The critical role of ZP genes in female infertility characterized by empty follicle syndrome and oocyte degeneration

Yang, Ping; Chen, Tailai; Liu, Yuqing; Hou, Zhenzhen; Wu, Keliang; Cao, Yongzhi; Zhang, Jiangtao; Wang, Zhao; Zhao, Han

doi:10.1016/j.fertnstert.2020.11.003

Cited by 23 publications

(19 citation statements)

References 37 publications

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“…Since 2014, dozens of mutations in human ZP genes have been identified as the cause of oocyte anomalies and female infertility. The mutations in ZP gene are the predominant causes of EFS (Yang et al, 2020 ). Most ZP mutations in EFS patients have been identified in ZP1 , while only two were found in ZP2 and ZP3 .…”

Section: Case Presentationmentioning

confidence: 99%

“…Follicle atresia and oocyte degeneration due to ovarian aging may be possible causes (Awonuga et al, 1998 ). In recent years, mutations in four genes, including LHCGR, ZP1, ZP2 , and ZP3 , have been linked to EFS (Yuan et al, 2017 ; Chen et al, 2018 ; Dai et al, 2019a ; Lu et al, 2019 ; Yang et al, 2020 ; Wang et al, 2021 ). Nevertheless, the pathogenesis of EFS, especially in patients with gene mutations, remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

“…The human ZP comprises four glycoproteins encoded by ZP1–ZP4 genes (Lefievre et al, 2004 ). In recent years, mutations in ZP genes have been reported to be responsible for oocyte anomalies and female infertility (Yang et al, 2020 ). An autosomal recessive truncating variant in ZP1 was identified in a consanguineous Chinese family, and this was suggested to explain infertility in females with abnormal oocytes lacking a ZP (Huang et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

“…This mutation exerts its effect via a dominant negative effect on the interaction of ZP proteins, thereby possibly affecting ZP assembly, preventing communication between the cumulus cells and the oocyte, and eventually leading to oocyte degeneration (Chen et al, 2017 ). In the past 3 years, 25 ZP1 mutations, two ZP2 mutations, and two ZP3 mutations were identified in patients with EFS (Dai et al, 2019 ; Yang et al, 2020 ; Wang et al, 2021 ; Zhang et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Case Report: A Novel Heterozygous ZP3 Deletion Associated With Empty Follicle Syndrome and Abnormal Follicular Development

Chen

Wang

et al. 2021

Front. Genet.

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Background: Empty follicle syndrome (EFS) is defined as the complete failure to retrieve oocytes after ovarian stimulation. Although several mutations in ZP1, ZP2, ZP3, and LHCGR have been identified as genetic causes of EFS, its pathogenesis is still not well-understood.Methods: Whole-exome sequencing (WES) was employed to identify the candidate pathogenic mutations, which were then verified by Sanger sequencing. A study in CHO-K1 cells was performed to analyze the effect of the mutation on protein expression. Additionally, immunohistochemistry (IHC) staining was used to examine follicular development and zona pellucida (ZP) assembly in the ovary of an EFS patient.Results: A novel heterozygous deletion in ZP3 (c.565_579del[p.Thr189_Gly193del]) was identified in the EFS patient. It was inherited dominantly and resulted in significant degradation of the ZP3 protein. Oocytes with degenerated cytoplasm and abnormal ZP assembly were observed in follicles up to the secondary stage, and many empty follicle-like structures were present.Conclusion: We identified a novel ZP3 mutation that expands the mutational spectrum associated with human EFS. We also showed the abnormal follicular development and ZP assembly of the EFS patient with the heterozygous ZP3 mutation, which provides new insights into the pathogenesis of EFS.

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Section: Case Presentationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Case Report: A Novel Heterozygous ZP3 Deletion Associated With Empty Follicle Syndrome and Abnormal Follicular Development

Chen

Wang

et al. 2021

Front. Genet.

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“…Yang et al, 15 recently reported a genetic study from a university based reproductive center in China that was comprised of a big cohort of patients that presented with gEFS. Genetic evaluation was conducted on 35 non correlated infertile patients who went through 16 failed IVF cycles in addition to oocyte degeneration, besides the subjects got a diagnosis of possessing a particular kind of EFS-cumulus oocytes complexes(COC's) but possessed oocytes that were undergoing degeneration, with the utilization of whole -exome sequencing along with targeted Sanger sequencing.…”

mentioning

confidence: 99%

Validation of the existence of genuine Empty follicle syndrome, versus false empty follicle syndrome to make definitive decisions in cases where recurrent IVF failure encountered secondary to absence of oocytes on ovum pick up-a short communication

