Novel zona pellucida gene variants identified in patients with oocyte anomalies

Yang, Ping; Luan, Xin; Peng, Ying; Chen, Tailai; Su, Shizhen; Zhang, Changming; Zhao, Wei; Cheng, Lei; Zhang, Xin; Wang, Ying; Chen, Zi‐Jiang; Zhao, Han

doi:10.1016/j.fertnstert.2017.03.029

Cited by 29 publications

(27 citation statements)

References 27 publications

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“…To our knowledge, this is the first report to describe a GEFS patient with compound heterozygous mutations in the ZP1 gene. Including our study, a total of four cases with four different ZP1 mutations have been identified [8,12]. In the previous studies, patients with ZP1 mutations displayed abnormal eggs that lacked ZP or degenerated or cracked oocytes [8,12].…”

Section: Discussionmentioning

confidence: 92%

“…The mutation was named according to the Human Genome Variation Society (HGVS) standards (http://www.hgvs.org/ mutnomen/) with + 1 corresponding to the A of the ATG translation initiation codon in the GenBank cDNA sequence (LHCGR for NM_000233, ZP1 for NM_ 207341, ZP2 for NM_003460, ZP3 for NM_001110354, and ZP4 for NM_021186). Similar to other studies [9][10][11][12], we analyzed the first five exons of ZP3 to avoid false interpretation of the sequencing results due to a polymorphic locus, POM-ZP3 [13]. We also sequenced DNA from 200 control subjects.…”

Section: Mutation Detection and Bioinformatics Analysismentioning

confidence: 99%

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Novel mutation in the ZP1 gene and clinical implications

Yuan

et al. 2019

J Assist Reprod Genet

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Purpose Empty follicle syndrome (EFS) is a complex reproductive disorder characterized by the repeated failure to aspirate oocytes from mature ovarian follicles during in vitro fertilization (IVF). In addition to some cases caused by iatrogenic problems and known genetic factors, there are still many unexplained aspects of EFS. Here, we aimed to assess the clinical and genetic characteristics of two EFS patients. Methods We have characterized two primary infertility patients with EFS in a nonconsanguineous family from China. Both the patients presented similar clinical phenotypes, that is a few granulosa cells but no oocytes could be retrieved during repeated cycles with normal follicular development, E2 levels, and bioavailable hCG plasma levels. Abnormal oocytes were obtained once or twice between multiple IVF cycles. We performed Sanger sequencing of the LHCGR and ZP1~ZP4 genes in the patients, and further bioinformatics analysis was performed to identify pathogenic elements in the genes. Results A novel mutation, c.181C>T (p.Arg61Cys), and a known mutation, c.1169_1176delTTTTCCCA (p.Ile390Thrfs*16), in the ZP1 gene were both identified in patient 2, but no mutations were identified in patient 1. The novel mutation inherited from her mother was absent in the control cohort and the ExAc database. The arginine residue is conserved at this position, and its replacement by cysteine was predicted to be deleterious. In another allele, a paternal frameshift mutation was predicted to introduce premature stop codons, resulting in the deletion of 234 amino acids from the C-terminus of the ZP1 protein. Conclusions Our findings presented compound heterozygous mutations in ZP1 associated with EFS and abnormal oocytes and provided further new evidence for the genetic basis of EFS and support for the genetic diagnosis of infertile individuals.

