ZP1

gene
On this page

Also known as ZPB1

Summary

ZP1 (zona pellucida glycoprotein 1, HGNC:13187) is a protein-coding gene on chromosome 11q12.2, encoding Zona pellucida sperm-binding protein 1 (P60852). Component of the zona pellucida, an extracellular matrix surrounding oocytes which mediates sperm binding, induction of the acrosome reaction and prevents post-fertilization polyspermy.

The zona pellucida is an extracellular matrix that surrounds the oocyte and early embryo. It is composed primarily of three or four glycoproteins with various functions during fertilization and preimplantation development. The protein encoded by this gene ensures the structural integrity of the zona pellucida. Mutations in this gene are a cause of oocyte maturation defect and infertility.

Source: NCBI Gene 22917 — RefSeq curated summary.

At a glance

  • Gene–disease (curated): female infertility due to zona pellucida defect (Strong, GenCC)
  • GWAS associations: 1
  • Clinical variants (ClinVar): 148 total — 11 pathogenic, 1 likely-pathogenic
  • Phenotypes (HPO): 4
  • Druggable target: yes
  • MANE Select transcript: NM_207341

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:13187
Approved symbolZP1
Namezona pellucida glycoprotein 1
Location11q12.2
Locus typegene with protein product
StatusApproved
AliasesZPB1
Ensembl geneENSG00000149506
Ensembl biotypeprotein_coding
OMIM195000
Entrez22917

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 retained_intron, 1 protein_coding, 1 nonsense_mediated_decay

ENST00000278853, ENST00000537203, ENST00000540908, ENST00000542971, ENST00000543020

RefSeq mRNA: 3 — MANE Select: NM_207341 NM_001391943, NM_001391944, NM_207341

CCDS: CCDS31572

Canonical transcript exons

ENST00000278853 — 12 exons

ExonStartEnd
ENSE000009909656086914560869266
ENSE000009909676086953760869900
ENSE000013040286086754260867757
ENSE000013058346087095760871144
ENSE000034591086087493360875014
ENSE000035080226087033260870475
ENSE000035242666087363460873775
ENSE000035535736087337560873564
ENSE000035732936087551460875687
ENSE000035936386087316260873289
ENSE000036105866087512960875248
ENSE000036534126087121760871314

Expression profiles

Bgee: expression breadth ubiquitous, 143 present calls, max score 96.41.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3623 / max 25.4543, expressed in 161 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter IDTPM avgSamples expressed
1145110.179182
1145120.117146
1145130.049123
1145090.01275
1145100.00433

Top tissues by expression

245 total, by Bgee expression score (0-100, higher = more expressed):

TissueAnatomy IDExpression scoreQuality
oocyteCL:000002396.41gold quality
male germ line stem cell (sensu Vertebrata) in testisCL:0000089 ∩ UBERON:000047388.86gold quality
secondary oocyteCL:000065586.98gold quality
pituitary glandUBERON:000000781.91gold quality
adenohypophysisUBERON:000219680.17gold quality
left testisUBERON:000453371.53gold quality
right testisUBERON:000453470.63gold quality
testisUBERON:000047369.14gold quality
primordial germ cell in gonadCL:0000670 ∩ UBERON:000099168.25gold quality
omental fat padUBERON:001041468.06gold quality
peritoneumUBERON:000235868.02gold quality
adipose tissue of abdominal regionUBERON:000780867.49gold quality
cerebellar hemisphereUBERON:000224565.41gold quality
cerebellar cortexUBERON:000212965.33gold quality
right hemisphere of cerebellumUBERON:001489064.97gold quality
cerebellumUBERON:000203764.59gold quality
subcutaneous adipose tissueUBERON:000219064.45gold quality
adipose tissueUBERON:000101363.32gold quality
granulocyteCL:000009461.39gold quality
islet of LangerhansUBERON:000000661.07gold quality
adrenal tissueUBERON:001830360.92gold quality
deltoidUBERON:000147660.85gold quality
parotid glandUBERON:000183160.26gold quality
buccal mucosa cellCL:000233660.04gold quality
body of stomachUBERON:000116160.04gold quality
nasal cavity epitheliumUBERON:000538459.96gold quality
tendon of biceps brachiiUBERON:000818859.63gold quality
right adrenal glandUBERON:000123359.13gold quality
upper leg skinUBERON:000426258.91silver quality
transverse colonUBERON:000115758.86gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

