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. 2019 Apr;36(4):741-747.
doi: 10.1007/s10815-019-01404-1. Epub 2019 Feb 18.

Novel mutation in the ZP1 gene and clinical implications

Affiliations

Novel mutation in the ZP1 gene and clinical implications

Ping Yuan et al. J Assist Reprod Genet. 2019 Apr.

Abstract

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.

Keywords: Empty follicle syndrome; Infertility; Mutation; Oocyte anomalies; ZP1.

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Conflict of interest statement

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethics approval and consent to participate

The study protocol and all subjects who participated in this study were approved by the Institutional Review Board of our institute, and informed consent was obtained from all patients prior to their participation in accordance with institutional and national guidelines.

Figures

Fig. 1
Fig. 1
Oocyte characteristics examined by light microscopy in both of the patients. a Phenotypes of oocytes from a normal individual. Left panel: a cumulus-oocyte complex (COC) on day 0. Middle panel: a metaphase II oocyte on day 0. Right panel: a fertilized oocyte with two pronuclei on day 1. “A” indicates granulosa cells, “B” indicates zona pellucida, “C” indicates oocyte, and “D” indicates polar body. The yellow arrowheads indicate adhesive sperm. Scale bars: 50 μm. b Phenotypes of oocytes from patient 1 on day 1. Left panel: a COC without oocyte and zona pellucida in the first cycle. Right panel: an oocyte without zona pellucida but with adhesive sperm (yellow arrowheads). Scale bars: 50 μm. c Phenotypes of oocytes from patient 2 on day 1. Five oocytes were closely surrounded by granulosa cells, and an oocyte structure (white arrow) might be seen in COCs. Scale bars 50 μm
Fig. 2
Fig. 2
Genetic and bioinformatic analysis of ZP1 mutations in the family of patient 2. a Pedigree of the family. The filled circle indicates the EFS patient 2 (II:2). The arrow indicates the proband. Open squares or circles indicate normal family members. The open rhombus indicates that II:4 was pregnant but with a baby of unknown gender. b Partial forward nucleotide sequences in the ZP1 gene. Upper panel: The arrow points to the wild-type c.181C in a control sample and the wild-type codon is underlined (left); the arrow points to the heterozygous c.181C>T (p.Arg61Cys) mutation in the patient (II:2), and the mutated codon is underlined (right). Bottom panel: The left arrow points to the wild-type in a control sample, and the right arrow points to the frameshift c.1169_1176delTTTTCCCA (p.Ile390Thrfs*16) mutation in the patient (II:2). c R61 was conserved among the majority of species, except for rodents such as the mouse. The arginine residue is at position 61 in Homo sapiens, Pan troglodytes, Macaca mulatta, Equus caballus, Oryctolagus cuniculus, and Mus musculus. d Schematic illustration of the motif and domains in ZP1. Wild-type ZP1 protein has 638 amino acids and contains a signal peptide motif (SP, yellow), a P-type trefoil domain (purple), a zona pellucida domain (gray), and a transmembrane domain (TM, blue). The arrows indicate the locations of the novel mutation (red) and a known frameshift mutation (black), the latter of which is predicted to delete 234 amino acids from the C-terminus of the ZP1 protein

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