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

Chen, Yongzhe; Wang, Zesong; Wu, Yueren; He, Wen‐Bin; Du, Juan; Cai, Sufen; Gong, Fei; Lu, Guangxiu; Lin, Ge; Dai, Chen

doi:10.3389/fgene.2021.690070

Cited by 7 publications

(6 citation statements)

References 25 publications

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“…ZP3 exerts pleiotropic effects on ovarian development because it is a critical component of the zona pellucida starting from the primordial follicle stage 18 . Interestingly, only missense variants or in-frame deletions in ZP3 have been reported in patients with defects in oocyte maturation 19 , 20 . However, these LoF mutations, which were identified in the current POI study, tend to induce more severe protein defects, possibly due to loss of the conserved ZP domain and transmembrane domain.…”

Section: Resultsmentioning

confidence: 99%

“…Pathogenic variants of ZAR1 , a maternal effect gene, were reported in human patients with POI and have a remarkably high prevalence. Identification of POI-associated variants in ZP3 broadens the phenotypic spectrum of this gene beyond its currently understood role in empty follicle syndrome 20 , 57 . The discovery of variants in PRDM1 demonstrates that the pathophysiology of POI may begin as early as PGC specification.…”

Section: Discussionmentioning

confidence: 99%

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Landscape of pathogenic mutations in premature ovarian insufficiency

Tang

Guo

et al. 2023

Nat Med

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Premature ovarian insufficiency (POI) is a major cause of female infertility due to early loss of ovarian function. POI is a heterogeneous condition, and its molecular etiology is unclear. To identify genetic variants associated with POI, here we performed whole-exome sequencing in a cohort of 1,030 patients with POI. We detected 195 pathogenic/likely pathogenic variants in 59 known POI-causative genes, accounting for 193 (18.7%) cases. Association analyses comparing the POI cohort with a control cohort of 5,000 individuals without POI identified 20 further POI-associated genes with a significantly higher burden of loss-of-function variants. Functional annotations of these novel 20 genes indicated their involvement in ovarian development and function, including gonadogenesis (LGR4 and PRDM1), meiosis (CPEB1, KASH5, MCMDC2, MEIOSIN, NUP43, RFWD3, SHOC1, SLX4 and STRA8) and folliculogenesis and ovulation (ALOX12, BMP6, H1-8, HMMR, HSD17B1, MST1R, PPM1B, ZAR1 and ZP3). Cumulatively, pathogenic and likely pathogenic variants in known POI-causative and novel POI-associated genes contributed to 242 (23.5%) cases. Further genotype–phenotype correlation analyses indicated that genetic contribution was higher in cases with primary amenorrhea compared to that in cases with secondary amenorrhea. This study expands understanding of the genetic landscape underlying POI and presents insights that have the potential to improve the utility of diagnostic genetic screenings.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Landscape of pathogenic mutations in premature ovarian insufficiency

Tang

Guo

et al. 2023

Nat Med

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“…Intriguingly, the mutation we identified was located in the ZPD of ZP3. Previous studies have linked mutations in ZP3 to impaired assembly of the zona pellucida, resulting in the abnormal assembly of the zona pellucida fiber network and oocyte degeneration associated with GEFS( Chen et al, 2017 ; Chen et al, 2021 ; Zhang et al, 2021 ; Zhang et al, 2022 ). Additionally, knockdown of ZP3 using specific siRNA has been shown to significantly increase the proportion of oocytes arrested at the GV stage ( Gao et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Case report: A novel homozygous variant in ZP3 is associated with human empty follicle syndrome

Kong,

Xu,

Shen

et al. 2023

Front. Genet.

