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Classifications

Harrison's Part

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Inheritance

3

Autosomal recessive inheritance HP:0000007

Most reported families and sporadic probands harbor homozygous or compound heterozygous loss-of-function or missense variants in ZP1. Disease manifestation is sex-limited to females; homozygous and heterozygous male carriers have normal fertility.

Autosomal recessive inheritance Penetrance: COMPLETE

Show evidence (2 references)

PMID:24670168 SUPPORT Human Clinical

"Here we describe a form of infertility with an autosomal recessive mode of inheritance, characterized by abnormal eggs that lack a zona pellucida. We identified a homozygous frameshift mutation in ZP1 in six family members."

Establishes autosomal recessive inheritance of ZP1-related female infertility due to zona pellucida defect in the original index family.

PMID:33272616 SUPPORT Human Clinical

"We identified zona pellucida (ZP) gene variants in 18 individuals, which included 20 variants in the ZP1 gene, two variants in the ZP2 gene, and one previously reported recurrent variant in the ZP3 gene. The women carrying ZP variants constituted 51.43% of the GEFS cohort. The ZP1 variants were..."

Confirms across a cohort of 35 women with genuine empty follicle syndrome and oocyte degeneration that ZP1-associated cases follow autosomal recessive inheritance.

Autosomal dominant inheritance HP:0000006

A subset of patients harbor heterozygous ZP1 variants (such as p.Trp83Arg, p.Arg109His, p.Tyr262Cys, and p.Glu267Glyfs*80), frequently transmitted paternally with sex-limited expression in females, that act via dominant-negative interference with ZP secretion or filament assembly or via haploinsufficiency.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:32573113 SUPPORT Human Clinical

"Here, we performed whole-exome sequencing in two probands with primary infertility whose oocytes lacked a ZP, and we identified a heterozygous mutation in ZP1 (NM_207341:c.326G>A p.Arg109His), which is situated in the N-terminus, and a heterozygous mutation in ZP3 (NM_001110354:c.400G>A..."

Demonstrates that heterozygous missense variants in ZP1 can cause zona pellucida formation failure and female infertility.

PMID:38966008 SUPPORT Human Clinical

"In a patient (II-1) displaying abnormal zona pellucida formation, we successfully identified the heterozygous ZP1 mutation (ZP1-Y262C) via whole-exome sequencing. Subsequent exome sequencing of the patient’s father (I-2) confirmed his carrier status for the ZP1 mutation, while the mother (I-1)..."

Documents paternal transmission of a heterozygous ZP1 trefoil-domain missense mutation causing zona pellucida-deficient oocytes in the affected daughter.

Sex-limited expression HP:0001470

Because the zona pellucida is an oocyte-specific extracellular matrix, ZP1 pathogenic variants manifest exclusively in females. Heterozygous and homozygous male carriers are fertile and can transmit pathogenic ZP1 alleles to affected daughters.

Sex-limited expression

Show evidence (1 reference)

PMID:38966008 SUPPORT Human Clinical

"In a patient (II-1) displaying abnormal zona pellucida formation, we successfully identified the heterozygous ZP1 mutation (ZP1-Y262C) via whole-exome sequencing. Subsequent exome sequencing of the patient’s father (I-2) confirmed his carrier status for the ZP1 mutation, while the mother (I-1)..."

Demonstrates sex-limited female expression of ZP1-related infertility, with an unaffected fertile father transmitting the pathogenic ZP1 variant to his affected daughter.

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Discussions and Knowledge Gaps

1

Why do human patients and Zp1-knock-in rats with ZP1 mutations exhibit complete absence of the zona pellucida or empty follicle syndrome, whereas Zp1-null knockout mice assemble a loosely organized ZP2/ZP3 coat and remain subfertile?

HUMAN MODEL MISMATCH RESOLVED oomd1_species_zp_composition_divergence

Attached to

animal_models#Zp1 p.I390fs404X homozygous knock-in rat (Zp1MT/MT) animal_models#Zp1-null knockout mouse (Zp1tm/tm) pathophysiology#ZP1 Loss-of-Function and Cytoplasmic Co-Sequestration of Zona Pellucida Glycoproteins

Humans, macaques, and rats express four zona pellucida glycoproteins (ZP1, ZP2, ZP3, ZP4), whereas mice have a pseudogenized Zp4 gene and express only three subunits (mZP1, mZP2, mZP3). Furthermore, human and rat truncating or missense ZP1 mutant proteins accumulate in the oocyte cytoplasm and actively bind and sequester ZP3 and ZP4 intracellularly, blocking their secretion and preventing any extracellular ZP matrix assembly, whereas complete Zp1 null alleles in mice allow unimpeded secretion of mZP2 and mZP3 to form an uncross-linked matrix.

Show evidence (2 references)

PMID:33624742 SUPPORT In Vitro

"Studies in 293T cells showed that mutant Zp1 resulted in a truncated ZP1 protein, which might be intracellularly sequestered and interacted with wild-type ZP3 or ZP4."

Demonstrates in HEK293T cells that truncated mutant ZP1 is intracellularly sequestered and interacts with wild-type ZP3 and ZP4.

PMID:33624742 SUPPORT Model Organism

"Our results suggest that the Zp1 point mutation led to infertility and loss of the ZP in oocytes in rats."

Confirms in the knock-in rat model that the Zp1 mutation leads to complete loss of the zona pellucida in oocytes and female infertility.

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Pathophysiology

5

ZP1 Loss-of-Function and Cytoplasmic Co-Sequestration of Zona Pellucida Glycoproteins

Pathogenic truncating, splice-site, or missense variants in ZP1 lead to premature stop codons, reduced protein stability, or misfolded ZP1 polypeptides that fail to undergo normal post-translational trafficking and cleavage-coupled secretion in growing oocytes. Instead of being secreted into the extracellular perivitelline space, mutant ZP1 accumulates inside the oocyte cytoplasm and endoplasmic reticulum and aberrantly binds and sequesters wild-type ZP1, ZP2, ZP3, and ZP4 intracellularly, preventing their transport to the oocyte surface.

oocyte CL:0000023

ZP1 hgnc:13187

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Germline homozygous, compound heterozygous, or heterozygous pathogenic ZP1 variants impair ZP1 expression, intracellular trafficking, secretion, and partner ZP glycoprotein transport.

protein secretion GO:0009306 ↓ DECREASED

structural constituent of egg coat GO:0035804

endoplasmic reticulum GO:0005783

ovary UBERON:0000992

Experimental models

HeLa, CHO, and HEK293T Mammalian Heterologous ZP Co-Expression and Secretion Systems CELL LINE Directly reproduces intracellular retention of mutant ZP1 and co-sequestration of wild-type ZP3/ZP4 in cultured mammalian cells.

Animal models

Zp1 p.I390fs404X homozygous knock-in rat (Zp1MT/MT) Rattus norvegicus recapitulates Homozygous Zp1MT/MT rat oocytes retain mutant ZP1 intracellularly and fail to incorporate ZP3 and ZP4 into an extracellular zona pellucida.

Downstream

Failure of ZP1-N1 Disulfide Cross-Linking and Zona Pellucida Extracellular Matrix Assembly Depletion of secreted ZP1 and intracellular trapping of partner ZP glycoproteins prevent extracellular filament polymerization and cross-linking around the growing oocyte.

Show evidence (3 references)

PMID:24670168 SUPPORT In Vitro

"In vitro studies showed that defective ZP1 proteins and normal ZP3 proteins colocalized throughout the cells and were not expressed at the cell surface, suggesting that the aberrant ZP1 results in the sequestration of ZP3 in the cytoplasm, thereby preventing the formation of the zona pellucida..."

Confocal microscopy of co-transfected HeLa cells demonstrates that truncated ZP1 colocalizes with and sequesters ZP3 in the cytoplasm, blocking transport to the cell surface.

PMID:31300655 SUPPORT In Vitro

"This showed that, whereas hZP1 is secreted into the medium as a mixture of monomer and disulphide-bonded dimer, secretion of hZP1Mut is completely abolished (Fig. 1b, left panel). Although the expression of hZP1Mut is lower than that of hZP1, the truncated mutant protein can be detected in the..."

Biochemical secretion assays in mammalian cells show that the human infertility mutant hZP1 I390fs404X is retained in the cell lysate and its secretion is completely abolished.

PMID:33272616 SUPPORT In Vitro

"Studies in CHO cells suggested that most ZP1 variants led to increased intracytoplasmic protein and some variants influenced the intracellular transportation of other ZP proteins."

Demonstrates intracytoplasmic protein accumulation and impaired intracellular transport of partner ZP proteins in CHO cells expressing mutant ZP1.

Failure of ZP1-N1 Disulfide Cross-Linking and Zona Pellucida Extracellular Matrix Assembly

In healthy human oocytes, secreted ZP2, ZP3, and ZP4 polymerize into long filaments that are covalently cross-linked into a stable three-dimensional extracellular matrix via intermolecular disulfide bonds (mediated by conserved Cys66 in chicken ZP1 and the corresponding Cys77 in the N-terminal ZP-N1 domain of human ZP1) forming ZP1-N1 homodimers, while human ZP4-N1 remains monomeric and cannot substitute for ZP1 cross-linking. Pathogenic ZP1 variants either eliminate secreted ZP1, disrupt ZP1-N1 homodimerization (such as p.Trp83Arg and p.Arg109His), alter the trefoil or ZP domains, or abolish heteromeric interaction with ZP2 and ZP3, resulting in a markedly thinned, fragile, or completely absent zona pellucida matrix.

oocyte CL:0000023

ZP1 hgnc:13187 ZP2 hgnc:13188 ZP3 hgnc:13189 ZP4 hgnc:15770

egg coat formation GO:0035803 ⚠ ABNORMAL extracellular matrix assembly GO:0085029 ⚠ ABNORMAL

structural constituent of egg coat GO:0035804 extracellular matrix structural constituent GO:0005201

egg coat GO:0035805 extracellular matrix GO:0031012

ovary UBERON:0000992

Animal models

Zp1-null knockout mouse (Zp1tm/tm) Mus musculus partially recapitulates Demonstrates loss of ZP1 filament cross-linking and porous ZP architecture, but mice retain an uncross-linked ZP2/ZP3 coat and remain subfertile rather than completely sterile.

Downstream

Impaired Cumulus-Oocyte Complex Organization and Granulosa-Oocyte Crosstalk Loss of a structurally intact zona pellucida matrix compromises physical support and bidirectional signaling between the growing oocyte and surrounding cumulus granulosa cells during the preantral-to-antral follicle transition.

Defective Sperm-Zona Pellucida Recognition and Fertilization Failure Absence or severe malformation of the zona pellucida deprives oocytes of the species-specific sperm-binding extracellular coat required for conventional sperm-oocyte interaction and fertilization.

Absent zona pellucida Complete failure of ZP1-mediated filament cross-linking and extracellular matrix assembly results in oocytes that completely lack a zona pellucida coat.

Thin zona pellucida Partial assembly of ZP2, ZP3, and ZP4 filaments without ZP1 cross-linking produces an abnormally thin and structurally unstable zona pellucida.

Show evidence (4 references)

PMID:31300655 SUPPORT In Vitro

"Consistent with an important role of W72 in the folding and dimerisation of cZP1-N1, this experiment showed that W83R not only decreases the secretion of hZP1-N1 but also significantly reduces its ability to form disulphide-bonded homodimers (Fig. 7b). This suggests that the mutation leads to..."

Biochemical analysis proves that the human ZP1 W83R variant impairs ZP1-N1 disulfide-bonded homodimerization, hindering human ZP filament cross-linking.

PMID:31300655 SUPPORT In Vitro

"The latter observation, together with the fact that the trefoil/ZP module region of hZP1 does not form non-covalent homodimers (Fig. 2j), suggest that hZP1-N1 cross-link formation is essential for the assembly or maintenance of the human ZP and, hence, fertility."

Demonstrates that ZP1-N1 intermolecular disulfide cross-linking is essential for assembly and maintenance of the human zona pellucida and cannot be rescued by ZP4.

PMID:31292994 SUPPORT In Vitro

"Coimmunoprecipitation tests and homology modeling analysis confirmed that both mutated ZP1 disrupt the formation of oocyte zona pellucida by interrupting the interaction among ZP1, ZP2, and ZP3."

Co-immunoprecipitation demonstrates that EFS-associated ZP1 mutations disrupt heteromeric assembly among ZP1, ZP2, and ZP3.