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Section: Discussionmentioning

confidence: 92%

Section: Mutation Detection and Bioinformatics Analysismentioning

confidence: 99%

Novel mutation in the ZP1 gene and clinical implications

Yuan

et al. 2019

J Assist Reprod Genet

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“…Human homozygous or compound heterozygous mutations reported in ZP1 result in similar albeit not identical phenotypes (Figure 2A, Table 3). Indeed, mutations in ZP1 can lead to oocyte degeneration, oocytes lacking zona pellucida or increased fragility of oocytes rendering follicular puncture tricky, ultimately resulting in an empty follicle syndrome [23][24][25][26][27][28] Among the mutations reported in the literature, seven of them (no 2,3,4,8,10,11,13 as indicated on Table 3) affect one of the zonae pellucidae domains (ZP-N1, ZP-N or ZP-C domain). These mutations result in a lack of oocytes or only degenerate oocytes.…”

Section: Discussionmentioning

confidence: 99%

“…(A) Schematic diagram of ZP1 exons is shown. The mutations identified so far on ZP1 are indicated in blue on top, numbered 1 to 17[23][24][25][26][27][28], details are given inTable 3. The bottom part indicates the newly identified nucleotide change within a sequence alignment among mammals.…”

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confidence: 99%

Homozygous Splice Site Mutation in ZP1 Causes Familial Oocyte Maturation Defect

Okutman

Demirel

Tülek

et al. 2020

Genes

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In vitro fertilization (IVF) involves controlled ovarian hyperstimulation using hormones to produce large numbers of oocytes. The success of IVF is tightly linked to the availability of mature oocytes. In most cases, about 70% to 80% of the oocytes are mature at the time of retrieval, however, in rare instances, all of them may be immature, implying that they were not able to reach the metaphase II (MII) stage. The failure to obtain any mature oocytes, despite a well conducted ovarian stimulation in repeated cycles is a very rare cause of primary female infertility, for which the underlying suspected genetic factors are still largely unknown. In this study, we present the whole exome sequencing analysis of a consanguineous Turkish family comprising three sisters with a recurrent oocyte maturation defect. Analysis of the data reveals a homozygous splice site mutation (c.1775-3C>A) in the zona pellucida glycoprotein 1 (ZP1) gene. Minigene experiments show that the mutation causes the retention of the intron 11 sequence between exon 11 and exon 12, resulting in a frameshift and the likely production of a truncated protein.

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“…Against this background, the recent identification of different ZP1 mutations in infertile patients [39][40][41][42][43] argues for a much more important role of this glycoprotein in human reproduction than previously recognized. To gain molecular insights into the biological function of ZP1 and its possible relation with that of ZP4, we undertook a biochemical and structural investigation that began with the analysis of a reported case of primary female infertility associated with a frameshift mutation in the human ZP1 gene (I390fs404X) 39 .…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of egg coat cross-linking sheds light on ZP1-associated female infertility

Nishimura

Dioguardi

Nishio

et al. 2019

Preprint

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Interaction between sperm and the egg zona pellucida (ZP) is the first step of mammalian fertilization, and ZP component ZP1 is important for fertility by covalently cross-linking ZP filaments into a matrix. Like ZP4, a structurally-related subunit absent in the mouse, ZP1 is predicted to contain an N-terminal ZP-N domain of unknown function. Characterization of ZP1 proteins carrying mutations from infertile patients suggests that, unlike in the mouse, filament cross-linking by ZP1 is crucial for human ZP assembly. We map the function of ZP1 to its ZP-N1 domain and determine crystal structures of ZP-N1 homodimers from a chicken homolog of ZP1.These reveal that ZP filament cross-linking is highly plastic and can be modulated by ZP1 fucosylation and, potentially, zinc sparks. Moreover, we show that ZP4 ZP-N1 forms non-covalent homodimers in chicken but not human. Together, these data identify human ZP1 cross-links as a promising target for non-hormonal contraception.

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Novel zona pellucida gene variants identified in patients with oocyte anomalies

Abstract: ZP gene variants may account for patients with oocyte morphologic abnormalities but not for those with oocyte maturation arrest.

Cited by 29 publications

References 27 publications

Novel mutation in the ZP1 gene and clinical implications

Novel mutation in the ZP1 gene and clinical implications

Homozygous Splice Site Mutation in ZP1 Causes Familial Oocyte Maturation Defect

Molecular basis of egg coat cross-linking sheds light on ZP1-associated female infertility

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