Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: ZP3
Cytogenetic location: 7q11.23 Genomic coordinates (GRCh38): 7:76,397,522-76,442,069 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q11.23 | Oocyte/zygote/embryo maturation arrest 3 | 617712 | Autosomal dominant | 3 |
During the process of fertilization, the initial interaction between male and female gametes is mediated by a sperm receptor, designated ZP3, which resides in the extracellular glycoprotein matrix (zona pellucida) surrounding the oocyte. Following sperm-oocyte binding, ZP3 triggers the sperm acrosome reaction that releases the protein machinery enabling a spermatozoon to penetrate the zona pellucida (summary by Dean, 1992).
Van Duin et al. (1992) demonstrated that the ZP3 gene encodes a protein of 424 amino acids with a 67% homology to mouse and hamster Zp3. By Southern blotting, gene cloning, and sequence analysis, van Duin et al. (1992) identified a ZP3 isoform, ZP3B, that contains an extra G residue in exon 8 and has the potential to encode a truncated protein of 372 amino acids. Direct sequence analysis of PCR-amplified exon 8 DNA of 56 persons from various populations demonstrated 3 different sequence patterns: 1 containing only ZP3-424-coding sequences and 2 containing ZP3-424- and ZP3-372-coding DNA. The distribution of these 3 patterns was significantly different between the Caucasian and Japanese populations, as indicated by ZP3-372 allele frequencies of 69 and 21%, respectively. Provided that ZP3-372 mRNA is translated in vivo, differences in the protein gene product might have an impact on human zona pellucida composition.
Dean (1992) reviewed the molecular biology of mammalian fertilization with particular reference to the ZP glycoproteins. He compared the structure of the mouse and human ZP2 (182888) and ZP3 genes and pointed out that the use of embryonic stem cell technology in animal models with null mutations in the ZP genes will define the phenotypes of genetic defects and facilitate the search for their human counterparts.
By immunofluorescence microscopy in human oocytes, Chen et al. (2017) observed that ZP3 signals were concentrated in the surrounding zona pellucida, and appeared diffusely in the ooplasm. Contrast staining revealed a distinct outline of the zona pellucida surrounding the oocyte.
Van Duin et al. (1992) demonstrated that the ZP3 gene contains 8 exons spread over 18 kb.
Kipersztok et al. (1995) found that 3-prime end of POMZP3 (600587) is 99% identical to the last 4 exons of ZP3 and likely represents a partial duplication of ZP3.
Crystal Structure
Monne et al. (2008) described a 2.3-angstrom resolution structure of the ZP amino-terminal fragment (ZP-N) of mouse primary sperm receptor ZP3. The ZP-N fold defines an immunoglobulin superfamily subtype with a beta-sheet extension characterized by an E-prime strand and an invariant tyrosine residue implicated in polymerization. The structure strongly supports the presence of ZP-N repeats within the N-terminal region of ZP2 and other vertebrate zona pellucida/vitelline envelope proteins, with implications for overall egg coat architecture, the postfertilization block to polyspermy and speciation.
By analysis of a rodent-human somatic cell hybrid panel, van Duin et al. (1991) and van Duin et al. (1993) mapped the ZP3 gene to chromosome 7. Using fluorescence in situ hybridization, Kipersztok et al. (1995) mapped the ZP3 gene to chromosome 7q11.23.
Lunsford et al. (1990) demonstrated that the mouse Zp2 and Zp3 genes are located on chromosomes 7 and 5, respectively.
In 10 women from 2 unrelated Chinese families as well as 2 unrelated Chinese women with infertility due to an oocyte maturation defect (OZEMA3; 617712), Chen et al. (2017) identified heterozygosity for a missense mutation in the ZP3 gene (A134T; 182889.0001). The mutation segregated fully with disease in both families, with heterozygous male carriers being unaffected. The A134T mutation appeared to act with a dominant-negative effect, interfering with binding between ZP3 and ZP2.
In a 29-year-old Chinese woman with infertility due to absence of oocyte zona pellucida, Zhou et al. (2019) identified heterozygosity for a missense mutation in the ZP3 gene (R255G; 182889.0002).
Zhao et al. (2002) found that mutation of the conserved furin (136950) cleavage site in mouse Zp3 did not affect the intracellular trafficking or secretion of Zp3. After transient expression in growing oocytes, normal and mutant Zp3 associated with the inner aspect of the zona pellucida. These results were confirmed in transgenic mice expressing Zp3 with or without the mutant furin site. In each case, Zp3 was incorporated throughout the width of the zona pellucida and the transgenic mice were fertile. Zhao et al. (2002) concluded that the zona matrix accrues from the inside out and that cleavage at the furin site is not required for formation of the extracellular zona pellucida surrounding mouse eggs.
Liu et al. (2017) generated mice with a truncated Zp3 protein and observed that oocytes from heterozygous female mice were surrounded by a zona pellucida that was less than half the thickness of the ZP seen in wildtype females. The heterozygous mutant females were as fertile as wildtype females; however, homozygous Zp3 -/- females were sterile, with oocytes completely lacking a ZP.