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Empty follicle syndrome (EFS) is a rare condition in female infertility. It is characterized by the inability to retrieve oocytes from visibly large, normally developing follicles in the ovaries, despite ovarian stimulation. The genetic factors contributing to this syndrome remain unclear. This study focused on patients who underwent three consecutive ovarian stimulation procedures for oocyte retrieval but experienced unsuccessful outcomes, despite the presence of observable large follicles. Ultrasound examinations were conducted to assess follicular development during each procedure. In order to investigate potential genetic causes, we performed whole exome sequencing on peripheral blood samples from the patient. Interestingly, we identified that this patient carries a homozygous mutation in the ZP3 genes. Within the ZP3 gene, we identified a homozygous variant [NM_001110354.2, c.176T>A (p.L59H)] specifically located in the zona pellucida (ZP) domain. Further analysis, including bioinformatics methods and protein structure modeling, was carried out to investigate the conservation of the ZP3L59H variant across different species. This homozygous variant exhibited a high degree of conservation across various species. Importantly, the homozygous ZP3L59H variant was associated with the occurrence of empty follicle syndrome in affected female patients. The homozygous ZP3L59H variant represents a newly discovered genetic locus implicated in the development of human empty follicle syndrome. Our findings contribute to a deeper understanding of the role of zona pellucida-related genes in infertility and provide valuable insights for the genetic diagnosis of female infertility.

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“…ZPD plays an essential role in the secretion of ZP and the polymerization of ZP into filaments; mutations mainly occur in this region [ 3 , 54 ]. Dysfunction of ZPD caused by mutation will not only influence the secretion of ZP but also primarily affect the interaction between ZP proteins [ 12 , 29 , 37 ]. Immediately after ZPD, all four human ZP glycoproteins have CFCS.…”

Section: Discussionmentioning

confidence: 99%

Can successful pregnancy be achieved and predicted from patients with identified ZP mutations? A literature review

Zhou

Wang

Yang

et al. 2022

Reprod Biol Endocrinol

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Background In mammals, normal fertilization depends on the structural and functional integrity of the zona pellucida (ZP), which is an extracellular matrix surrounding oocytes. Mutations in ZP may affect oogenesis, fertilization and early embryonic development, which may cause female infertility. Methods A PubMed literature search using the keywords ‘zona pellucida’, ‘mutation’ and ‘variant’ limited to humans was performed, with the last research on June 30, 2022. The mutation types, clinical phenotypes and pregnancy outcomes were summarized and analyzed. The naive Bayes classifier was used to predict clinical pregnancy outcomes for patients with ZP mutations. Results A total of 29 publications were included in the final analysis. Sixty-nine mutations of the ZP genes were reported in 87 patients with different clinical phenotypes, including empty follicle syndrome (EFS), ZP-free oocytes (ZFO), ZP-thin oocytes (ZTO), degenerated and immature oocytes. The phenotypes of patients were influenced by the types and location of the mutations. The most common effects of ZP mutations are protein truncation and dysfunction. Three patients with ZP1 mutations, two with ZP2 mutations, and three with ZP4 mutations had successful pregnancies through Intracytoplasmic sperm injection (ICSI) from ZFO or ZTO. A prediction model of pregnancy outcome in patients with ZP mutation was constructed to assess the chance of pregnancy with the area under the curve (AUC) of 0.898. The normalized confusion matrix showed the true positive rate was 1.00 and the true negative rate was 0.38. Conclusion Phenotypes in patients with ZP mutations might be associated with mutation sites or the degree of protein dysfunction. Successful pregnancy outcomes could be achieved in some patients with identified ZP mutations. Clinical pregnancy prediction model based on ZP mutations and clinical characteristics will be helpful to precisely evaluate pregnancy chance and provide references and guidance for the clinical treatment of relevant patients.

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

Cited by 7 publications

References 25 publications

Landscape of pathogenic mutations in premature ovarian insufficiency

Landscape of pathogenic mutations in premature ovarian insufficiency

Case report: A novel homozygous variant in ZP3 is associated with human empty follicle syndrome

Can successful pregnancy be achieved and predicted from patients with identified ZP mutations? A literature review

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