Kaur¹,

Allahbadia²,

Singh³

2021

IPCB

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Aim: Worldwide a big altercation exists with regards to the actual existence of the term “ Empty follicle syndrome’’(EFS), so much so that certain big authorities in the field have been believing that true EFS does not exist. Basically EFS is a syndrome when no functionally intact oocyte get retrieved when attempting an oocyte pick up (OPU) for a successful in vitro fertilization (IVF), however such patients encounter recurrent IVF failures. Since it is has become a big problem for the treating reproductive endocrinologist, besides the patient encountering recurrent IVF failures, it has become essential to differentiate the true EFS alias genuine Empty follicle syndrome (gEFS) from what is labeled today as the false empty follicle syndrome (fEFS). In view of the recently documented presence of mutations, gEFS got verified and appears to silence this biggest conflict that arose secondary to the existence of a false empty follicle syndrome(fEFS), where one could manage to get successful IVF outcomes subsequent to repeated hCG injections/ gonadotropin releasing hormone (GnRH) agonist in addition to pregnancy, with lot of clinicians believing there is no true term like EFS. Methods: Recently Yang et al., performed a study In tertiary a university based reproductive center in China that was comprised of a big cohort of patients that presented with gEFS. Genetic evaluation was conducted on 35 non correlated infertile patients who went through 16 failed IVF cycles in addition to oocyte degeneration, besides the subjects got a diagnosis of possessing a particular kind of EFS- cumulus oocytes complexes (COC’s) but possessed oocytes that were undergoing degeneration, with the utilization of whole –exome sequencing along with targeted Sanger sequencing. Results: Yang et al., found 22 innovative genetic variant of zona pellucida (ZP), genes in 18 subjects, that were inclusive of 20 variants in ZP 1 gene, 2 in ZP 2 gene in addition to 1 recurring variant in ZP3 gene that had been earlier documented. The homogenous /compound heterogenous ZP 1 mutations were inherited in an autosomal recessive manner, while the heterogenous variants of ZP 2 as well as ZP3 genes possessed an autosomal dominant manner of inheritance. Conclusions: These mutations were anticipated to be harmful in silico along with got further experimentally corroborated to be functionally null dependent on their ectopic expression in vitro. Thus with this further evidence that has been recently provided with regards to the existence of genuine Empty follicle syndrome (gEFS), it is significant for the youngsters to realize if they encounter similar cases after trial of rescue hCG injections / GnRH) agonist, not to further keep waiting, but evaluate further with regards to the existence of mutations for Zona Pellucida (ZP), ZP 1, ZP2 as well as ZP3 genes mutations, or LH/ chorionic gonadotropins receptor (LHCGR) gene mutation without subjecting the patient to repeated IVF, with her psychological as well as financial health in mind

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Gene mutations impede oocyte maturation, fertilization, and early embryonic development

Fei

Zhou

2022

BioEssays

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Reproductive diseases are a long-standing problem and have become more common in the world. Currently, 15% of the world's population suffers from infertility, and half of them are women. Maturation of oocytes, successful fertilization, and high-quality embryos are prerequisites for pregnancy. With the development of assisted reproductive technology and advanced genetic assays, we have found that infertility in many young female patients is caused by mutations in various developmental regulators.These pathogenic factors may result in impediment of oocyte maturation, failure of fertilization or early embryonic development arrest. In this review, we categorize these clinically-identified, mutated genetic factors by their molecular characteristics: nuclear factors (PALT2, TRIP13, WEE2, TBPL2, REC114, MEI1 and CDC20), cytoplasmic factors (TLE6, PADI6, NLRP2/5, FBXO43, MOS and BTG4), a factor unique to primates (TUBB8), cell membrane factor (PANX1), and zona pellucida factors (ZP1-3). We compared discrepancies observed in phenotypes between human and mouse models to provide clues for clinical diagnosis and treatment of related reproductive diseases.

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The critical role of ZP genes in female infertility characterized by empty follicle syndrome and oocyte degeneration

Cited by 23 publications

References 37 publications

Case Report: A Novel Heterozygous ZP3 Deletion Associated With Empty Follicle Syndrome and Abnormal Follicular Development

Case Report: A Novel Heterozygous ZP3 Deletion Associated With Empty Follicle Syndrome and Abnormal Follicular Development

Validation of the existence of genuine Empty follicle syndrome, versus false empty follicle syndrome to make definitive decisions in cases where recurrent IVF failure encountered secondary to absence of oocytes on ovum pick up-a short communication

Gene mutations impede oocyte maturation, fertilization, and early embryonic development

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