+ 1 more reference

Impaired Cumulus-Oocyte Complex Organization and Granulosa-Oocyte Crosstalk

During ovarian folliculogenesis, the zona pellucida provides the structural scaffold that stabilizes transzonal projections and gap-junctional communication between surrounding cumulus granulosa cells and the growing primary oocyte. In ZP1-deficient follicles, preantral follicles initially form a thin ZP composed of ZP2, ZP3, and ZP4 without ZP1; however, as follicles expand into the antral stage and antral cavity fluid accumulates, the uncross-linked ZP separates from surrounding granulosa cells, cumulus-oocyte complex (COC) architecture collapses, and bidirectional nutrient and paracrine signaling between cumulus granulosa cells and the oocyte is disrupted.

primary oocyte CL:0000654 granulosa cell CL:0000501

ovarian follicle development GO:0001541 ⚠ ABNORMAL

ovary UBERON:0000992

Animal models

ZP1 CRISPR/Cas9 loss-of-function cynomolgus macaque (#ZP1-2) Macaca fascicularis recapitulates Recapitulates ZP absence/thinning and disrupted oocyte-granulosa signaling in late antral follicles of a non-human primate with a four-ZP-subunit matrix.

Downstream

Oocyte Mitochondrial Dysfunction, Fragility, and Intra-Follicular Degeneration Disruption of cumulus-oocyte complex architecture and loss of granulosa-oocyte nutritional and metabolic support induce oocyte oxidative stress, mitochondrial swelling, mechanical fragility, and intra-follicular oocyte degeneration.

Show evidence (3 references)

PMID:31734689 SUPPORT Human Clinical

"Immunohistochemistry using ovarian serial sections demonstrated that all preantral follicles had normal architecture, but with a thin ZP, lacking ZP1, surrounding the growing oocytes. The antral follicles were also defective in normal cumulus-oocyte complex organisation, leading us to speculate..."

Human ovarian biopsy immunohistochemistry demonstrates that ZP1 deficiency permits a thin ZP in preantral follicles that fails to maintain cumulus-oocyte complex organization in antral follicles.

PMID:36476320 SUPPORT REVIEW SYNTHESIS Human Clinical

"Lack of ZP might interfere with the bidirectional communication between oocytes and cumulus cells, then impedes nutritional supplements from cumulus cells leading to oocyte degeneration or increases in the fragility of oocytes during follicular puncture, ultimately resulting in EFS [8, 53, 70]."

Explains how absence of the ZP disrupts bidirectional oocyte-cumulus cell communication and nutrient supply.

PMID:40923306 SUPPORT Model Organism

"Additionally, a clear separation between the ZP and granulosa cells was observed in #ZP1-2 macaques, whereas #WT macaques displayed an intact ZP-granulosa cell interface."

Demonstrates structural separation of the zona pellucida-granulosa cell interface in ZP1-mutant primate follicles.

Oocyte Mitochondrial Dysfunction, Fragility, and Intra-Follicular Degeneration

Deprived of a protective zona pellucida scaffold and cumulus-oocyte metabolic coupling, ZP1-deficient oocytes develop transcriptomic and ultrastructural hallmarks of cellular stress, including downregulation of antioxidant defenses (such as SOD2), oxidative stress, extensive mitochondrial swelling at germinal vesicle and metaphase II stages, increased autophagy, and extreme mechanical vulnerability to shear stress. Consequently, oocytes either degenerate within antral follicles prior to ovulation or rupture during transvaginal follicular aspiration, resulting in retrieval of shriveled, dark degenerated oocytes or genuine empty follicle syndrome (GEFS).

oocyte CL:0000023

oocyte development GO:0048599 ⚠ ABNORMAL

mitochondrion GO:0005739

ovary UBERON:0000992

Downstream

Empty ovarian follicle Complete intra-follicular oocyte degeneration or mechanical lysis of fragile ZP-deficient oocytes during follicular puncture results in failure to recover any oocytes despite normal follicular development (genuine empty follicle syndrome).

Oocyte degeneration Oxidative stress, mitochondrial swelling, and loss of zona pellucida protection cause growing and mature oocytes to undergo atresia and cytoplasmic shrinkage, yielding shriveled, dark degenerated oocytes upon retrieval.

Show evidence (3 references)

PMID:40923306 SUPPORT Model Organism

"Collectively, these data suggest that ZP1 deficiency induces oxidative stress and mitochondrial dysregulation, leading to increased autophagy and eventual oocyte degeneration. Supporting this conclusion, TEM analysis further revealed extensive mitochondrial swelling in #ZP1-2 oocytes at both the..."

Single-oocyte multi-omics and electron microscopy in ZP1-mutant macaques demonstrate oxidative stress, mitochondrial swelling, and autophagy driving oocyte degeneration.

PMID:35460069 SUPPORT Human Clinical

"All the oocytes from ZP1-associated patients appeared shriveled and dark indicating that the abnormal ZP1 protein induced oocyte death and degeneration."

Demonstrates in human patients that ZP1 deficiency results in oocyte death and dark, shriveled degenerated oocytes.

PMID:31734689 SUPPORT Human Clinical

"The antral follicles were also defective in normal cumulus-oocyte complex organisation, leading us to speculate that the lack of ZP1 might lead to oocyte degeneration or increased fragility of the oocyte during follicular puncture, ultimately resulting in EFS."

Supports the mechanism of intra-follicular oocyte degeneration and mechanical fragility during follicular aspiration.

Defective Sperm-Zona Pellucida Recognition and Fertilization Failure

In patients whose oocytes survive follicular aspiration as viable metaphase II (MII) gametes despite an absent or severely thinned zona pellucida, the naked oolemma lacks the ZP glycoprotein matrix required for normal species-specific sperm binding, acrosome reaction induction, and block to polyspermy. Consequently, conventional in vitro fertilization (IVF) fails completely, whereas direct intracytoplasmic sperm injection (ICSI) into the ooplasm can bypass the extracellular ZP defect.

oocyte CL:0000023

binding of sperm to zona pellucida GO:0007339 ⚠ ABNORMAL

ovary UBERON:0000992

Downstream

Female infertility Failure of conventional sperm-zona recognition and natural fertilization renders affected women unable to conceive naturally or via standard IVF.

Show evidence (2 references)

PMID:40923306 SUPPORT BACKGROUND Human Clinical

"Among ZP genes, ZP1 has emerged as a critical determinant of matrix assembly and oocyte viability. Loss-of-function mutations in ZP1 can result in incomplete or dysfunctional ZP formation, leading to failed fertilization (Wassarman & Litscher, 2021)."

Summarizes how loss-of-function ZP1 mutations impair ZP matrix formation and result in failed fertilization.

PMID:36476320 SUPPORT REVIEW SYNTHESIS Human Clinical

"Sixty-nine mutations of the ZP genes were reported in 87 patients with different clinical phenotypes, including empty follicle syndrome (EFS), ZP-free oocytes (ZFO), ZP-thin oocytes (ZTO), degenerated and immature oocytes. The phenotypes of patients were influenced by the types and location of..."

Literature synthesis defines the clinical endpoints of ZP mutations (EFS, degenerated/immature oocytes, and ZP-free or ZP-thin oocytes) and shows that ICSI can rescue fertilization in patients yielding ZP-free oocytes.

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Pathograph

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Phenotypes

5

Genitourinary 2

Female infertility OBLIGATE HP:0008222

Show evidence (3 references)

PMID:24670168 SUPPORT Human Clinical

"Her age at menarche was 13 years, her menstrual cycle was normal (lasting 3 to 7 days and occurring every 29 days), and she had no dysmenorrhea. Infertility-related examinations did not reveal abnormalities"

Establishes primary female infertility with normal menarche, regular menstrual cycles, and normal baseline fertility examinations in the proband homozygous for the ZP1 mutation.

PMID:35460069 SUPPORT Human Clinical

"All the oocytes from ZP1-associated patients appeared shriveled and dark indicating that the abnormal ZP1 protein induced oocyte death and degeneration. Overall ZP1-associated patients had degenerated or absent oocytes contrary to PATL2-associated subjects who had immature oocytes blocked mainly..."

Describes the characteristic retrieval of shriveled, dark, degenerated or absent oocytes in patients homozygous for ZP1 p.Arg366Gln.

PMID:36476320 SUPPORT REVIEW SYNTHESIS Human Clinical

"Their genotypes are homozygous, heterozygous, or compound heterozygous, and are inherited in autosomal dominant (AD) or autosomal recessive (AR) manners, which cause different phenotypes like empty follicle syndrome (EFS), ZP-free oocytes (ZFO), degenerated or immature oocytes"

Summarizes the clinical spectrum of ZP1-related female infertility across 48 reported patients, encompassing empty follicle syndrome, ZP-free oocytes, and degenerated or immature oocytes.

Empty ovarian follicle VERY_FREQUENT HP:0031067

Sequelae: Female infertility

Show evidence (2 references)

PMID:33272616 SUPPORT Human Clinical

"We identified zona pellucida (ZP) gene variants in 18 individuals, which included 20 variants in the ZP1 gene, two variants in the ZP2 gene, and one previously reported recurrent variant in the ZP3 gene. The women carrying ZP variants constituted 51.43% of the GEFS cohort."

Establishes ZP1 as the major genetic cause of genuine empty follicle syndrome (GEFS).

PMID:31734689 SUPPORT Human Clinical

"The antral follicles were also defective in normal cumulus-oocyte complex organisation, leading us to speculate that the lack of ZP1 might lead to oocyte degeneration or increased fragility of the oocyte during follicular puncture, ultimately resulting in EFS."

Demonstrates that ZP1 mutations present clinically as empty follicle syndrome upon follicular puncture.

Cellular 2

Absent zona pellucida OCCASIONAL HP:6000328

Sequelae: Female infertility

Show evidence (2 references)

PMID:24670168 SUPPORT Human Clinical

"Our data suggest that the mutation prevents the formation of the zona pellucida around ova: all observed oocytes from affected family members lacked a zona pellucida when examined with light microscopy"

Demonstrates complete absence of the zona pellucida on light microscopy of oocytes retrieved from affected family members with homozygous ZP1 frameshift variants.

PMID:32573113 SUPPORT Human Clinical

"Here, we performed whole-exome sequencing in two probands with primary infertility whose oocytes lacked a ZP, and we identified a heterozygous mutation in ZP1 (NM_207341:c.326G>A p.Arg109His), which is situated in the N-terminus, and a heterozygous mutation in ZP3 (NM_001110354:c.400G>A..."

Documents retrieval of zona pellucida-free oocytes in a proband carrying a heterozygous ZP1 p.Arg109His variant.

Thin zona pellucida OCCASIONAL HP:0020157

Sequelae: Female infertility

Show evidence (2 references)

PMID:31734689 SUPPORT Human Clinical

"Immunohistochemistry using ovarian serial sections demonstrated that all preantral follicles had normal architecture, but with a thin ZP, lacking ZP1, surrounding the growing oocytes."

Histopathological evidence of a thin zona pellucida lacking ZP1 around growing oocytes in an affected woman with biallelic ZP1 mutations.

PMID:36476320 SUPPORT REVIEW SYNTHESIS Human Clinical

"Sixty-nine mutations of the ZP genes were reported in 87 patients with different clinical phenotypes, including empty follicle syndrome (EFS), ZP-free oocytes (ZFO), ZP-thin oocytes (ZTO), degenerated and immature oocytes."

Confirms ZP-thin oocytes (ZTO) as a recognized clinical phenotype of ZP gene mutations.

Other 1

Oocyte degeneration FREQUENT

HPO currently lacks a specific term for oocyte degeneration or oocyte atresia (distinct from Arrested oocyte maturation, HP:0031068, and Empty ovarian follicle, HP:0031067); preferred_term is recorded without an HPO ID pending upstream term addition.

Sequelae: Female infertility

Show evidence (2 references)

PMID:35460069 SUPPORT Human Clinical

"All the oocytes from ZP1-associated patients appeared shriveled and dark indicating that the abnormal ZP1 protein induced oocyte death and degeneration. Overall ZP1-associated patients had degenerated or absent oocytes contrary to PATL2-associated subjects who had immature oocytes blocked mainly..."

Establishes oocyte degeneration (shriveled, dark oocytes) as a hallmark clinical phenotype of ZP1-associated infertility.

PMID:33272616 SUPPORT Human Clinical

"Our findings not only reveal the critical roles of ZP genes but also pave the way for the efficient genetic diagnosis of females with GEFS and oocyte degeneration."

Confirms oocyte degeneration alongside genuine empty follicle syndrome as a defining clinical manifestation of ZP1 variants.

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Genetic Associations

1

ZP1 (Causative)

Gene: ZP1 hgnc:13187

Show evidence (3 references)

PMID:24670168 SUPPORT Human Clinical

"Sequencing of candidate genes ZP1, ZP2, ZP3, and ZP4 revealed that six members of generation IV (the four patients and two unmarried family members) carried a homozygous frameshift deletion of 8 bp encompassing nucleotides 1169 through 1176 in ZP1 (GenBank accession number, KJ489454)."

Identifies the first causal homozygous frameshift deletion in ZP1 in four infertile sisters from a consanguineous pedigree.

PMID:36476320 SUPPORT REVIEW SYNTHESIS Human Clinical

"A total of 47 ZP1 mutations have been reported in 19 pieces of literature, most of which are exon mutations, and only seven are intron splicing mutations. Mutations are distributed in all 12 exons of ZP1 gene. Corresponding protein variants are distributed in all seven functional domains of ZP1..."