ExperimentMarker?Max mean expression
E-ANND-3no2.25

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FIGLA, SOHLH1

Literature-anchored findings (GeneRIF, showing 20)

  • ZP proteins were detected in both the oocyte and the granulosa cells as early as the primordial follicle stage in the human. The detection of ZP proteins in the quiescent primordial follicle suggests that these proteins have been present since oogenesis. (PMID:18033806)
  • ZP1 binds to capacitated spermatozoa and induces acrosomal exocytosis. (PMID:20504872)
  • The ‘ZP domain’ module of human ZP1 has functional activity and may have a role during fertilization in humans. (PMID:20831819)
  • observed sequence variations in exons of ZP1 gene in women with infertility of unknown origin who exhibit abnormal zona pellucida; sperm-ovum interactions appear relatively normal in these patients [CASE REPORTS] (PMID:22889493)
  • this study identified a homozygous frameshift mutation in ZP1 in six family members with a form of infertility with an autosomal recessive mode of inheritance. (PMID:24670168)
  • Our findings presented compound heterozygous mutations in ZP1 associated with Empty follicle syndrome (EFS) and abnormal oocytes and provided further new evidence for the genetic basis of EFS and support for the genetic diagnosis of infertile individuals (PMID:30778819)
  • Mutations in ZP1, ZP2, and ZP3 might affect the corresponding protein expression, secretion, and interaction, thus providing a mechanistic explanation for the phenotypes for female infertility. (PMID:30810869)
  • Study report a characterization of ZP1 proteins carrying mutations from infertile patients, which suggests that, in human, filament cross-linking by ZP1 is crucial to form a stable zona pellucida (ZP) and map the function of ZP1 to its ZP-N1 domain and determine crystal structures of ZP-N1 homodimers from a chicken homolog of ZP1. (PMID:31300655)
  • ZP1 mutations are associated with empty follicle syndrome: evidence for the existence of an intact oocyte and a zona pellucida in follicles up to the early antral stage. A case report. (PMID:31734689)
  • Novel ZP1 pathogenic variants identified in an infertile patient and a successful live birth following ICSI treatment. (PMID:31909477)
  • Homozygous Splice Site Mutation in ZP1 Causes Familial Oocyte Maturation Defect. (PMID:32244758)
  • Novel biallelic loss-of-function variants in ZP1 identified in an infertile female with empty follicle syndrome. (PMID:32556881)
  • Zona Pellucida Proteins, Fibrils, and Matrix. (PMID:32569527)
  • Heterozygous mutations in ZP1 and ZP3 cause formation disorder of ZP and female infertility in human. (PMID:32573113)
  • Novel mutations in ZP1 and ZP2 cause primary infertility due to empty follicle syndrome and abnormal zona pellucida. (PMID:32829425)
  • Novel mutations in ZP1: Expanding the mutational spectrum associated with empty follicle syndrome in infertile women. (PMID:33423275)
  • A novel homozygous nonsense mutation in zona pellucida 1 (ZP1) causes human female empty follicle syndrome. (PMID:33665726)
  • A recurrent ZP1 variant is responsible for oocyte maturation defect with degenerated oocytes in infertile females. (PMID:35460069)
  • A Novel Homozygous Nonsense Mutation in ZP1 Causes Female Infertility due to Empty Follicle Syndrome. (PMID:35773450)
  • Novel variants in ZP1, ZP2 and ZP3 associated with empty follicle syndrome and abnormal zona pellucida. (PMID:36931917)

Cross-species orthologs

3 orthologs

OrganismSymbolGene ID
danio_reriozpax4ENSDARG00000079034
mus_musculusZp1ENSMUSG00000024734
rattus_norvegicusZp1ENSRNOG00000020907

Paralogs (4): ZP2 (ENSG00000103310), ZP4 (ENSG00000116996), QRICH2 (ENSG00000129646), C16orf96 (ENSG00000205832)

Protein

Protein identifiers

Zona pellucida sperm-binding protein 1P60852 (reviewed: P60852)

Alternative names: Zona pellucida glycoprotein 1

All UniProt accessions (3): P60852, H0YG11, V9HWI9

UniProt curated annotations — full annotation on UniProt →

Function. Component of the zona pellucida, an extracellular matrix surrounding oocytes which mediates sperm binding, induction of the acrosome reaction and prevents post-fertilization polyspermy. The zona pellucida is composed of 3 to 4 glycoproteins, ZP1, ZP2, ZP3, and ZP4. ZP1 ensures the structural integrity of the zona pellucida.

