HGNC Approved Gene Symbol: ZP1
Cytogenetic location: 11q12.2 Genomic coordinates (GRCh38): 11:60,867,542-60,875,687 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q12.2 | Oocyte/zygote/embryo maturation arrest 1 | 615774 | Autosomal recessive | 3 |
The zona pellucida is a thick glycoprotein coat that surrounds the oocyte to mediate sperm binding and induction of the acrosome reaction, prevent postfertilization polyspermy, and protect the developing embryo prior to implantation. ZP1 is 1 of 4 glycoproteins that form the human zona pellucida (Hughes and Barratt, 1999).
By EST database analysis, Hughes and Barratt (1999) identified human ZP1. The predicted protein contains 638 amino acids and has a calculated molecular mass of 70.1 kD. It has an N-terminal signal sequence, highly conserved trefoil and ZP domains, and a C-terminal transmembrane domain. ZP1 contains 97 possible O-glycosylation sites, 4 possible N-glycosylation sites, and a potential furin (136950) cleavage site. Human ZP1 shares 67% and 68% amino acid identity with mouse and rat Zp1, respectively.
Using RT-PCR and mass spectrometry, Lefievre et al. (2004) identified 4 ZP mRNAs and proteins in human oocytes, including ZP4 (613514). Of the 4, ZP1 was the least abundant in both human and mouse oocytes. However, despite its low abundance, Rankin et al. (1999) showed that Zp1 was essential for the structural integrity of the zona matrix in mice.
In his review, Dean (1992) stated that the human and mouse zona pellucida is composed of 3 major glycoproteins, ZP1, ZP2 (182888), and ZP3 (182889). ZP3, the molecule responsible for the major sperm-receptor activity of the zona, plays a significant role in fertilization. ZP2 is implicated as a secondary sperm receptor that binds sperm only after the induction of the sperm acrosome reaction. Hughes and Barratt (1999) and Lefievre et al. (2004) later determined that the human zona pellucida is composed of 4 glycoproteins, ZP1, ZP2, ZP3, and ZP4.
The ZP1 gene contains 12 exons. Upstream of the translation initiation site, ZP1 has a TATAA box and a consensus E box involved in oocyte-specific expression.
Hughes and Barratt (1999) mapped the ZP1 gene to chromosome 11q12.2 based on its inclusion within a PAC from that region. They noted that the mouse Zp1 gene maps to chromosome 19 in a region of conserved synteny with human chromosome 11q12.2.
Gross (2014) confirmed that the ZP1 gene maps to chromosome 11q12.2 based on an alignment of the ZP1 sequence (GenBank BC067899) with the genomic sequence (GRCh37).
Pang et al. (2011) used ultrasensitive mass spectrometric analyses to demonstrate that the sialyl-Lewis(X) (SLEX) sequence, composed of NeuAc-alpha2-3Gal-beta1-4(Fuc-alpha1-3)GlcNAc, a well-known selectin ligand, is the most abundant terminal sequence on the N- and O-glycans of human zona pellucida. Sperm-ZP binding was largely inhibited by glycoconjugates terminated with sialyl-Lewis(X) sequences or by antibodies directed against this sequence. Thus, Pang et al. (2011) concluded that the sialyl-Lewis(X) sequence represents the major carbohydrate ligand for human sperm-egg binding.
In a consanguineous Han Chinese family in which 4 sisters were infertile and 2 had documented absence of the zona pellucida around their oocytes (OZEMA1; 615774), Huang et al. (2014) analyzed 4 candidate genes and identified homozygosity for a frameshift mutation in the ZP1 gene (195000.0001). The mutation, which segregated with disease in the family, was not found in 210 ethnically matched controls or in public databases.
In 4 unrelated Chinese women with primary infertility due to absence of the oocyte zona pellucida, Zhou et al. (2019) identified homozygosity or compound heterozygosity for mutations in the ZP1 gene (see, e.g., 195000.0002-195000.0004).
