates the critical role of PATL2 in oocyte maturation and early embryo development and will provide a basis for pursuing the determination of genetic variation in PALT2 as an additional criterion for evaluating the quality of oocytes and embryos for assisted reproduction techniques.

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The comprehensive mutational and phenotypic spectrum of TUBB8 in female 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).