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.
Similar content being viewed by others
References
Zreik TG, Garcia-Velasco JA, Vergara TM, Arici A, Olive D, Jones EF. Empty follicle syndrome: evidence for recurrence. Hum Reprod. 2000;15:999–1002.
Stevenson TL, Lashen H. Empty follicle syndrome:the reality of a controversial syndrome, a systematic review. Fertil Steril. 2008;90:691–8.
Beck-Fruchter R, Weiss A, Lavee M, Geslevich Y, Shalev E. Empty follicle syndrome: successful treatment in a recurrent case and review of the literature. Hum Reprod. 2012;27:1357–67.
Yuan P, He Z, Zheng L, Wang W, Li Y, Zhao H, et al. Genetic evidence of ‘genuine’ empty follicle syndrome: a novel effective mutation in the LHCGR gene and review of the literature. Hum Reprod. 2017;32:944–53.
Chen T, Bian Y, Liu X, Zhao S, Wu K, Yan L, et al. A recurrent missense mutation in ZP3 causes empty follicle syndrome and female infertility. Am J Hum Genet. 2017;101:459–65.
Liu W, Li K, Bai D, Yin J, Tang Y, Chi F, et al. Dosage effects of ZP2 and ZP3 heterozygous mutations cause human infertility. Hum Genet. 2017;136:975–85.
Gook DA, Edgar DH, Borg J, Martic M. Detection of zona pellucida proteins during human folliculogenesis. Hum Reprod. 2008;23:394–402.
Huang HL, Lv C, Zhao YC, Li W, He XM, Li P, et al. Mutant ZP1 in familial infertility. N Engl J Med. 2014;370:1220–6.
Pökkylä RM, Lakkakorpi JT, Nuojua-Huttunen SH, Tapanainen JS. Sequence variations in human ZP genes as potential modifiers of zona pellucida architecture. Fertil Steril. 2011;95:2669–72.
Margalit M, Paz G, Yavetz H, Yogev L, Amit A, Hevlin-Schwartz T, et al. Genetic and physiological study of morphologically abnormal human zona pellucida. Eur J Obstet Gynecol Reprod Biol. 2012;165:70–6.
Ferre M, Amati-Bonneau P, Moriniere C, Ferre-L’Hotellier V, Lemerle S, Przyrowski D, et al. Are zona pellucida genes involved in recurrent oocyte lysis observed during in vitro fertilization? J Assist Reprod Genet. 2014;31:221–7.
Yang P, Luan X, Peng Y, Chen T, Su S, Zhang C, et al. Novel zona pellucida gene variants identified in patients with oocyte anomalies. Fertil Steril. 2017;107:1364–9.
Kipersztok S, Osawa GA, Liang L-F, Modi WS, Dean J. POM-ZP3, a bipartite transcript derived from human ZP3 and a POM121 homologue. Genomics. 1995;25:354–9.
Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG. The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res. 1997;25:4876–82.
Keshava Prasad TS, Goel R, Kandasamy K, Keerthikumar S, Kumar S, Mathivanan S, et al. Human protein reference database—2009 update. Nucleic Acids Res. 2009;37:D767–72.
Vujisic S, Stipoljev F, Bauman R, Dmitrovic R, Jezek D. Pericentric inversion of chromosome 2 in a patient with the empty follicle syndrome: case report. Hum Reprod. 2005;20:2552–5.
Wassarman PM, Litscher ES. Biogenesis of the mouse egg’s extracellular coat, the zona pellucida. Curr Top Dev Biol. 2013;102:243–66.
Rankin TL, O'Brien M, Lee E, Wigglesworth K, Eppig J, Dean J. Defective zonae pellucidae in Zp2-null mice disrupt folliculogenesis, fertility and development. Development. 2001;128:1119–26.
Liu C, Litscher ES, Mortillo S, Sakai Y, Kinloch RA, Stewart CL, et al. Targeted disruption of the mZP3 gene results in production of eggs lacking a zona pellucida and infertility in female mice. Proc Natl Acad Sci U S A. 1996;93:5431–6.
Rankin T, Talbot P, Lee E, Dean J. Abnormal zonae pellucidae in mice lacking ZP1 result in early embryonic loss. Development. 1999;126:3847–55.
Lefièvre L, Conner SJ, Salpekar A, Olufowobi O, Ashton P, Pavlovic B, et al. Four zona pellucida glycoproteins are expressed in the human. Hum Reprod. 2004;19:1580–6.
Wassarman PM, Litscher ES. Influence of the zona pellucida of the mouse egg on folliculogenesis and fertility. Int J Dev Biol. 2012;56:833–9.
Anderson E, Albertini DF. Gap junctions between the oocyte and companion follicle cells in the mammalian ovary. J Cell Biol. 1976;71:680–6.
Acknowledgments
The authors thank the patients and the control subjects for their participation in this study.
Funding
This work was partially supported by the National Natural Science Foundation of China (No. 81801431).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(DOCX 23 kb)
Rights and permissions
About this article
Cite this article
Yuan, P., Li, R., Li, D. et al. Novel mutation in the ZP1 gene and clinical implications. J Assist Reprod Genet 36, 741–747 (2019). https://doi.org/10.1007/s10815-019-01404-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10815-019-01404-1