Catalogs 47 distinct pathogenic ZP1 mutations across all 12 exons and 7 functional domains of ZP1, making ZP1 the most frequently mutated zona pellucida gene in human female infertility.

PMID:42060237 SUPPORT Human Clinical

"Both patients and two affected siblings harbored a homozygous ZP1 c.1097G > A p.(Arg366Gln) variant inherited from both heterozygous parents. This previously described variant appears to be recurrent in North African populations."

Confirms recurrence of the homozygous ZP1 c.1097G>A p.(Arg366Gln) founder variant in North African families with empty follicle syndrome.

Variants (5)

c.1169_1176del (p.Ile390Thrfs*16) Pathogenic

Gene: ZP1 hgnc:13187 deletion

Variant detail: frameshift variant

Genomic context: coding sequence

Index homozygous 8-bp frameshift deletion in the ZP-C subdomain of ZP1 resulting in premature truncation (p.Ile390Thrfs*16, also referred to as I390fs404X), abolishing the C-terminal consensus furin cleavage site and transmembrane domain, blocking ZP1 secretion, and causing cytoplasmic sequestration of ZP3 and ZP4.

Show evidence (1 reference)

PMID:24670168 SUPPORT Human Clinical

"Sequencing of candidate genes ZP1, ZP2, ZP3, and ZP4 revealed that six members of generation IV (the four patients and two unmarried family members) carried a homozygous frameshift deletion of 8 bp encompassing nucleotides 1169 through 1176 in ZP1 (GenBank accession number, KJ489454)."

Identifies the index homozygous frameshift deletion c.1169_1176del in ZP1 in a familial cases of zona pellucida-free infertility.

c.1097G>A (p.Arg366Gln) Pathogenic

Gene: ZP1 hgnc:13187 single nucleotide variant

Variant detail: missense variant

Genomic context: coding sequence

Recurrent North African founder missense variant in exon 6 within the ZP-N subdomain of ZP1; homozygosity causes oocyte death, retrieval of shriveled dark degenerated oocytes, or genuine empty follicle syndrome.

Show evidence (2 references)

PMID:35460069 SUPPORT Human Clinical

"Here, we included four additional OMD patients and reanalyzed all 27 subjects. In addition to the seven patients with a previously identified defect, five carried the same deleterious homozygous ZP1 variant (c.1097G>A; p.Arg366Gln)."

Identifies the recurrent homozygous ZP1 c.1097G>A (p.Arg366Gln) variant in five North African patients with severe oocyte maturation defect.

PMID:42060237 SUPPORT Human Clinical

"Both patients and two affected siblings harbored a homozygous ZP1 c.1097G > A p.(Arg366Gln) variant inherited from both heterozygous parents. This previously described variant appears to be recurrent in North African populations."

Confirms recurrence of homozygous ZP1 c.1097G>A p.(Arg366Gln) in North African families with empty follicle syndrome.

c.326G>A (p.Arg109His) Pathogenic

Gene: ZP1 hgnc:13187 single nucleotide variant

Variant detail: missense variant

Genomic context: coding sequence

N-terminal ZP-N1 cross-linking domain missense variant that impairs ZP1 secretion and cross-linking function, reported in heterozygous state in a woman with ZP-free oocytes who achieved live birth after ICSI.

Show evidence (1 reference)

PMID:32573113 SUPPORT Human Clinical

"Here, we performed whole-exome sequencing in two probands with primary infertility whose oocytes lacked a ZP, and we identified a heterozygous mutation in ZP1 (NM_207341:c.326G>A p.Arg109His), which is situated in the N-terminus, and a heterozygous mutation in ZP3 (NM_001110354:c.400G>A..."

Identifies the heterozygous ZP1 c.326G>A (p.Arg109His) variant in a patient with ZP-free oocytes.

c.247T>C (p.Trp83Arg) Pathogenic

Gene: ZP1 hgnc:13187 single nucleotide variant

Variant detail: missense variant

Genomic context: coding sequence

Missense variant in the N-terminal ZP-N1 domain (c.247T>C, p.Trp83Arg) that reduces hZP1-N1 secretion and disrupts intermolecular disulfide-bonded homodimerization required for human ZP filament cross-linking.

Show evidence (1 reference)

PMID:31300655 SUPPORT In Vitro

"Consistent with an important role of W72 in the folding and dimerisation of cZP1-N1, this experiment showed that W83R not only decreases the secretion of hZP1-N1 but also significantly reduces its ability to form disulphide-bonded homodimers (Fig. 7b). This suggests that the mutation leads to..."

Demonstrates that the ZP1 p.Trp83Arg (W83R) variant impairs ZP1-N1 secretion and disulfide homodimerization.

c.785A>G (p.Tyr262Cys) Pathogenic

Gene: ZP1 hgnc:13187 single nucleotide variant

Variant detail: missense variant

Genomic context: coding sequence

Paternally inherited heterozygous missense variant in the trefoil domain of ZP1 (c.785A>G, p.Tyr262Cys) that introduces an unpaired cysteine, impairs ZP1 glycosylation and secretion, and causes abnormal zona pellucida formation.

Show evidence (1 reference)

PMID:38966008 SUPPORT Human Clinical

"In a patient (II-1) displaying abnormal zona pellucida formation, we successfully identified the heterozygous ZP1 mutation (ZP1-Y262C) via whole-exome sequencing."

Identifies the heterozygous ZP1 p.Tyr262Cys (Y262C) mutation in a patient with abnormal zona pellucida formation and primary infertility.

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Medical Actions

3

Intracytoplasmic Sperm Injection (ICSI)

Category: Therapeutic Action: Intracytoplasmic Sperm Injection NCIT:C185482

Platform: Surgery

For the subset of ZP1-mutant patients (~20 to 25%) from whom mature metaphase II (MII) zona pellucida-free oocytes can be successfully aspirated (often facilitated by gentle follicular aspiration at reduced suction pressure or diagnostic natural-cycle aspiration), intracytoplasmic sperm injection (ICSI) directly injects a single spermatozoon into the ooplasm, bypassing the absent ZP required for conventional IVF sperm binding. Following careful individual microdrop culture of fragile ZP-free embryos to the blastocyst stage and embryo transfer, live births of healthy infants have been achieved.

Target Phenotypes: Female infertility HP:0008222 Absent zona pellucida HP:6000328 Thin zona pellucida HP:0020157

Show evidence (3 references)

PMID:32573113 SUPPORT Human Clinical

"Additionally, the patient with the ZP1 mutation delivered a baby following intracytoplasmic sperm injection (ICSI); thus, we suggest the targeted genetic diagnosis of ZP genes to choose appropriate fertilization methods and improve the success rate of assisted reproductive technology (ART) treatments."

Documents successful clinical rescue of ZP1-mutant ZP-free oocytes via ICSI resulting in a healthy live birth.

PMID:32847637 SUPPORT Human Clinical

"Diagnostic ICSI provided information about the embryo development potential from ZP-free oocytes and allowed better planning of the subsequent ICSI cycle. WES revealed that the absence of ZP was likely to be due to a new (ZP1) mutation. The subsequent ICSI cycle resulted in the delivery of a..."

Demonstrates that diagnostic ICSI followed by therapeutic ICSI can achieve live birth in a patient with genetically determined ZP1-mutant ZP-free oocytes.

PMID:36476320 SUPPORT REVIEW SYNTHESIS Human Clinical

"If oocytes with ZP defects could be obtained from the affected patients, ICSI could be preferentially chosen instead of the traditional IVF, which may improve the probability of successful pregnancy via ART."

Recommends ICSI over conventional IVF whenever ZP-defective oocytes can be retrieved from patients with ZP gene mutations.

Oocyte Donation

Category: Therapeutic Action: Therapeutic Procedure NCIT:C49236

For the majority of ZP1-mutant patients (~75 to 80%, particularly those carrying biallelic truncating, frameshift, or severe missense variants such as p.Arg366Gln) who present with genuine empty follicle syndrome or complete intra-follicular oocyte degeneration where no viable metaphase II oocytes can be recovered, autologous ICSI is not feasible and in vitro fertilization using donor oocytes is the definitive therapeutic option to achieve pregnancy.

Target Phenotypes: Female infertility HP:0008222 Empty ovarian follicle HP:0031067

Show evidence (1 reference)

PMID:36476320 SUPPORT REVIEW SYNTHESIS Human Clinical

"For patients with the most severe phenotypes of EFS caused by ZP gene mutations, the current optimal treatment choice would be egg donation."

Establishes oocyte (egg) donation as the optimal treatment for patients with severe empty follicle syndrome caused by ZP gene mutations.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Genetic counseling is recommended for affected women and their family members to explain autosomal recessive or sex-limited autosomal dominant inheritance, screen female siblings of reproductive age who may share pathogenic ZP1 variants, and guide reproductive decision-making between autologous ICSI attempts and oocyte donation to avoid repeated futile ovarian stimulation cycles.

Show evidence (1 reference)

PMID:42060237 SUPPORT Human Clinical

"The recurrent ZP1 c.1097G > A p.(Arg366Gln) variant contributes to EFS in consanguineous North African families. Genetic diagnosis using targeted gene panels is valuable for personalized infertility care and counseling."

Supports targeted genetic diagnosis and genetic counseling to guide personalized infertility care in families with ZP1 variants.

🔬

Diagnosis

1

Genetic Testing (ZP1 Sequencing / Infertility Gene Panel / Exome Sequencing)

Definitive molecular diagnosis is established by identifying biallelic (or pathogenic heterozygous) variants in ZP1 via whole-exome sequencing or targeted female infertility gene panel sequencing in women presenting with genuine empty follicle syndrome, degenerated/fragile oocytes, or zona pellucida-free oocytes upon transvaginal follicular aspiration despite normal ovarian reserve and hormonal response.

Genetic Testing NCIT:C15709

Results: Identification of homozygous, compound heterozygous, or pathogenic heterozygous variants in ZP1 (NM_207341.4). In patients of North African ancestry presenting with empty follicle syndrome or degenerated oocytes, targeted screening for the recurrent founder variant c.1097G>A p.(Arg366Gln) accounts for ~18% of OMD cases.

Show evidence (2 references)

PMID:35460069 SUPPORT Human Clinical

"In this cohort of North African OMD patients, whole exome sequencing permitted to diagnose 44% of the patients studied and to identify a new frequent ZP1 variant."

Demonstrates the diagnostic utility of whole-exome sequencing and targeted ZP1 variant detection in North African patients with oocyte maturation defect.

PMID:33272616 SUPPORT Human Clinical

"Our findings not only reveal the critical roles of ZP genes but also pave the way for the efficient genetic diagnosis of females with GEFS and oocyte degeneration."

Highlights the high diagnostic yield of ZP1 genetic testing in patients with GEFS and oocyte degeneration.

📊

Prevalence

1

General population

Unknown

Population-level prevalence of OOMD1 in the general population is unknown because affected women are asymptomatic until attempting conception or undergoing oocyte retrieval. In selected clinical cohorts, combined ZP1, ZP2, and ZP3 variants accounted for 18 of 35 (51.43%) unrelated Chinese women with genuine empty follicle syndrome and oocyte degeneration (with 20 ZP1 variants identified across the cohort), and the recurrent homozygous ZP1 c.1097G>A (p.Arg366Gln) founder variant alone accounted for 5 of 27 (18.5%; reported as an allelic frequency of 17.9% in the study text) North African women with severe oocyte maturation defect; gene-specific cohort attribution is recorded under genetic.case_fractions.

Show evidence (2 references)

PMID:33272616 SUPPORT Human Clinical

"We identified zona pellucida (ZP) gene variants in 18 individuals, which included 20 variants in the ZP1 gene, two variants in the ZP2 gene, and one previously reported recurrent variant in the ZP3 gene. The women carrying ZP variants constituted 51.43% of the GEFS cohort."

In a clinical cohort of 35 women with genuine empty follicle syndrome and oocyte degeneration, combined ZP gene variants (predominantly ZP1) accounted for 51.43% of cases, whereas general-population prevalence remains undetermined.

PMID:35460069 SUPPORT Human Clinical

"Here, we included four additional OMD patients and reanalyzed all 27 subjects. In addition to the seven patients with a previously identified defect, five carried the same deleterious homozygous ZP1 variant (c.1097G>A; p.Arg366Gln)."

Shows that a single recurrent North African founder variant in ZP1 accounts for 5 of 27 cases in a selected oocyte maturation defect cohort.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Female_Infertility_Due_To_Zona_Pellucida_Defect:

🧫

Experimental Models

1

HeLa, CHO, and HEK293T Mammalian Heterologous ZP Co-Expression and Secretion Systems CELL_LINE

Transient co-transfection of wild-type and patient-derived mutant human ZP1 constructs alongside ZP2, ZP3, and ZP4 in HeLa, Chinese hamster ovary (CHO), or HEK293T cells, coupled with confocal immunofluorescence, co-immunoprecipitation, and conditioned-medium immunoblotting. Used to assay intracellular ER retention, dominant-negative or recessive co-sequestration of ZP3/ZP4, ZP1-N1 homodimerization, and secretion into the culture medium.

