2. Academic Validation
  3. A Recurrent Missense Mutation in ZP3 Causes Empty Follicle Syndrome and Female Infertility

A Recurrent Missense Mutation in ZP3 Causes Empty Follicle Syndrome and Female Infertility

  • Am J Hum Genet. 2017 Sep 7;101(3):459-465. doi: 10.1016/j.ajhg.2017.08.001.
Tailai Chen 1,  Yuehong Bian 1,  Xiaoman Liu 1,  Shigang Zhao 1,  Keliang Wu 1,  Lei Yan 1,  Mei Li 1,  Zhenglin Yang 2,  Hongbin Liu 1,  Han Zhao 3,  Zi-Jiang Chen 4
Affiliations

Affiliations

  • 1 Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250001, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan 250001, China; The Key Laboratory for Reproductive Endocrinology, Shandong University, Ministry of Education, Jinan 250001, China.
  • 2 The Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
  • 3 Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250001, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan 250001, China; The Key Laboratory for Reproductive Endocrinology, Shandong University, Ministry of Education, Jinan 250001, China. Electronic address: hanzh80@yahoo.com.
  • 4 Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250001, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan 250001, China; The Key Laboratory for Reproductive Endocrinology, Shandong University, Ministry of Education, Jinan 250001, China; Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China. Electronic address: chenzijiang@hotmail.com.
PMID: 28886344 DOI: 10.1016/j.ajhg.2017.08.001
Abstract

Empty follicle syndrome (EFS) is defined as the failure to aspirate oocytes from mature ovarian follicles during in vitro fertilization. Except for some cases caused by pharmacological or iatrogenic problems, the etiology of EFS remains enigmatic. In the present study, we describe a large family with a dominant inheritance pattern of female infertility characterized by recurrent EFS. Genome-wide linkage analyses and whole-exome Sequencing revealed a paternally transmitted heterozygous missense mutation of c.400 G>A (p.Ala134Thr) in zona pellucida glycoprotein 3 (ZP3). The same mutation was identified in an unrelated EFS pedigree. Haplotype analysis revealed that the disease allele of these two families came from different origins. Furthermore, in a cohort of 21 cases of EFS, two were also found to have the ZP3 c.400 G>A mutation. Immunofluorescence and histological analysis indicated that the oocytes of the EFS female had degenerated and lacked the zona pellucida (ZP). ZP3 is a major component of the ZP filament. When mutant ZP3 was co-expressed with wild-type ZP3, the interaction between wild-type ZP3 and ZP2 was markedly decreased as a result of the binding of wild-type ZP3 and mutant ZP3, via dominant negative inhibition. As a result, the assembly of ZP was impeded and the communication between cumulus cells and the oocyte was prevented, resulting in oocyte degeneration. These results identified a genetic basis for EFS and oocyte degeneration and, moreover, might pave the way for genetic diagnosis of infertile females with this phenotype.

Keywords

ZP3; empty follicle syndrome; infertility; oocyte degeneration; pedigree; whole exome sequencing; zona pellucida.

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