In affected members of a consanguineous Han Chinese family with oocyte/zygote/embryo maturation arrest-1 (OZEMA1; 615774), Huang et al. (2014) identified homozygosity for an 8-bp deletion (c.1169_1176delTTTTCCCA) in the ZP1 gene, causing a frameshift predicted to result in a premature termination codon (Ile390fs404Ter). The deletion disrupts the zona pellucida domain with a terminal sequence of 15 amino acids bearing no homology to the corresponding sequence of normal ZP1. The mutation was present in heterozygosity in 4 family members of known fertility, but was not found in 210 Han Chinese controls or in the 1000 Genomes or Human Gene Mutation databases. Immunofluorescence analysis by confocal microscopy of oocytes from 1 of the affected individuals revealed diffuse staining of mutant ZP1 and ZP3 (182889) in patient oocytes, in contrast to concentrated staining of ZP1 and ZP3 in the peripheral zona matrix region in unaffected ova.
In a 30-year-old Chinese woman (family 1) with primary infertility due to an oocyte maturation defect (OZEMA1; 615774), Zhou et al. (2019) identified homozygosity for a c.1708G-A transition (chr11:60,642,655) in exon 11 of the ZP1 gene, resulting in a val570-to-met (V570M) substitution at a conserved residue. Her unaffected consanguineous parents were heterozygous for the mutation. Analysis of transfected CHO cells showed that V570M was nearly undetectable in cell-culture media, suggesting possible secretory obstruction and subsequent failed assembly of the zona pellucida in vivo.
In a 33-year-old Chinese woman (family 4) with primary infertility due to an oocyte maturation defect (OZEMA1; 615774), Zhou et al. (2019) identified compound heterozygosity for splicing mutations in the ZP1 gene: a c.1430+1G-T transversion (chr11:60,641,038) in intron 8 and a c.1775-8C-T transition in intron 11 (195000.0004). Her unaffected parents were each heterozygous for 1 of the mutations. Analysis of cDNA from patient granulosa cells showed retention of the 69-bp and 265-bp intronic sequences with the respective mutations, predicted to result in premature truncation in both cases (C478X and Asp592GlyfsTer29, respectively). Patient granulosa cells showed relatively decreased endogenous ZP1 proteins, consistent with degradation of the majority of truncated proteins.
For discussion of the c.1775-8C-T transition (chr:1160,642,979) in intron 11 of the ZP1 gene that was found in compound heterozygous state in a 33-year-old Chinese woman (family 4) with primary infertility due to an oocyte maturation defect (OZEMA1; 615774) by Zhou et al. (2019), see 195000.0003.
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]
Gross, M. B. Personal Communication. Baltimore, Md. 6/24/2014.
Huang, H.-L., Lv, C., Zhao, Y.-C., Li, W., He, X.-M., Li, P., Sha, A.-G., Tian, X., Papasian, C. J., Deng, H.-W., Lu, G.-X., Xiao, H.-M. Mutant ZP1 in familial infertility. New Eng. J. Med. 370: 1220-1226, 2014. [PubMed: 24670168] [Full Text: https://doi.org/10.1056/NEJMoa1308851]
Hughes, D. C., Barratt, C. L. R. Identification of the true human orthologue of the mouse Zp1 gene: evidence for greater complexity in the mammalian zona pellucida. Biochim. Biophys. Acta 1447: 303-306, 1999. [PubMed: 10542331] [Full Text: https://doi.org/10.1016/s0167-4781(99)00181-5]
Lefievre, L., Conner, S. J., Salpekar, A., Olufowobi, O., Ashton, P., Pavlovic, B., Lenton, W., Afnan, M., Brewis, I. A., Monk, M., Hughes, D. C., Barratt, C. L. R. Four zona pellucida glycoproteins are expressed in the human. Hum. Reprod. 19: 1580-1586, 2004. [PubMed: 15142998] [Full Text: https://doi.org/10.1093/humrep/deh301]
Pang, P.-C., Chiu, P. C. N., Lee, C.-L., Chang, L.-Y., Panico, M., Morris, H. R., Haslam, S. M., Khoo, K.-H., Clark, G. F., Yeung, W. S. B., Dell, A. Human sperm binding is mediated by the sialyl-Lewis(X) oligosaccharide on the zona pellucida. Science 333: 1761-1764, 2011. [PubMed: 21852454] [Full Text: https://doi.org/10.1126/science.1207438]
Rankin, T., Talbot, P., Lee, E., Dean, J. Abnormal zonae pellucidae in mice lacking ZP1 result in early embryonic loss. Development 126: 3847-3855, 1999. [PubMed: 10433913] [Full Text: https://doi.org/10.1242/dev.126.17.3847]
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]