Subunit / interactions. Polymers of ZP2 and ZP3 organized into long filaments cross-linked by ZP1 homodimers. Interacts with ZP3.

Subcellular location. Zona pellucida Cell membrane.

Tissue specificity. Expressed in oocytes (at protein level).

Post-translational modifications. Proteolytically cleaved before the transmembrane segment to yield the secreted ectodomain incorporated in the zona pellucida. O-glycosylated.

Disease relevance. Oocyte/zygote/embryo maturation arrest 1 (OZEMA1) [MIM:615774] An autosomal recessive infertility disorder caused by defective oocyte maturation that results in abnormal eggs lacking a zona pellucida. Affected females have normal menstrual cycles and sex hormone levels, no obstruction in the fallopian tubes or abnormalities of the uterus or adnexa. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The ZP domain is involved in the polymerization of the ZP proteins to form the zona pellucida.

Similarity. Belongs to the ZP domain family. ZPB subfamily.

RefSeq proteins (3): NP_001378872, NP_001378873, NP_997224* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR000519P_trefoil_domDomain
IPR001507ZP_domDomain
IPR017957P_trefoil_CSConserved_site
IPR017977ZP_dom_CSConserved_site
IPR042235ZP-C_domHomologous_superfamily
IPR044913P_trefoil_dom_sfHomologous_superfamily
IPR048290ZP_chrDomain
IPR051148Zona_Pellucida_Domain_gpFamily
IPR054554ZP1/4_Ig-likeDomain
IPR055355ZP-CDomain
IPR055356ZP-NDomain

Pfam: PF00100, PF22821, PF23344

UniProt features (21 total): glycosylation site 4, disulfide bond 4, chain 2, region of interest 2, topological domain 2, domain 2, signal peptide 1, compositionally biased region 1, sequence variant 1, propeptide 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-P60852-F173.670.38

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (4): 236–261, 245–260, 255–270, 457–478

Glycosylation sites (4): 76, 379, 561, 596

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

IDPathway
R-HSA-2534343Interaction With Cumulus Cells And The Zona Pellucida

MSigDB gene sets: 76 (showing top): GOBP_SINGLE_FERTILIZATION, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, SP3_Q3, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, TGCTGAY_UNKNOWN, GOBP_SPERM_EGG_RECOGNITION, GOBP_REGULATION_OF_REPRODUCTIVE_PROCESS, RFX1_02, GOBP_FERTILIZATION, GOBP_CELL_CELL_RECOGNITION, TGTYNNNNNRGCARM_UNKNOWN, GOBP_BINDING_OF_SPERM_TO_ZONA_PELLUCIDA, MATZUK_FERTILIZATION, HEB_Q6, YOSHIMURA_MAPK8_TARGETS_UP

GO Biological Process (3): binding of sperm to zona pellucida (GO:0007339), prevention of polyspermy (GO:0060468), single fertilization (GO:0007338)

GO Molecular Function (3): acrosin binding (GO:0032190), structural constituent of egg coat (GO:0035804), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), plasma membrane (GO:0005886), egg coat (GO:0035805), membrane (GO:0016020), extracellular matrix (GO:0031012)

Reactome top-level categories

Rollup of top-1 pathways:

CategoryPathways
Fertilization1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
cellular anatomical structure2
sperm-egg recognition1
egg activation1
negative regulation of fertilization1
fertilization1
enzyme binding1
extracellular matrix structural constituent1
egg coat1
binding1
membrane1
cell periphery1
specialized extracellular matrix1
external encapsulating structure1

Protein interactions and networks

STRING

1130 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
ZP1ZP3P21754999
ZP1ZP2Q05996986
ZP1ZP4Q12836864
ZP1GDF9O60383769
ZP1FIGLAQ6QHK4749
ZP1MMUTP22033673
ZP1NOBOXO60393659
ZP1ASTLQ6HA08657
ZP1IZUMO1Q8IYV9647
ZP1BMP15O95972613
ZP1OOSP1A8MZH6571
ZP1SOHLH1Q5JUK2554
ZP1SPESP1Q6UW49544
ZP1DAZLQ92904537
ZP1ZAR1Q86SH2536

IntAct

7 interactions, top by confidence:

ABTypeScore
ZP3ZP3psi-mi:“MI:0914”(association)0.500
ZP1ZP3psi-mi:“MI:0914”(association)0.350
ZP2ZP3psi-mi:“MI:0914”(association)0.350
ZP3ZP1psi-mi:“MI:0914”(association)0.350
ORF61USP11psi-mi:“MI:0914”(association)0.350

BioGRID (2): ZP1 (Positive Genetic), ZP1 (Affinity Capture-MS)

ESM2 similar proteins: A6NKQ9, B1AWI6, I6M4H4, O14931, O35714, O46641, O54766, O70394, O95428, P08751, P0DN86, P0DN87, P17813, P19794, P21563, P43021, P51500, P51670, P60852, P61484, Q07104, Q1L6U9, Q3HRV3, Q3S2X5, Q3TYX2, Q4TUC0, Q5DQQ6, Q6AXW8, Q6NT52, Q6UWN5, Q7TPG6, Q86T13, Q86UD1, Q8BZT7, Q8CJH3, Q8IZF5, Q8K1T6, Q8MII8, Q8MJ02, Q8N386

Diamond homologs: I6M4H4, O54766, O54767, O77726, P20239, P42099, P47983, P47984, P48829, P48834, P60852, Q00193, Q05996, Q07287, Q12836, Q62005, Q8CH34, Q9BH10, Q9BH11, Q5DID3, Q96PL2, P54097

SIGNOR signaling

1 interactions.

AEffectBMechanism
SOHLH1“up-regulates quantity by expression”ZP1“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

148 variants total. Per-class counts are floors (≥ shown; pagination cap):

ClassificationCount (floor)
Pathogenic11
Likely pathogenic1
Uncertain significance114
Likely benign11
Benign8

Top pathogenic / likely-pathogenic (12)

Variant IDHGVSClassification
127200NM_207341.4(ZP1):c.1169_1176del (p.Ile390fs)Pathogenic
2065331NM_207341.4(ZP1):c.628C>T (p.Gln210Ter)Pathogenic
3353935NM_207341.4(ZP1):c.670C>T (p.Arg224Ter)Pathogenic
3382275NM_207341.4(ZP1):c.1129_1130del (p.Val377fs)Pathogenic
3383023NM_207341.4(ZP1):c.1602C>A (p.Cys534Ter)Pathogenic
3780815NM_207341.4(ZP1):c.874C>T (p.Gln292Ter)Pathogenic
689404NM_207341.4(ZP1):c.1708G>A (p.Val570Met)Pathogenic
689405NM_207341.4(ZP1):c.1430+1G>TPathogenic
689406NM_207341.4(ZP1):c.1775-8T>CPathogenic
695115NM_207341.4(ZP1):c.769C>T (p.Gln257Ter)Pathogenic
812693NM_207341.4(ZP1):c.1168del (p.Ile390fs)Pathogenic
3347218NM_207341.4(ZP1):c.1015-1G>ALikely pathogenic

SpliceAI

1513 predictions. Top by Δscore:

VariantEffectΔscore
11:60871315:G:GGdonor_gain1.0000
11:60871321:G:Tdonor_gain1.0000
11:60873139:A:AGacceptor_gain1.0000
11:60873140:C:Gacceptor_gain1.0000
11:60873146:T:TAacceptor_gain1.0000
11:60873149:A:AGacceptor_gain1.0000
11:60873149:AC:Aacceptor_gain1.0000
11:60873149:ACGT:Aacceptor_gain1.0000
11:60873149:ACGTG:Aacceptor_gain1.0000
11:60873150:C:CAacceptor_gain1.0000
11:60873153:G:Aacceptor_gain1.0000
11:60873287:AAGGT:Adonor_loss1.0000
11:60873288:AGGTA:Adonor_loss1.0000
11:60873290:G:Tdonor_loss1.0000
11:60873291:T:Adonor_loss1.0000
11:60873372:CA:Cacceptor_loss1.0000
11:60873373:A:AGacceptor_gain1.0000
11:60873373:AGAC:Aacceptor_gain1.0000
11:60873374:G:GAacceptor_gain1.0000
11:60873374:GA:Gacceptor_gain1.0000
11:60873374:GAC:Gacceptor_gain1.0000
11:60873374:GACG:Gacceptor_gain1.0000
11:60873374:GACGA:Gacceptor_gain1.0000
11:60873560:GACGG:Gdonor_gain1.0000
11:60873563:GG:Gdonor_gain1.0000
11:60873564:GG:Gdonor_gain1.0000
11:60875015:G:GGdonor_gain1.0000
11:60869139:CTGCA:Cacceptor_loss0.9900
11:60869140:TGCA:Tacceptor_loss0.9900
11:60869141:GCA:Gacceptor_loss0.9900