Cell source

HeLa, Chinese hamster ovary (CHO), and HEK293T mammalian cell lines

Culture

Transient plasmid transfection and conditioned-medium secretion assay

Publication

PMID:24670168

Pathograph links

ZP1 Loss-of-Function and Cytoplasmic Co-Sequestration of Zona Pellucida Glycoproteins recapitulates fidelity: moderate Directly reproduces intracellular retention of mutant ZP1 and co-sequestration of wild-type ZP3/ZP4 in cultured mammalian cells.

Show evidence (2 references)

PMID:24670168 SUPPORT In Vitro

"In vitro studies showed that defective ZP1 proteins and normal ZP3 proteins colocalized throughout the cells and were not expressed at the cell surface, suggesting that the aberrant ZP1 results in the sequestration of ZP3 in the cytoplasm, thereby preventing the formation of the zona pellucida..."

Demonstrates in HeLa cells that mutant ZP1 colocalizes with and sequesters ZP3 in the cytoplasm, preventing cell-surface expression.

PMID:31300655 SUPPORT In Vitro

"Importantly, this conclusion can be extended to the mammalian homologue of the protein because, mirroring full-length hZP1 (Fig. 1b, left panel), a construct corresponding to hZP1-N1 is also secreted as a homodimer linked by intermolecular disulphide(s) (Fig. 2i)."

Uses mammalian cell secretion and cross-linking assays to demonstrate that human ZP1-N1 is secreted as an intermolecular disulfide-linked homodimer.

🐁

Animal Models

3

Zp1 p.I390fs404X homozygous knock-in rat (Zp1MT/MT)

Rats knocked in for the human frameshift mutation Zp1 p.I390fs404X (Zp1MT/MT) closely phenocopy human OOMD1 because rats, like humans, express four zona pellucida glycoproteins (ZP1, ZP2, ZP3, and ZP4). Homozygous Zp1MT/MT female rats completely lack a zona pellucida around growing oocytes due to intracellular retention of mutant ZP1 and impeded incorporation of ZP3 and ZP4, ovulate drastically fewer eggs (1–2 naked eggs versus ~21 in wild-type controls), fail in vitro fertilization, and exhibit complete female infertility.

Species

Rattus norvegicus

Genotype

Zp1 p.I390fs404X homozygous knock-in (Zp1MT/MT)

Background

Sprague-Dawley

Genes

ZP1 hgnc:13187

Publication

PMID:33624742

Pathograph links

ZP1 Loss-of-Function and Cytoplasmic Co-Sequestration of Zona Pellucida Glycoproteins recapitulates fidelity: high Homozygous Zp1MT/MT rat oocytes retain mutant ZP1 intracellularly and fail to incorporate ZP3 and ZP4 into an extracellular zona pellucida.

Show evidence (1 reference)

PMID:33624742 SUPPORT Model Organism

"The ovaries of homozygous (Zp1MT/MT) females possessed both growing and fully grown oocytes; the oocytes completely lacked a ZP, but ZP1 was detectable inside the cytoplasm. Only 1-2 eggs were recovered from oviducts of superovulated Zp1MT/MT females, while an average of 21 eggs were recovered..."

Demonstrates that the Zp1 knock-in rat model recapitulates human ZP1-related absence of the zona pellucida, cytoplasmic ZP1 retention, severe reduction in ovulated eggs, IVF failure, and complete female infertility.

ZP1 CRISPR/Cas9 loss-of-function cynomolgus macaque (#ZP1-2)

First non-human primate model of ZP1 deficiency, generated by CRISPR/Cas9 editing in cynomolgus macaques. The ZP1-mutant female macaque (#ZP1-2) exhibited oocytes with thin, irregular, or completely absent zona pellucida, markedly reduced in vitro maturation (IVM) and blastocyst formation rates after ICSI, disrupted granulosa-oocyte transcriptomic signaling in late antral follicles, and oocyte mitochondrial swelling associated with SOD2 downregulation.

Species

Macaca fascicularis

Genotype

ZP1 CRISPR/Cas9 loss-of-function mutant (#ZP1-2)

Background

Cynomolgus macaque

Genes

ZP1 hgnc:13187

Publication

PMID:40923306

Pathograph links

Impaired Cumulus-Oocyte Complex Organization and Granulosa-Oocyte Crosstalk recapitulates fidelity: high Recapitulates ZP absence/thinning and disrupted oocyte-granulosa signaling in late antral follicles of a non-human primate with a four-ZP-subunit matrix.

Show evidence (1 reference)

PMID:40923306 SUPPORT Model Organism

"Following sexual maturation, oocytes retrieved from #ZP1-2 through superovulation exhibited a marked increase in zona pellucida-deficient oocytes and a significant reduction in maturation rates compared to controls. Integrated analyses, including immunofluorescence staining, transmission..."

Establishes the cynomolgus macaque CRISPR ZP1 model showing ZP-deficient oocytes, disrupted folliculogenesis, and reduced oocyte maturation consistent with human empty follicle syndrome.

Zp1-null knockout mouse (Zp1tm/tm)

Unlike humans and rats, mice possess only three functional zona pellucida genes (Zp1, Zp2, and Zp3, with Zp4 pseudogenized). Homozygous Zp1-null female mice still assemble a loosely organized, porous zona pellucida matrix composed of mZP2 and mZP3, with ectopic clusters of granulosa cells trapped in the perivitelline space. Zp1-null female mice remain fertile with reduced litter sizes (~50% of wild-type) due to fragile cleavage-stage embryos and precocious hatching in the oviduct, making the mouse knock-out a milder structural phenotype than the truncating/missense ZP1 mutations seen in humans and knock-in rats.

Species

Mus musculus

Genotype

Zp1-/- (Zp1tm/tm null)

Background

C57BL/6

Genes

ZP1 hgnc:13187

Publication

PMID:10433913

Pathograph links

Failure of ZP1-N1 Disulfide Cross-Linking and Zona Pellucida Extracellular Matrix Assembly partially recapitulates fidelity: moderate Demonstrates loss of ZP1 filament cross-linking and porous ZP architecture, but mice retain an uncross-linked ZP2/ZP3 coat and remain subfertile rather than completely sterile.

Show evidence (1 reference)

PMID:10433913 SUPPORT Model Organism

"Although a zona pellucida composed of ZP2 and ZP3 was formed around growing Zp1(tm/tm) oocytes, the matrix was more loosely organized than zonae around normal oocytes. In some Zp1 null follicles, this structural abnormality resulted in ectopic clusters of granulosa cells, lodged between the zona..."

Characterizes the Zp1-null mouse model, showing a loosely organized ZP2/ZP3 matrix, ectopic perivitelline granulosa cells, and reduced fertility due to early embryonic loss.

