Novel mutations in ZP1 and ZP2 cause primary infertility due to empty follicle syndrome and abnormal zona pellucida
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GENETICS
Novel mutations in ZP1 and ZP2 cause primary infertility due to empty follicle syndrome and abnormal zona pellucida Geng Luo 1 & Lixia Zhu 2 & Zhenxing Liu 1 & Xue Yang 1 & Qingsong Xi 2 & Zhou Li 2 & Jinliang Duan 3 & Lei Jin 2 & Xianqin Zhang 1 Received: 9 February 2020 / Accepted: 13 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose Mutations in the zona pellucida glycoprotein genes have been reported to be associated with empty follicle syndrome (EFS) and abnormal zona pellucida (ZP). In this study, we performed genetic analysis in the patients with female infertility due to abnormal zona pellucida and empty follicle syndrome to identify the disease-causing gene mutations in these patients. Methods We characterized three patients from two independent families who had suffered from empty follicle syndrome or abnormal zona pellucida. Whole exome sequencing and Sanger sequencing were used to identify the mutations in the families. Western blot was used to check the expression of wild type and mutant disease genes. Results We identified two novel mutations in these patients, including a novel compound heterozygous mutation (c.507delC, p. His170fs; c.239 G>A, p. Cys80Tyr and c.241 T>C, p. Tyr81His) in ZP1 gene and a compound mutation in ZP2 gene (c.860_861delTG, p.Val287fs and c.1924 C>T, p.Arg642Ter). Expression of the mutant ZP1 protein (p. Cys80Tyr and p. Tyr81His) is significantly decreased compared with the wild-type ZP1. Other three mutations produce truncated proteins. Conclusions Our findings expand the mutational spectrum of ZP1 and ZP2 genes associated with EFS and abnormal oocytes and provide new support for the genetic diagnosis of female infertility. Keywords ZP1 . ZP2 . Female infertility . Empty follicle syndrome
Introduction
Geng Luo and Lixia Zhu contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10815-020-01926-z) contains supplementary material, which is available to authorized users. * Lei Jin [email protected] * Xianqin Zhang [email protected] 1
Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan 430074, Hubei, China
2
Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
3
Reproductive Medical Center, No.924 Hospital of Chinese People’s Liberation Army, Guilin, Guangxi, China
The zona pellucida (ZP) is an extracellular glycoprotein matrix universally surrounding mammalian eggs, which is essential to mediate sperm binding, prevent postfertilization polyspermy, and provide physical barrier for protecting the developing embryo [1]. The ZP matrix of human is composed of four glycoproteins of the ZP family, ZP1, ZP2, ZP3, and ZP4. It has been reported that in humans, ZP can bind to capacitated spermatozoa and induce acrosom