AlphaMissense

4114 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
11:60873731:T:CF510L0.992
11:60873733:C:AF510L0.992
11:60873733:C:GF510L0.992
11:60873383:T:CF417L0.991
11:60873385:C:AF417L0.991
11:60873385:C:GF417L0.991
11:60873717:T:CF505S0.991
11:60873716:T:CF505L0.986
11:60873717:T:GF505C0.986
11:60873718:C:AF505L0.986
11:60873718:C:GF505L0.986
11:60873547:G:CW471C0.984
11:60873547:G:TW471C0.984
11:60869145:A:TD66V0.982
11:60873732:T:GF510C0.982
11:60867746:T:CF62S0.980
11:60874946:G:AC529Y0.980
11:60874945:T:AC529S0.979
11:60874946:G:CC529S0.979
11:60867757:G:CD66H0.977
11:60869186:T:AC80S0.977
11:60869187:G:CC80S0.977
11:60873503:T:AC457S0.977
11:60873504:G:CC457S0.977
11:60869150:T:CF68L0.976
11:60869152:T:AF68L0.976
11:60869152:T:GF68L0.976
11:60873508:G:CW458C0.975
11:60873508:G:TW458C0.975
11:60869162:T:CF72L0.974

dbSNP variants (sampled 300 via entrez): RS1000045418 (11:60870068 A>G), RS1000378159 (11:60871579 C>T), RS1000644568 (11:60868556 C>T), RS1000809029 (11:60872997 C>T), RS1000824996 (11:60874765 C>G), RS1000922290 (11:60866979 G>A), RS1001378093 (11:60867186 C>T), RS1001775590 (11:60869211 C>A,G,T), RS1001888185 (11:60873864 T>A,C), RS1001941958 (11:60874250 A>C), RS1002386528 (11:60867638 G>A), RS1002408946 (11:60866286 C>T), RS1002766622 (11:60875372 G>C), RS1002767205 (11:60872672 A>C,G), RS1002847636 (11:60867821 G>C)

Disease associations

OMIM: gene MIM:195000 | disease phenotypes: MIM:615774, MIM:617712

GenCC curated gene-disease

DiseaseClassificationInheritance
female infertility due to zona pellucida defectStrongAutosomal recessive

Mondo (2): female infertility due to zona pellucida defect (MONDO:0014342), oocyte maturation defect 3 (MONDO:0021574)

Orphanet (1): Female infertility due to zona pellucida defect (Orphanet:404466)

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPOTerm
HP:0000007Autosomal recessive inheritance
HP:0008222Female infertility
HP:0011462Young adult onset
HP:6000328Absent zona pellucida

GWAS associations

1 associations (top):

StudyTraitp-value
GCST006296_3Response to ziprazidone in schizophrenia3.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067247 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChemblTypeValueUnitMolecule
8.62Kd2.409nMCHEMBL3752910
8.62ED502.409nMCHEMBL3752910
5.37Kd4247nMCHEMBL5653589
5.37ED504247nMCHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide2149818: Binding affinity to human ZP1 incubated for 45 mins by Kinobead based pull down assaykd0.0024uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide2149818: Binding affinity to human ZP1 incubated for 45 mins by Kinobead based pull down assaykd4.2473uM

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

ChemicalActions (top 5)PubMed papers
Benzo(a)pyreneaffects methylation, decreases methylation, increases expression4
methyleugenolincreases expression1
bisphenol Adecreases methylation1
tris(1,3-dichloro-2-propyl)phosphatedecreases expression1
perfluorooctanoic acidincreases expression1
perfluorooctane sulfonic acidincreases expression1
CGP 52608affects binding, increases reaction1
archazolid Bincreases expression1
Cadmiumincreases expression1
N-Nitrosopyrrolidineincreases expression1
Silicon Dioxidedecreases expression1
Valproic Acidincreases methylation1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL5652860BindingBinding affinity to human ZP1 incubated for 45 mins by Kinobead based pull down assayNVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.