{ }

Source YAML

click to show

name: Female_Infertility_Due_To_Zona_Pellucida_Defect
creation_date: '2026-10-14T00:00:00Z'
description: >-
  Female infertility due to zona pellucida defect (also designated oocyte maturation
  defect 1, OOMD1; OMIM:615774) is a Mendelian disorder of female gamete development
  and extracellular matrix assembly caused by pathogenic variants in ZP1, which encodes
  zona pellucida glycoprotein 1, the intermolecular disulfide-forming cross-linker of
  human zona pellucida (ZP) filaments. Affected women have normal female karyotypes,
  normal secondary sexual development, normal menstrual cycles, and normal ovarian
  reserve and hormone profiles, yet present with primary female infertility revealed
  during assisted reproductive technology (ART) cycles. Loss-of-function or dominant-negative
  ZP1 variants impair ZP1 homodimerization, intracellular transport, secretion, or
  heteromeric assembly with ZP2, ZP3, and ZP4, resulting in a clinical spectrum ranging
  from retrieval of viable metaphase II oocytes with a thin or completely absent zona
  pellucida that fail conventional in vitro fertilization (IVF), to intra-follicular
  cumulus-oocyte complex disorganization, fragile or degenerated atretic oocytes, and
  genuine empty follicle syndrome (GEFS) in which no oocytes are recovered despite normal
  follicular growth and steroidogenesis. While conventional IVF fails because the absent
  or defective ZP cannot support normal sperm-egg interaction, intracytoplasmic sperm
  injection (ICSI) of viable ZP-free metaphase II oocytes can bypass the zona pellucida
  barrier and achieve blastocyst development and live birth in a subset of patients.
category: Mendelian
parents:
- Female Infertility
- Oocyte Maturation Defect
synonyms:
- OOMD1
- oocyte maturation defect 1
- female infertility due to zona pellucida defect
- ZP1-related oocyte maturation defect
- ZP1-related empty follicle syndrome
disease_term:
  preferred_term: female infertility due to zona pellucida defect
  term:
    id: MONDO:0014342
    label: female infertility due to zona pellucida defect
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: COMPLETE
  description: >-
    Most reported families and sporadic probands harbor homozygous or compound
    heterozygous loss-of-function or missense variants in ZP1. Disease manifestation
    is sex-limited to females; homozygous and heterozygous male carriers have normal
    fertility.
  evidence:
  - reference: PMID:24670168
    reference_title: "Mutant ZP1 in familial infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe a form of infertility with an autosomal recessive mode of
      inheritance, characterized by abnormal eggs that lack a zona pellucida. We
      identified a homozygous frameshift mutation in ZP1 in six family members.
    explanation: >-
      Establishes autosomal recessive inheritance of ZP1-related female infertility
      due to zona pellucida defect in the original index family.
  - reference: PMID:33272616
    reference_title: "The critical role of ZP genes in female infertility characterized by empty follicle syndrome and oocyte degeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified zona pellucida (ZP) gene variants in 18 individuals, which
      included 20 variants in the ZP1 gene, two variants in the ZP2 gene, and one
      previously reported recurrent variant in the ZP3 gene. The women carrying ZP
      variants constituted 51.43% of the GEFS cohort. The ZP1 variants were inherited
      in an autosomal recessive pattern; the ZP2 and ZP3 variants were inherited in
      an autosomal dominant pattern.
    explanation: >-
      Confirms across a cohort of 35 women with genuine empty follicle syndrome and
      oocyte degeneration that ZP1-associated cases follow autosomal recessive
      inheritance.
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    A subset of patients harbor heterozygous ZP1 variants (such as p.Trp83Arg,
    p.Arg109His, p.Tyr262Cys, and p.Glu267Glyfs*80), frequently transmitted paternally
    with sex-limited expression in females, that act via dominant-negative interference
    with ZP secretion or filament assembly or via haploinsufficiency.
  evidence:
  - reference: PMID:32573113
    reference_title: "Heterozygous mutations in ZP1 and ZP3 cause formation disorder of ZP and female infertility in human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we performed whole-exome sequencing in two probands with primary
      infertility whose oocytes lacked a ZP, and we identified a heterozygous
      mutation in ZP1 (NM_207341:c.326G>A p.Arg109His), which is situated in the
      N-terminus, and a heterozygous mutation in ZP3 (NM_001110354:c.400G>A
      p.Ala134Thr), which is situated in the ZP domain.
    explanation: >-
      Demonstrates that heterozygous missense variants in ZP1 can cause zona pellucida
      formation failure and female infertility.
  - reference: PMID:38966008
    reference_title: "ZP1-Y262C mutation causes abnormal zona pellucida formation and female infertility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a patient (II-1) displaying abnormal zona pellucida formation, we successfully
      identified the heterozygous ZP1 mutation (ZP1-Y262C) via whole-exome sequencing.
      Subsequent exome sequencing of the patient’s father (I-2) confirmed his carrier
      status for the ZP1 mutation, while the mother (I-1) exhibited a normal genotype
      (Figures 2A,B).
    explanation: >-
      Documents paternal transmission of a heterozygous ZP1 trefoil-domain missense
      mutation causing zona pellucida-deficient oocytes in the affected daughter.
- name: Sex-limited expression
  inheritance_term:
    preferred_term: Sex-limited expression
    term:
      id: HP:0001470
      label: Sex-limited expression
  description: >-
    Because the zona pellucida is an oocyte-specific extracellular matrix, ZP1
    pathogenic variants manifest exclusively in females. Heterozygous and homozygous
    male carriers are fertile and can transmit pathogenic ZP1 alleles to affected
    daughters.
  evidence:
  - reference: PMID:38966008
    reference_title: "ZP1-Y262C mutation causes abnormal zona pellucida formation and female infertility in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a patient (II-1) displaying abnormal zona pellucida formation, we successfully
      identified the heterozygous ZP1 mutation (ZP1-Y262C) via whole-exome sequencing.
      Subsequent exome sequencing of the patient’s father (I-2) confirmed his carrier
      status for the ZP1 mutation, while the mother (I-1) exhibited a normal genotype
      (Figures 2A,B).
    explanation: >-
      Demonstrates sex-limited female expression of ZP1-related infertility, with an
      unaffected fertile father transmitting the pathogenic ZP1 variant to his
      affected daughter.
prevalence:
- population: General population
  measure_type: UNKNOWN
  notes: >-
    Population-level prevalence of OOMD1 in the general population is unknown because
    affected women are asymptomatic until attempting conception or undergoing oocyte
    retrieval. In selected clinical cohorts, combined ZP1, ZP2, and ZP3 variants
    accounted for 18 of 35 (51.43%) unrelated Chinese women with genuine empty follicle
    syndrome and oocyte degeneration (with 20 ZP1 variants identified across the cohort),
    and the recurrent homozygous ZP1 c.1097G>A (p.Arg366Gln) founder variant alone
    accounted for 5 of 27 (18.5%; reported as an allelic frequency of 17.9% in the
    study text) North African women with severe oocyte maturation defect; gene-specific
    cohort attribution is recorded under genetic.case_fractions.
  evidence:
  - reference: PMID:33272616
    reference_title: "The critical role of ZP genes in female infertility characterized by empty follicle syndrome and oocyte degeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified zona pellucida (ZP) gene variants in 18 individuals, which
      included 20 variants in the ZP1 gene, two variants in the ZP2 gene, and one
      previously reported recurrent variant in the ZP3 gene. The women carrying ZP
      variants constituted 51.43% of the GEFS cohort.
    explanation: >-
      In a clinical cohort of 35 women with genuine empty follicle syndrome and oocyte
      degeneration, combined ZP gene variants (predominantly ZP1) accounted for 51.43%
      of cases, whereas general-population prevalence remains undetermined.
  - reference: PMID:35460069
    reference_title: "A recurrent ZP1 variant is responsible for oocyte maturation defect with degenerated oocytes in infertile females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we included four additional OMD patients and reanalyzed all 27 subjects.
      In addition to the seven patients with a previously identified defect, five
      carried the same deleterious homozygous ZP1 variant (c.1097G>A; p.Arg366Gln).
    explanation: >-
      Shows that a single recurrent North African founder variant in ZP1 accounts
      for 5 of 27 cases in a selected oocyte maturation defect cohort.
pathophysiology:
- name: ZP1 Loss-of-Function and Cytoplasmic Co-Sequestration of Zona Pellucida Glycoproteins
  description: >-
    Pathogenic truncating, splice-site, or missense variants in ZP1 lead to premature
    stop codons, reduced protein stability, or misfolded ZP1 polypeptides that fail
    to undergo normal post-translational trafficking and cleavage-coupled secretion
    in growing oocytes. Instead of being secreted into the extracellular perivitelline
    space, mutant ZP1 accumulates inside the oocyte cytoplasm and endoplasmic reticulum
    and aberrantly binds and sequesters wild-type ZP1, ZP2, ZP3, and ZP4 intracellularly,
    preventing their transport to the oocyte surface.
  role: TRIGGER
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Germline homozygous, compound heterozygous, or heterozygous pathogenic ZP1
      variants impair ZP1 expression, intracellular trafficking, secretion, and
      partner ZP glycoprotein transport.
  genes:
  - preferred_term: ZP1
    term:
      id: hgnc:13187
      label: ZP1
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  locations:
  - preferred_term: ovary
    term:
      id: UBERON:0000992
      label: ovary
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  biological_processes:
  - preferred_term: protein secretion
    term:
      id: GO:0009306
      label: protein secretion
    modifier: DECREASED
  molecular_functions:
  - preferred_term: structural constituent of egg coat
    term:
      id: GO:0035804
      label: structural constituent of egg coat
  downstream:
  - target: Failure of ZP1-N1 Disulfide Cross-Linking and Zona Pellucida Extracellular Matrix Assembly
    description: >-
      Depletion of secreted ZP1 and intracellular trapping of partner ZP glycoproteins
      prevent extracellular filament polymerization and cross-linking around the
      growing oocyte.
    evidence:
    - reference: PMID:24670168
      reference_title: "Mutant ZP1 in familial infertility."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The intracellular sequestration of these proteins could impede their
        trafficking to the extracellular milieu, thus precluding the formation of a
        zona pellucida (Fig. 2A) and leading to infertility.
      explanation: >-
        Explains the causal link between intracellular sequestration of ZP proteins
        and failure of extracellular zona pellucida formation.
    - reference: PMID:33272616
      reference_title: "The critical role of ZP genes in female infertility characterized by empty follicle syndrome and oocyte degeneration."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Variants of ZP genes caused protein intracellular sequestration and failure
        to assemble the ZP filaments, resulting in EFS and female infertility.
      explanation: >-
        Demonstrates that intracellular sequestration of ZP proteins directly prevents
        assembly of ZP filaments.
  evidence:
  - reference: PMID:24670168
    reference_title: "Mutant ZP1 in familial infertility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro studies showed that defective ZP1 proteins and normal ZP3 proteins
      colocalized throughout the cells and were not expressed at the cell surface,
      suggesting that the aberrant ZP1 results in the sequestration of ZP3 in the
      cytoplasm, thereby preventing the formation of the zona pellucida around the
      oocyte.
    explanation: >-
      Confocal microscopy of co-transfected HeLa cells demonstrates that truncated
      ZP1 colocalizes with and sequesters ZP3 in the cytoplasm, blocking transport
      to the cell surface.
  - reference: PMID:31300655
    reference_title: "Molecular basis of egg coat cross-linking sheds light on ZP1-associated female infertility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This showed that, whereas hZP1 is secreted into the medium as a mixture of
      monomer and disulphide-bonded dimer, secretion of hZP1Mut is completely
      abolished (Fig. 1b, left panel). Although the expression of hZP1Mut is lower
      than that of hZP1, the truncated mutant protein can be detected in the cell
      lysate (Fig. 1b, right panel).
    explanation: >-
      Biochemical secretion assays in mammalian cells show that the human infertility
      mutant hZP1 I390fs404X is retained in the cell lysate and its secretion is
      completely abolished.
  - reference: PMID:33272616
    reference_title: "The critical role of ZP genes in female infertility characterized by empty follicle syndrome and oocyte degeneration."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Studies in CHO cells suggested that most ZP1 variants led to increased
      intracytoplasmic protein and some variants influenced the intracellular
      transportation of other ZP proteins.
    explanation: >-
      Demonstrates intracytoplasmic protein accumulation and impaired intracellular
      transport of partner ZP proteins in CHO cells expressing mutant ZP1.
- name: Failure of ZP1-N1 Disulfide Cross-Linking and Zona Pellucida Extracellular Matrix Assembly
  description: >-
    In healthy human oocytes, secreted ZP2, ZP3, and ZP4 polymerize into long filaments
    that are covalently cross-linked into a stable three-dimensional extracellular matrix
    via intermolecular disulfide bonds (mediated by conserved Cys66 in chicken ZP1 and
    the corresponding Cys77 in the N-terminal ZP-N1 domain of human ZP1) forming
    ZP1-N1 homodimers, while human ZP4-N1 remains monomeric and cannot substitute for
    ZP1 cross-linking. Pathogenic ZP1 variants either eliminate secreted ZP1, disrupt
    ZP1-N1 homodimerization (such as p.Trp83Arg and p.Arg109His), alter the trefoil
    or ZP domains, or abolish heteromeric interaction with ZP2 and ZP3, resulting in
    a markedly thinned, fragile, or completely absent zona pellucida matrix.
  genes:
  - preferred_term: ZP1
    term:
      id: hgnc:13187
      label: ZP1
  - preferred_term: ZP2
    term:
      id: hgnc:13188
      label: ZP2
  - preferred_term: ZP3
    term:
      id: hgnc:13189
      label: ZP3
  - preferred_term: ZP4
    term:
      id: hgnc:15770
      label: ZP4
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  locations:
  - preferred_term: ovary
    term:
      id: UBERON:0000992
      label: ovary
  cellular_components:
  - preferred_term: egg coat
    term:
      id: GO:0035805
      label: egg coat
  - preferred_term: extracellular matrix
    term:
      id: GO:0031012
      label: extracellular matrix
  biological_processes:
  - preferred_term: egg coat formation
    term:
      id: GO:0035803
      label: egg coat formation
    modifier: ABNORMAL
  - preferred_term: extracellular matrix assembly
    term:
      id: GO:0085029
      label: extracellular matrix assembly
    modifier: ABNORMAL
  molecular_functions:
  - preferred_term: structural constituent of egg coat
    term:
      id: GO:0035804
      label: structural constituent of egg coat
  - preferred_term: extracellular matrix structural constituent
    term:
      id: GO:0005201
      label: extracellular matrix structural constituent
  downstream:
  - target: Impaired Cumulus-Oocyte Complex Organization and Granulosa-Oocyte Crosstalk
    description: >-