In 10 women from 2 unrelated Chinese families as well as 2 unrelated Chinese women with infertility due to an oocyte maturation defect (OZEMA3; 617712), Chen et al. (2017) identified heterozygosity for a c.400G-A transition (c.400G-A, NM_001110354.1) in exon 2 of the ZP3 gene, resulting in an ala134-to-thr (A134T) substitution at a conserved residue within the ZP domain. The mutation segregated fully with disease in both families, and was shown to have arisen de novo in 1 of the sporadic cases; parental DNA was not available in the other case. The A134T variant was not found in 400 Han Chinese women with normal fertility or 2,213 population-based Han Chinese controls, or in the gnomAD database. ZP3 was barely detectable by immunofluorescence in patient oocytes, and the nucleus was completely disassembled; contrast staining showed no obvious ZP3 signal and the zona pellucida was not observed. Experiments in transfected CHO-K1 cells showed that unlike wildtype ZP3, the A134T mutant had no interaction with ZP2 (182888), and wildtype binding to ZP2 was greatly diminished in the presence of the mutant. In addition, binding between wildtype and mutant ZP3 was observed, indicating that the A134T mutant exerts a dominant-negative effect.
In a 29-year-old Chinese woman (family 6) with infertility due to absence of oocyte zona pellucida (OZEMA3; 617712), Zhou et al. (2019) identified heterozygosity for a c.763C-G transversion (chr7:76,063,404) in exon 5 of the ZP3 gene, resulting in an arg255-to-gly (R255G) substitution at a conserved residue. The mutation status of her parents was unknown. Studies in CHO cells revealed that expression of the R255G mutant was significantly increased when transfected with the other 3 ZP glycoproteins (ZP1, 195000; ZP2, 182888; and ZP4, 613514), and immunoprecipitation experiments suggested that the R255G mutant bound more efficiently to the other 3 wildtype ZP proteins than did wildtype ZP3.
Chen, T., Bian, Y., Liu, X., Zhao, S., Wu, K., Yan, L., Li, M., Yang, Z., Liu, H., Zhao, H., Chen, Z.-J. A recurrent missense mutation in ZP3 causes empty follicle syndrome and female infertility. Am. J. Hum. Genet. 101: 459-465, 2017. [PubMed: 28886344] [Full Text: https://doi.org/10.1016/j.ajhg.2017.08.001]
Dean, J. Biology of mammalian fertilization: role of the zona pellucida. J. Clin. Invest. 89: 1055-1059, 1992. [PubMed: 1556174] [Full Text: https://doi.org/10.1172/JCI115684]
Kipersztok, S., Osawa, G. A., Liang, L. F., Modi, W. S., Dean, J. POM-ZP3, a bipartite transcript derived from human ZP3 and POM121 homologue. Genomics 25: 354-359, 1995. [PubMed: 7789967] [Full Text: https://doi.org/10.1016/0888-7543(95)80033-i]
Liu, W., Li, K., Bai, D., Yin, J., Tang, Y., Chi, F., Zhang, L., Wang, Y., Pan, J., Liang, S., Guo, Y., Ruan, J., Kou, X., Zhao, Y., Wang, H., Chen, J., Teng, X., Gao, S. Dosage effects of ZP2 and ZP3 heterozygous mutations cause human infertility. Hum. Genet. 136: 975-985, 2017. [PubMed: 28646452] [Full Text: https://doi.org/10.1007/s00439-017-1822-7]
Lunsford, R. D., Jenkins, N. A., Kozak, C. A., Liang, L.-F., Silan, C. M., Copeland, N. G., Dean, J. Genomic mapping of murine Zp-2 and Zp-3, two oocyte-specific loci encoding zona pellucida proteins. Genomics 6: 184-187, 1990. [PubMed: 1968044] [Full Text: https://doi.org/10.1016/0888-7543(90)90465-7]
Monne, M., Han, L., Schwend, T., Burendahl, S., Jovine, L. Crystal structure of the ZP-N domain of ZP3 reveals the core fold of animal egg coats. Nature 456: 653-657, 2008. [PubMed: 19052627] [Full Text: https://doi.org/10.1038/nature07599]
van Duin, M., Polman, J. E. M., Suikerbuijk, R. F., Geurts van Kessel, A. H. M., Olijve, W. The human gene for the zona pellucida glycoprotein ZP3 and a second polymorphic locus are located on chromosome 7. Cytogenet. Cell Genet. 63: 111-113, 1993. [PubMed: 8467708] [Full Text: https://doi.org/10.1159/000133512]
van Duin, M., Polman, J. E. M., Verkoelen, C. C. E. H., Bunschoten, H., Meyerink, J. H., Olijve, W., Aitken, R. J. Cloning and characterization of the human sperm receptor ligand ZP3: evidence for a second polymorphic allele with a different frequency in the Caucasian and Japanese populations. Genomics 14: 1064-1070, 1992. [PubMed: 1478648] [Full Text: https://doi.org/10.1016/s0888-7543(05)80130-2]
van Duin, M., Polman, J., Suijkerbuijk, R., Geurts van Kessel, A. The human sperm receptor gene ZP3 is located on chromosome 7. (Abstract) Cytogenet. Cell Genet. 58: 1927 only, 1991.
Zhao, M., Gold, L., Ginsberg, A. M., Liang, L.-F., Dean, J. Conserved furin cleavage site not essential for secretion and integration of ZP3 into the extracellular egg coat of transgenic mice. Molec. Cell. Biol. 22: 3111-3120, 2002. [PubMed: 11940668] [Full Text: https://doi.org/10.1128/MCB.22.9.3111-3120.2002]
Zhou, Z., Ni, C., Wu, L., Chen, B., Xu, Y., Zhang, Z., Mu, J., Li, B., Yan, Z., Fu, J., Wang, W., Zhao, L., Dong, J., Sun, X., Kuang, Y., Sang, Q., Wang, L. Novel mutations in ZP1, ZP2, and ZP3 cause female infertility due to abnormal zona pellucida formation. Hum. Genet. 138: 327-337, 2019. [PubMed: 30810869] [Full Text: https://doi.org/10.1007/s00439-019-01990-1]