      Loss of a structurally intact zona pellucida matrix compromises physical
      support and bidirectional signaling between the growing oocyte and surrounding
      cumulus granulosa cells during the preantral-to-antral follicle transition.
    evidence:
    - reference: PMID:31734689
      reference_title: "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."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Immunohistochemistry using ovarian serial sections demonstrated that all
        preantral follicles had normal architecture, but with a thin ZP, lacking ZP1,
        surrounding the growing oocytes. The antral follicles were also defective in
        normal cumulus-oocyte complex organisation, leading us to speculate that the
        lack of ZP1 might lead to oocyte degeneration or increased fragility of the
        oocyte during follicular puncture, ultimately resulting in EFS.
      explanation: >-
        Serial ovarian histopathology from an affected patient links the thin,
        ZP1-deficient zona pellucida in preantral follicles to defective
        cumulus-oocyte complex organization in antral follicles.
  - target: Defective Sperm-Zona Pellucida Recognition and Fertilization Failure
    description: >-
      Absence or severe malformation of the zona pellucida deprives oocytes of the
      species-specific sperm-binding extracellular coat required for conventional
      sperm-oocyte interaction and fertilization.
    evidence:
    - reference: PMID:33624742
      reference_title: "Mutant Zp1 impedes incorporation of ZP3 and ZP4 in the zona pellucida, resulting in zona absence and female infertility in rats†."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The eggs of Zp1MT/MT females were not surrounded by a ZP and lost their
        fertilization capacity in vitro.
      explanation: >-
        Directly demonstrates that loss of the extracellular zona pellucida matrix
        around Zp1-mutant ova abolishes in vitro fertilization capacity.
    - reference: PMID:40923306
      reference_title: "Abnormal zona pellucida and follicular development in ZP1-mutant macaques."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        Loss-of-function mutations in ZP1 can result in incomplete or dysfunctional
        ZP formation, leading to failed fertilization (Wassarman & Litscher, 2021).
      explanation: >-
        Links incomplete or dysfunctional ZP matrix formation directly to failed
        fertilization.
  - target: Absent zona pellucida
    description: >-
      Complete failure of ZP1-mediated filament cross-linking and extracellular
      matrix assembly results in oocytes that completely lack a zona pellucida coat.
    evidence:
    - reference: PMID:24670168
      reference_title: "Mutant ZP1 in familial infertility."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our data suggest that the mutation prevents the formation of the zona
        pellucida around ova: all observed oocytes from affected family members
        lacked a zona pellucida when examined with light microscopy
      explanation: >-
        Directly links the ZP1 mutation and failure of ZP formation to the clinical
        phenotype of absent zona pellucida around retrieved oocytes.
    - reference: PMID:32573113
      reference_title: "Heterozygous mutations in ZP1 and ZP3 cause formation disorder of ZP and female infertility in human."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The effects of the mutations were investigated through structure prediction
        and in vitro studies in HeLa cells. The results, which were in line with the
        phenotype, suggested that these mutations might impede the function of
        cross-linking and secretion of ZP proteins.
      explanation: >-
        Connects impaired ZP cross-linking and secretion directly to the ZP-free
        oocyte phenotype.
  - target: Thin zona pellucida
    description: >-
      Partial assembly of ZP2, ZP3, and ZP4 filaments without ZP1 cross-linking
      produces an abnormally thin and structurally unstable zona pellucida.
    evidence:
    - reference: PMID:31734689
      reference_title: "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."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Immunohistochemistry using ovarian serial sections demonstrated that all
        preantral follicles had normal architecture, but with a thin ZP, lacking ZP1,
        surrounding the growing oocytes.
      explanation: >-
        Demonstrates that absence of ZP1 in growing follicles directly results in
        a thin zona pellucida surrounding the oocyte.
  evidence:
  - reference: PMID:31300655
    reference_title: "Molecular basis of egg coat cross-linking sheds light on ZP1-associated female infertility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consistent with an important role of W72 in the folding and dimerisation of
      cZP1-N1, this experiment showed that W83R not only decreases the secretion of
      hZP1-N1 but also significantly reduces its ability to form disulphide-bonded
      homodimers (Fig. 7b). This suggests that the mutation leads to lack of the ZP
      by hindering human ZP filament cross-linking.
    explanation: >-
      Biochemical analysis proves that the human ZP1 W83R variant impairs ZP1-N1
      disulfide-bonded homodimerization, hindering human ZP filament cross-linking.
  - reference: PMID:31300655
    reference_title: "Molecular basis of egg coat cross-linking sheds light on ZP1-associated female infertility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The latter observation, together with the fact that the trefoil/ZP module
      region of hZP1 does not form non-covalent homodimers (Fig. 2j), suggest that
      hZP1-N1 cross-link formation is essential for the assembly or maintenance of
      the human ZP and, hence, fertility.
    explanation: >-
      Demonstrates that ZP1-N1 intermolecular disulfide cross-linking is essential
      for assembly and maintenance of the human zona pellucida and cannot be
      rescued by ZP4.
  - reference: PMID:31292994
    reference_title: "Compound heterozygous ZP1 mutations cause empty follicle syndrome in infertile sisters."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Coimmunoprecipitation tests and homology modeling analysis confirmed that both
      mutated ZP1 disrupt the formation of oocyte zona pellucida by interrupting the
      interaction among ZP1, ZP2, and ZP3.
    explanation: >-
      Co-immunoprecipitation demonstrates that EFS-associated ZP1 mutations disrupt
      heteromeric assembly among ZP1, ZP2, and ZP3.
  - reference: PMID:32573113
    reference_title: "Heterozygous mutations in ZP1 and ZP3 cause formation disorder of ZP and female infertility in human."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The effects of the mutations were investigated through structure prediction
      and in vitro studies in HeLa cells. The results, which were in line with the
      phenotype, suggested that these mutations might impede the function of
      cross-linking and secretion of ZP proteins. Our study showed that the two
      mutations in ZP1 and ZP3 influenced the formation of the ZP, causing female
      infertility.
    explanation: >-
      Confirms that the ZP-N1 domain missense variant ZP1 p.Arg109His impedes ZP
      cross-linking and secretion in HeLa cells.
- name: Impaired Cumulus-Oocyte Complex Organization and Granulosa-Oocyte Crosstalk
  description: >-
    During ovarian folliculogenesis, the zona pellucida provides the structural scaffold
    that stabilizes transzonal projections and gap-junctional communication between
    surrounding cumulus granulosa cells and the growing primary oocyte. In ZP1-deficient
    follicles, preantral follicles initially form a thin ZP composed of ZP2, ZP3, and
    ZP4 without ZP1; however, as follicles expand into the antral stage and antral cavity
    fluid accumulates, the uncross-linked ZP separates from surrounding granulosa cells,
    cumulus-oocyte complex (COC) architecture collapses, and bidirectional nutrient and
    paracrine signaling between cumulus granulosa cells and the oocyte is disrupted.
  cell_types:
  - preferred_term: primary oocyte
    term:
      id: CL:0000654
      label: primary oocyte
  - preferred_term: granulosa cell
    term:
      id: CL:0000501
      label: granulosa cell
  locations:
  - preferred_term: ovary
    term:
      id: UBERON:0000992
      label: ovary
  biological_processes:
  - preferred_term: ovarian follicle development
    term:
      id: GO:0001541
      label: ovarian follicle development
    modifier: ABNORMAL
  downstream:
  - target: Oocyte Mitochondrial Dysfunction, Fragility, and Intra-Follicular Degeneration
    description: >-
      Disruption of cumulus-oocyte complex architecture and loss of granulosa-oocyte
      nutritional and metabolic support induce oocyte oxidative stress, mitochondrial
      swelling, mechanical fragility, and intra-follicular oocyte degeneration.
    evidence:
    - reference: PMID:36476320
      reference_title: "Can successful pregnancy be achieved and predicted from patients with identified ZP mutations? A literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Lack of ZP might interfere with the bidirectional communication between oocytes
        and cumulus cells, then impedes nutritional supplements from cumulus cells
        leading to oocyte degeneration or increases in the fragility of oocytes during
        follicular puncture, ultimately resulting in EFS [8, 53, 70].
      explanation: >-
        Explains how impaired bidirectional communication and nutrient transfer between
        cumulus cells and the oocyte lead to oocyte degeneration and fragility.
    - reference: PMID:31734689
      reference_title: "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."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The antral follicles were also defective in normal cumulus-oocyte complex
        organisation, leading us to speculate that the lack of ZP1 might lead to
        oocyte degeneration or increased fragility of the oocyte during follicular
        puncture, ultimately resulting in EFS.
      explanation: >-
        Connects defective cumulus-oocyte complex organization in antral follicles
        to downstream oocyte degeneration and mechanical fragility during puncture.
  evidence:
  - reference: PMID:31734689
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunohistochemistry using ovarian serial sections demonstrated that all
      preantral follicles had normal architecture, but with a thin ZP, lacking ZP1,
      surrounding the growing oocytes. The antral follicles were also defective in
      normal cumulus-oocyte complex organisation, leading us to speculate that the
      lack of ZP1 might lead to oocyte degeneration or increased fragility of the
      oocyte during follicular puncture, ultimately resulting in EFS.
    explanation: >-
      Human ovarian biopsy immunohistochemistry demonstrates that ZP1 deficiency
      permits a thin ZP in preantral follicles that fails to maintain cumulus-oocyte
      complex organization in antral follicles.
  - reference: PMID:36476320
    reference_title: "Can successful pregnancy be achieved and predicted from patients with identified ZP mutations? A literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Lack of ZP might interfere with the bidirectional communication between oocytes
      and cumulus cells, then impedes nutritional supplements from cumulus cells
      leading to oocyte degeneration or increases in the fragility of oocytes during
      follicular puncture, ultimately resulting in EFS [8, 53, 70].
    explanation: >-
      Explains how absence of the ZP disrupts bidirectional oocyte-cumulus cell
      communication and nutrient supply.
  - reference: PMID:40923306
    reference_title: "Abnormal zona pellucida and follicular development in ZP1-mutant macaques."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Additionally, a clear separation between the ZP and granulosa cells was
      observed in #ZP1-2 macaques, whereas #WT macaques displayed an intact
      ZP-granulosa cell interface.
    explanation: >-
      Demonstrates structural separation of the zona pellucida-granulosa cell
      interface in ZP1-mutant primate follicles.
- name: Oocyte Mitochondrial Dysfunction, Fragility, and Intra-Follicular Degeneration
  description: >-
    Deprived of a protective zona pellucida scaffold and cumulus-oocyte metabolic
    coupling, ZP1-deficient oocytes develop transcriptomic and ultrastructural
    hallmarks of cellular stress, including downregulation of antioxidant defenses
    (such as SOD2), oxidative stress, extensive mitochondrial swelling at germinal
    vesicle and metaphase II stages, increased autophagy, and extreme mechanical
    vulnerability to shear stress. Consequently, oocytes either degenerate within
    antral follicles prior to ovulation or rupture during transvaginal follicular
    aspiration, resulting in retrieval of shriveled, dark degenerated oocytes or
    genuine empty follicle syndrome (GEFS).
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  locations:
  - preferred_term: ovary
    term:
      id: UBERON:0000992
      label: ovary
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  biological_processes:
  - preferred_term: oocyte development
    term:
      id: GO:0048599
      label: oocyte development
    modifier: ABNORMAL
  downstream:
  - target: Empty ovarian follicle
    description: >-
      Complete intra-follicular oocyte degeneration or mechanical lysis of fragile
      ZP-deficient oocytes during follicular puncture results in failure to recover
      any oocytes despite normal follicular development (genuine empty follicle
      syndrome).
    evidence:
    - reference: PMID:31734689
      reference_title: "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."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The antral follicles were also defective in normal cumulus-oocyte complex
        organisation, leading us to speculate that the lack of ZP1 might lead to
        oocyte degeneration or increased fragility of the oocyte during follicular
        puncture, ultimately resulting in EFS.
      explanation: >-
        Links intra-follicular oocyte degeneration and increased oocyte fragility
        during follicular puncture directly to empty follicle syndrome.
    - reference: PMID:33272616
      reference_title: "The critical role of ZP genes in female infertility characterized by empty follicle syndrome and oocyte degeneration."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Variants of ZP genes caused protein intracellular sequestration and failure
        to assemble the ZP filaments, resulting in EFS and female infertility.
      explanation: >-
        Confirms that ZP filament failure and oocyte pathology culminate clinically
        in empty follicle syndrome.
  - target: Oocyte degeneration
    description: >-
      Oxidative stress, mitochondrial swelling, and loss of zona pellucida protection
      cause growing and mature oocytes to undergo atresia and cytoplasmic shrinkage,
      yielding shriveled, dark degenerated oocytes upon retrieval.
    evidence:
    - reference: PMID:35460069
      reference_title: "A recurrent ZP1 variant is responsible for oocyte maturation defect with degenerated oocytes in infertile females."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All the oocytes from ZP1-associated patients appeared shriveled and dark
        indicating that the abnormal ZP1 protein induced oocyte death and degeneration.
      explanation: >-
        Directly demonstrates that ZP1 deficiency induces oocyte death and retrieval
        of shriveled, dark degenerated oocytes.
    - reference: PMID:40923306
      reference_title: "Abnormal zona pellucida and follicular development in ZP1-mutant macaques."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Collectively, these data suggest that ZP1 deficiency induces oxidative stress
        and mitochondrial dysregulation, leading to increased autophagy and eventual
        oocyte degeneration.
      explanation: >-
        Shows that ZP1 deficiency drives oxidative stress, mitochondrial dysregulation,
        and eventual oocyte degeneration.
  evidence:
  - reference: PMID:40923306
    reference_title: "Abnormal zona pellucida and follicular development in ZP1-mutant macaques."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Collectively, these data suggest that ZP1 deficiency induces oxidative stress
      and mitochondrial dysregulation, leading to increased autophagy and eventual
      oocyte degeneration. Supporting this conclusion, TEM analysis further revealed
      extensive mitochondrial swelling in #ZP1-2 oocytes at both the GV and MII
      stages (Figure 6E).
    explanation: >-
      Single-oocyte multi-omics and electron microscopy in ZP1-mutant macaques
      demonstrate oxidative stress, mitochondrial swelling, and autophagy driving
      oocyte degeneration.
  - reference: PMID:35460069
    reference_title: "A recurrent ZP1 variant is responsible for oocyte maturation defect with degenerated oocytes in infertile females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the oocytes from ZP1-associated patients appeared shriveled and dark
      indicating that the abnormal ZP1 protein induced oocyte death and degeneration.
    explanation: >-
      Demonstrates in human patients that ZP1 deficiency results in oocyte death
      and dark, shriveled degenerated oocytes.
  - reference: PMID:31734689
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The antral follicles were also defective in normal cumulus-oocyte complex
      organisation, leading us to speculate that the lack of ZP1 might lead to
      oocyte degeneration or increased fragility of the oocyte during follicular
      puncture, ultimately resulting in EFS.
    explanation: >-
      Supports the mechanism of intra-follicular oocyte degeneration and mechanical
      fragility during follicular aspiration.
- name: Defective Sperm-Zona Pellucida Recognition and Fertilization Failure
  description: >-
    In patients whose oocytes survive follicular aspiration as viable metaphase II (MII)
    gametes despite an absent or severely thinned zona pellucida, the naked oolemma
    lacks the ZP glycoprotein matrix required for normal species-specific sperm binding,
    acrosome reaction induction, and block to polyspermy. Consequently, conventional
    in vitro fertilization (IVF) fails completely, whereas direct intracytoplasmic
    sperm injection (ICSI) into the ooplasm can bypass the extracellular ZP defect.
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  locations:
  - preferred_term: ovary
    term:
      id: UBERON:0000992
      label: ovary
  biological_processes:
  - preferred_term: binding of sperm to zona pellucida
    term:
      id: GO:0007339
      label: binding of sperm to zona pellucida
    modifier: ABNORMAL
  downstream:
  - target: Female infertility
    description: >-
      Failure of conventional sperm-zona recognition and natural fertilization
      renders affected women unable to conceive naturally or via standard IVF.
    evidence:
    - reference: PMID:24670168
      reference_title: "Mutant ZP1 in familial infertility."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we describe a form of infertility with an autosomal recessive mode of
        inheritance, characterized by abnormal eggs that lack a zona pellucida.
      explanation: >-
        Establishes that eggs lacking a zona pellucida cause primary female infertility.
    - reference: PMID:40923306
      reference_title: "Abnormal zona pellucida and follicular development in ZP1-mutant macaques."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        Loss-of-function mutations in ZP1 can result in incomplete or dysfunctional
        ZP formation, leading to failed fertilization (Wassarman & Litscher, 2021).
      explanation: >-
        Links failed fertilization from dysfunctional ZP formation directly to
        female infertility.
  evidence:
  - reference: PMID:40923306
    reference_title: "Abnormal zona pellucida and follicular development in ZP1-mutant macaques."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Among ZP genes, ZP1 has emerged as a critical determinant of matrix assembly
      and oocyte viability. Loss-of-function mutations in ZP1 can result in
      incomplete or dysfunctional ZP formation, leading to failed fertilization
      (Wassarman & Litscher, 2021).
    explanation: >-
      Summarizes how loss-of-function ZP1 mutations impair ZP matrix formation and
      result in failed fertilization.
  - reference: PMID:36476320
    reference_title: "Can successful pregnancy be achieved and predicted from patients with identified ZP mutations? A literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Sixty-nine mutations of the ZP genes were reported in 87 patients with
      different clinical phenotypes, including empty follicle syndrome (EFS),
      ZP-free oocytes (ZFO), ZP-thin oocytes (ZTO), degenerated and immature oocytes.
      The phenotypes of patients were influenced by the types and location of the
      mutations. The most common effects of ZP mutations are protein truncation and
      dysfunction. Three patients with ZP1 mutations, two with ZP2 mutations, and
      three with ZP4 mutations had successful pregnancies through Intracytoplasmic
      sperm injection (ICSI) from ZFO or ZTO.
    explanation: >-
      Literature synthesis defines the clinical endpoints of ZP mutations (EFS,
      degenerated/immature oocytes, and ZP-free or ZP-thin oocytes) and shows that
      ICSI can rescue fertilization in patients yielding ZP-free oocytes.
phenotypes:
- category: Reproductive
  name: Female infertility
  frequency: OBLIGATE
  diagnostic: true
  description: >-
    Primary female infertility despite regular menstrual cycles, normal female
    reproductive tract anatomy, normal basal serum gonadotropins (FSH, LH, estradiol)
    and anti-Müllerian hormone (AMH), and normal follicular growth on ovarian
    ultrasound during controlled ovarian stimulation. Affected women fall into two
    overlapping assisted-reproduction phenotypes upon follicular aspiration: (1)
    genuine empty follicle syndrome (GEFS) or retrieval of only degenerated, atretic,
    or germinal-vesicle-arrested oocytes (reported in 37 of 48 reviewed ZP1-mutant
    patients, ~77%), and (2) retrieval of mature metaphase II oocytes with a severely
    thinned or completely absent zona pellucida (reported in 11 of 48 patients, ~23%)
    that fail conventional in vitro fertilization.
  phenotype_term:
    preferred_term: Female infertility
    term:
      id: HP:0008222
      label: Female infertility
  evidence:
  - reference: PMID:24670168
    reference_title: "Mutant ZP1 in familial infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her age at menarche was 13 years, her menstrual cycle was normal (lasting 3 to
      7 days and occurring every 29 days), and she had no dysmenorrhea.
      Infertility-related examinations did not reveal abnormalities
    explanation: >-
      Establishes primary female infertility with normal menarche, regular menstrual
      cycles, and normal baseline fertility examinations in the proband homozygous
      for the ZP1 mutation.
  - reference: PMID:35460069
    reference_title: "A recurrent ZP1 variant is responsible for oocyte maturation defect with degenerated oocytes in infertile females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the oocytes from ZP1-associated patients appeared shriveled and dark
      indicating that the abnormal ZP1 protein induced oocyte death and degeneration.
      Overall ZP1-associated patients had degenerated or absent oocytes contrary to
      PATL2-associated subjects who had immature oocytes blocked mainly at the
      germinal vesicle stage.
    explanation: >-
      Describes the characteristic retrieval of shriveled, dark, degenerated or
      absent oocytes in patients homozygous for ZP1 p.Arg366Gln.
  - reference: PMID:36476320
    reference_title: "Can successful pregnancy be achieved and predicted from patients with identified ZP mutations? A literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Their genotypes are homozygous, heterozygous, or compound heterozygous, and are
      inherited in autosomal dominant (AD) or autosomal recessive (AR) manners, which
      cause different phenotypes like empty follicle syndrome (EFS), ZP-free oocytes
      (ZFO), degenerated or immature oocytes
    explanation: >-
      Summarizes the clinical spectrum of ZP1-related female infertility across
      48 reported patients, encompassing empty follicle syndrome, ZP-free oocytes,
      and degenerated or immature oocytes.
- category: Reproductive
  name: Absent zona pellucida
  frequency: OCCASIONAL
  diagnostic: true
  description: >-
    Complete absence of the extracellular zona pellucida coat surrounding retrieved
    oocytes (ZP-free oocytes, ZFO), observed on light microscopy after transvaginal
    follicular aspiration in approximately 20 to 25% of reported ZP1-mutant patients.
    Viable metaphase II ZP-free oocytes fail conventional IVF but can be fertilized
    by intracytoplasmic sperm injection (ICSI).
  phenotype_term:
    preferred_term: Absent zona pellucida
    term:
      id: HP:6000328
      label: Absent zona pellucida
  sequelae:
  - target: Female infertility
    description: >-
      Absence of the zona pellucida prevents normal sperm-egg binding, block to
      polyspermy, and oviductal embryo transport, resulting in primary female
      infertility.
    evidence:
    - reference: PMID:24670168
      reference_title: "Mutant ZP1 in familial infertility."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we describe a form of infertility with an autosomal recessive mode of
        inheritance, characterized by abnormal eggs that lack a zona pellucida.
      explanation: >-
        Links the absence of a zona pellucida around retrieved ova directly to
        female infertility.
  evidence:
  - reference: PMID:24670168
    reference_title: "Mutant ZP1 in familial infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data suggest that the mutation prevents the formation of the zona
      pellucida around ova: all observed oocytes from affected family members
      lacked a zona pellucida when examined with light microscopy
    explanation: >-
      Demonstrates complete absence of the zona pellucida on light microscopy of
      oocytes retrieved from affected family members with homozygous ZP1 frameshift
      variants.
  - reference: PMID:32573113
    reference_title: "Heterozygous mutations in ZP1 and ZP3 cause formation disorder of ZP and female infertility in human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we performed whole-exome sequencing in two probands with primary
      infertility whose oocytes lacked a ZP, and we identified a heterozygous
      mutation in ZP1 (NM_207341:c.326G>A p.Arg109His), which is situated in the
      N-terminus, and a heterozygous mutation in ZP3 (NM_001110354:c.400G>A
      p.Ala134Thr), which is situated in the ZP domain.
    explanation: >-
      Documents retrieval of zona pellucida-free oocytes in a proband carrying a
      heterozygous ZP1 p.Arg109His variant.
- category: Reproductive
  name: Thin zona pellucida
  frequency: OCCASIONAL
  description: >-
    Markedly thinned, poorly compacted, and structurally fragile zona pellucida
    surrounding growing preantral oocytes or retrieved metaphase II oocytes (ZP-thin
    oocytes, ZTO), composed of uncross-linked ZP2, ZP3, and ZP4 filaments lacking
    ZP1 cross-bridges.
  phenotype_term:
    preferred_term: Thin zona pellucida
    term:
      id: HP:0020157
      label: Thin zona pellucida
  sequelae:
  - target: Female infertility
    description: >-
      A severely thinned, uncross-linked zona pellucida fails to maintain normal
      cumulus-oocyte complex stability or normal fertilization, leading to female
      infertility.
    evidence:
    - reference: PMID:31734689
      reference_title: "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."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Immunohistochemistry using ovarian serial sections demonstrated that all
        preantral follicles had normal architecture, but with a thin ZP, lacking ZP1,
        surrounding the growing oocytes. The antral follicles were also defective in
        normal cumulus-oocyte complex organisation, leading us to speculate that the
        lack of ZP1 might lead to oocyte degeneration or increased fragility of the
        oocyte during follicular puncture, ultimately resulting in EFS.
      explanation: >-
        Demonstrates how a thin, ZP1-deficient zona pellucida in preantral follicles
        leads to cumulus-oocyte complex breakdown, empty follicle syndrome, and
        infertility.
  evidence:
  - reference: PMID:31734689
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunohistochemistry using ovarian serial sections demonstrated that all
      preantral follicles had normal architecture, but with a thin ZP, lacking ZP1,
      surrounding the growing oocytes.
    explanation: >-
      Histopathological evidence of a thin zona pellucida lacking ZP1 around growing
      oocytes in an affected woman with biallelic ZP1 mutations.
  - reference: PMID:36476320
    reference_title: "Can successful pregnancy be achieved and predicted from patients with identified ZP mutations? A literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Sixty-nine mutations of the ZP genes were reported in 87 patients with
      different clinical phenotypes, including empty follicle syndrome (EFS),
      ZP-free oocytes (ZFO), ZP-thin oocytes (ZTO), degenerated and immature oocytes.
    explanation: >-
      Confirms ZP-thin oocytes (ZTO) as a recognized clinical phenotype of ZP gene
      mutations.
- category: Reproductive
  name: Empty ovarian follicle
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Genuine empty follicle syndrome (GEFS), defined by the failure to recover any
    oocytes from mature ovarian follicles after repeated aspiration and flushing
    despite normal follicular development and appropriate hCG/estradiol levels during
    controlled ovarian stimulation.
  phenotype_term:
    preferred_term: Empty ovarian follicle
    term:
      id: HP:0031067
      label: Empty ovarian follicle
  sequelae:
  - target: Female infertility
    description: >-
      Failure to recover viable oocytes from mature ovarian follicles precludes
      fertilization and embryo transfer, resulting in intractable autologous female
      infertility.
    evidence:
    - reference: PMID:33272616
      reference_title: "The critical role of ZP genes in female infertility characterized by empty follicle syndrome and oocyte degeneration."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Variants of ZP genes caused protein intracellular sequestration and failure
        to assemble the ZP filaments, resulting in EFS and female infertility.
      explanation: >-
        Directly links empty follicle syndrome caused by ZP gene variants to female
        infertility.
  evidence:
  - reference: PMID:33272616
    reference_title: "The critical role of ZP genes in female infertility characterized by empty follicle syndrome and oocyte degeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified zona pellucida (ZP) gene variants in 18 individuals, which
      included 20 variants in the ZP1 gene, two variants in the ZP2 gene, and one
      previously reported recurrent variant in the ZP3 gene. The women carrying ZP
      variants constituted 51.43% of the GEFS cohort.
    explanation: >-
      Establishes ZP1 as the major genetic cause of genuine empty follicle syndrome
      (GEFS).
  - reference: PMID:31734689
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The antral follicles were also defective in normal cumulus-oocyte complex
      organisation, leading us to speculate that the lack of ZP1 might lead to
      oocyte degeneration or increased fragility of the oocyte during follicular
      puncture, ultimately resulting in EFS.
    explanation: >-
      Demonstrates that ZP1 mutations present clinically as empty follicle syndrome
      upon follicular puncture.
- category: Reproductive
  name: Oocyte degeneration
  frequency: FREQUENT
  diagnostic: true
  description: >-
    Retrieval of shriveled, dark, atretic, or lysed oocytes (or degenerated ooplasm
    fragments within empty zonae or cumulus complexes) upon follicular aspiration,
    reflecting intra-follicular oocyte death and mechanical fragility.
  phenotype_term:
    preferred_term: Oocyte degeneration
  notes: >-
    HPO currently lacks a specific term for oocyte degeneration or oocyte atresia
    (distinct from Arrested oocyte maturation, HP:0031068, and Empty ovarian follicle,
    HP:0031067); preferred_term is recorded without an HPO ID pending upstream term
    addition.
  sequelae:
  - target: Female infertility
    description: >-
      Degenerated, non-viable oocytes cannot undergo fertilization or embryonic
      cleavage, directly causing primary female infertility.
    evidence:
    - reference: PMID:35460069
      reference_title: "A recurrent ZP1 variant is responsible for oocyte maturation defect with degenerated oocytes in infertile females."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All the oocytes from ZP1-associated patients appeared shriveled and dark
        indicating that the abnormal ZP1 protein induced oocyte death and degeneration.
      explanation: >-
        Demonstrates that ZP1-induced oocyte death and degeneration underlie the
        infertility of affected patients.
  evidence:
  - reference: PMID:35460069
    reference_title: "A recurrent ZP1 variant is responsible for oocyte maturation defect with degenerated oocytes in infertile females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the oocytes from ZP1-associated patients appeared shriveled and dark
      indicating that the abnormal ZP1 protein induced oocyte death and degeneration.
      Overall ZP1-associated patients had degenerated or absent oocytes contrary to
      PATL2-associated subjects who had immature oocytes blocked mainly at the
      germinal vesicle stage.
    explanation: >-
      Establishes oocyte degeneration (shriveled, dark oocytes) as a hallmark clinical
      phenotype of ZP1-associated infertility.
  - reference: PMID:33272616
    reference_title: "The critical role of ZP genes in female infertility characterized by empty follicle syndrome and oocyte degeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings not only reveal the critical roles of ZP genes but also pave the
      way for the efficient genetic diagnosis of females with GEFS and oocyte
      degeneration.
    explanation: >-
      Confirms oocyte degeneration alongside genuine empty follicle syndrome as a
      defining clinical manifestation of ZP1 variants.
genetic:
- name: ZP1
  association: Causative
  gene_term:
    preferred_term: ZP1
    term:
      id: hgnc:13187
      label: ZP1
  case_fractions:
  - population: North African cohort of women with oocyte maturation defect
    case_fraction_percent: 18.5
    cohort_size: 27
    notes: >-
      Five of 27 (18.5%) North African patients with severe oocyte maturation defect
      harbored the homozygous founder variant ZP1 c.1097G>A (p.Arg366Gln), reported
      in the study text as an allelic frequency of 17.9% (10 of 56 alleles across
      analyzed subjects). In a separate Chinese cohort of 35 women with genuine
      empty follicle syndrome and oocyte degeneration (PMID:33272616), combined
      ZP1, ZP2, and ZP3 variants accounted for 18 of 35 cases (51.43%), with 20
      distinct ZP1 variants identified across the cohort.
    evidence:
    - reference: PMID:35460069
      reference_title: "A recurrent ZP1 variant is responsible for oocyte maturation defect with degenerated oocytes in infertile females."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here, we included four additional OMD patients and reanalyzed all 27 subjects.
        In addition to the seven patients with a previously identified defect, five
        carried the same deleterious homozygous ZP1 variant (c.1097G>A; p.Arg366Gln).
      explanation: >-
        Establishes the gene-specific case fraction (5 of 27 patients, 18.5%) of
        homozygous ZP1 p.Arg366Gln in a North African oocyte maturation defect cohort.
  variants:
  - name: c.1169_1176del (p.Ile390Thrfs*16)
    gene:
      preferred_term: ZP1
      term:
        id: hgnc:13187
        label: ZP1
    clinical_significance: PATHOGENIC
    variant_type: deletion
    type: frameshift_variant
    genomic_contexts:
    - coding sequence
    description: >-
      Index homozygous 8-bp frameshift deletion in the ZP-C subdomain of ZP1
      resulting in premature truncation (p.Ile390Thrfs*16, also referred to as
      I390fs404X), abolishing the C-terminal consensus furin cleavage site and
      transmembrane domain, blocking ZP1 secretion, and causing cytoplasmic
      sequestration of ZP3 and ZP4.
    evidence:
    - reference: PMID:24670168
      reference_title: "Mutant ZP1 in familial infertility."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Sequencing of candidate genes ZP1, ZP2, ZP3, and ZP4 revealed that six members
        of generation IV (the four patients and two unmarried family members) carried a
        homozygous frameshift deletion of 8 bp encompassing nucleotides 1169 through
        1176 in ZP1 (GenBank accession number, KJ489454).
      explanation: >-
        Identifies the index homozygous frameshift deletion c.1169_1176del in ZP1 in
        a familial cases of zona pellucida-free infertility.
  - name: c.1097G>A (p.Arg366Gln)
    gene:
      preferred_term: ZP1
      term:
        id: hgnc:13187
        label: ZP1
    clinical_significance: PATHOGENIC
    variant_type: single nucleotide variant
    type: missense_variant
    genomic_contexts:
    - coding sequence
    description: >-
      Recurrent North African founder missense variant in exon 6 within the ZP-N
      subdomain of ZP1; homozygosity causes oocyte death, retrieval of shriveled
      dark degenerated oocytes, or genuine empty follicle syndrome.
    evidence:
    - reference: PMID:35460069
      reference_title: "A recurrent ZP1 variant is responsible for oocyte maturation defect with degenerated oocytes in infertile females."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here, we included four additional OMD patients and reanalyzed all 27 subjects.
        In addition to the seven patients with a previously identified defect, five
        carried the same deleterious homozygous ZP1 variant (c.1097G>A; p.Arg366Gln).
      explanation: >-
        Identifies the recurrent homozygous ZP1 c.1097G>A (p.Arg366Gln) variant in
        five North African patients with severe oocyte maturation defect.
    - reference: PMID:42060237
      reference_title: "A recurrent North African ZP1 variant and a literature review of genotype-phenotype correlations in ZP-related infertility."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both patients and two affected siblings harbored a homozygous ZP1 c.1097G > A
        p.(Arg366Gln) variant inherited from both heterozygous parents. This previously
        described variant appears to be recurrent in North African populations.
      explanation: >-
        Confirms recurrence of homozygous ZP1 c.1097G>A p.(Arg366Gln) in North African
        families with empty follicle syndrome.
  - name: c.326G>A (p.Arg109His)
    gene:
      preferred_term: ZP1
      term:
        id: hgnc:13187
        label: ZP1
    clinical_significance: PATHOGENIC
    variant_type: single nucleotide variant
    type: missense_variant
    genomic_contexts:
    - coding sequence
    description: >-
      N-terminal ZP-N1 cross-linking domain missense variant that impairs ZP1
      secretion and cross-linking function, reported in heterozygous state in a
      woman with ZP-free oocytes who achieved live birth after ICSI.
    evidence:
    - reference: PMID:32573113
      reference_title: "Heterozygous mutations in ZP1 and ZP3 cause formation disorder of ZP and female infertility in human."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here, we performed whole-exome sequencing in two probands with primary
        infertility whose oocytes lacked a ZP, and we identified a heterozygous
        mutation in ZP1 (NM_207341:c.326G>A p.Arg109His), which is situated in the
        N-terminus, and a heterozygous mutation in ZP3 (NM_001110354:c.400G>A
        p.Ala134Thr), which is situated in the ZP domain.
      explanation: >-
        Identifies the heterozygous ZP1 c.326G>A (p.Arg109His) variant in a patient
        with ZP-free oocytes.
  - name: c.247T>C (p.Trp83Arg)
    gene:
      preferred_term: ZP1
      term:
        id: hgnc:13187
        label: ZP1
    clinical_significance: PATHOGENIC
    variant_type: single nucleotide variant
    type: missense_variant
    genomic_contexts:
    - coding sequence
    description: >-
      Missense variant in the N-terminal ZP-N1 domain (c.247T>C, p.Trp83Arg) that
      reduces hZP1-N1 secretion and disrupts intermolecular disulfide-bonded
      homodimerization required for human ZP filament cross-linking.
    evidence:
    - reference: PMID:31300655
      reference_title: "Molecular basis of egg coat cross-linking sheds light on ZP1-associated female infertility."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Consistent with an important role of W72 in the folding and dimerisation of
        cZP1-N1, this experiment showed that W83R not only decreases the secretion of
        hZP1-N1 but also significantly reduces its ability to form disulphide-bonded
        homodimers (Fig. 7b). This suggests that the mutation leads to lack of the ZP
        by hindering human ZP filament cross-linking.
      explanation: >-
        Demonstrates that the ZP1 p.Trp83Arg (W83R) variant impairs ZP1-N1 secretion
        and disulfide homodimerization.
  - name: c.785A>G (p.Tyr262Cys)
    gene:
      preferred_term: ZP1
      term:
        id: hgnc:13187
        label: ZP1
    clinical_significance: PATHOGENIC
    variant_type: single nucleotide variant
    type: missense_variant
    genomic_contexts:
    - coding sequence
    description: >-
      Paternally inherited heterozygous missense variant in the trefoil domain of
      ZP1 (c.785A>G, p.Tyr262Cys) that introduces an unpaired cysteine, impairs ZP1
      glycosylation and secretion, and causes abnormal zona pellucida formation.
    evidence:
    - reference: PMID:38966008
      reference_title: "ZP1-Y262C mutation causes abnormal zona pellucida formation and female infertility in humans."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In a patient (II-1) displaying abnormal zona pellucida formation, we successfully
        identified the heterozygous ZP1 mutation (ZP1-Y262C) via whole-exome sequencing.
      explanation: >-
        Identifies the heterozygous ZP1 p.Tyr262Cys (Y262C) mutation in a patient
        with abnormal zona pellucida formation and primary infertility.
  notes: >-
    Over 47 pathogenic variants in ZP1 have been identified across all structural
    domains of the 638-amino-acid glycoprotein, including the N-terminal ZP-N1
    cross-linking domain (e.g., p.Cys80Tyr, p.Tyr81His, p.Trp83Arg, p.Arg109Cys,
    p.Arg109His), the proline-rich linker, the trefoil domain (e.g., p.Gln257Ter,
    p.Tyr262Cys, p.Glu267Glyfs*80), the bipartite zona pellucida domain (ZP-N and
    ZP-C subdomains, including the recurrent North African founder variant c.1097G>A
    p.Arg366Gln, the frameshift c.1169_1176del p.Ile390Thrfs*16, and p.Arg410Trp),
    the consensus furin cleavage site (CFCS), and the C-terminal transmembrane domain.
    Biallelic truncating or splice-site variants most frequently cause genuine empty
    follicle syndrome or severe oocyte degeneration, whereas certain missense or
    frameshift variants allow retrieval of ZP-free metaphase II oocytes.
  evidence:
  - reference: PMID:24670168
    reference_title: "Mutant ZP1 in familial infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequencing of candidate genes ZP1, ZP2, ZP3, and ZP4 revealed that six members
      of generation IV (the four patients and two unmarried family members) carried a
      homozygous frameshift deletion of 8 bp encompassing nucleotides 1169 through
      1176 in ZP1 (GenBank accession number, KJ489454).
    explanation: >-
      Identifies the first causal homozygous frameshift deletion in ZP1 in four
      infertile sisters from a consanguineous pedigree.
  - reference: PMID:36476320
    reference_title: "Can successful pregnancy be achieved and predicted from patients with identified ZP mutations? A literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      A total of 47 ZP1 mutations have been reported in 19 pieces of literature, most
      of which are exon mutations, and only seven are intron splicing mutations.
      Mutations are distributed in all 12 exons of ZP1 gene. Corresponding protein
      variants are distributed in all seven functional domains of ZP1 protein,
      including 13 nonsense mutations, 16 missense mutations, seven splicing
      mutations and 11 frameshift mutations
    explanation: >-
      Catalogs 47 distinct pathogenic ZP1 mutations across all 12 exons and 7
      functional domains of ZP1, making ZP1 the most frequently mutated zona
      pellucida gene in human female infertility.
  - reference: PMID:42060237
    reference_title: "A recurrent North African ZP1 variant and a literature review of genotype-phenotype correlations in ZP-related infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients and two affected siblings harbored a homozygous ZP1 c.1097G > A
      p.(Arg366Gln) variant inherited from both heterozygous parents. This previously
      described variant appears to be recurrent in North African populations.
    explanation: >-
      Confirms recurrence of the homozygous ZP1 c.1097G>A p.(Arg366Gln) founder
      variant in North African families with empty follicle syndrome.
treatments:
- name: Intracytoplasmic Sperm Injection (ICSI)
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  description: >-
    For the subset of ZP1-mutant patients (~20 to 25%) from whom mature metaphase II (MII)
    zona pellucida-free oocytes can be successfully aspirated (often facilitated by
    gentle follicular aspiration at reduced suction pressure or diagnostic natural-cycle
    aspiration), intracytoplasmic sperm injection (ICSI) directly injects a single
    spermatozoon into the ooplasm, bypassing the absent ZP required for conventional
    IVF sperm binding. Following careful individual microdrop culture of fragile
    ZP-free embryos to the blastocyst stage and embryo transfer, live births of
    healthy infants have been achieved.
  treatment_term:
    preferred_term: Intracytoplasmic Sperm Injection
    term:
      id: NCIT:C185482
      label: Intracytoplasmic Sperm Injection
  target_phenotypes:
  - preferred_term: Female infertility
    term:
      id: HP:0008222
      label: Female infertility
  - preferred_term: Absent zona pellucida
    term:
      id: HP:6000328
      label: Absent zona pellucida
  - preferred_term: Thin zona pellucida
    term:
      id: HP:0020157
      label: Thin zona pellucida
  evidence:
  - reference: PMID:32573113
    reference_title: "Heterozygous mutations in ZP1 and ZP3 cause formation disorder of ZP and female infertility in human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, the patient with the ZP1 mutation delivered a baby following
      intracytoplasmic sperm injection (ICSI); thus, we suggest the targeted genetic
      diagnosis of ZP genes to choose appropriate fertilization methods and improve
      the success rate of assisted reproductive technology (ART) treatments.
    explanation: >-
      Documents successful clinical rescue of ZP1-mutant ZP-free oocytes via ICSI
      resulting in a healthy live birth.
  - reference: PMID:32847637
    reference_title: "Role of diagnostic intracytoplasmic sperm injection (ICSI) in the management of genetically determined zona pellucida-free oocytes during in vitro fertilization: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diagnostic ICSI provided information about the embryo development potential
      from ZP-free oocytes and allowed better planning of the subsequent ICSI cycle.
      WES revealed that the absence of ZP was likely to be due to a new (ZP1)
      mutation. The subsequent ICSI cycle resulted in the delivery of a healthy baby.
    explanation: >-
      Demonstrates that diagnostic ICSI followed by therapeutic ICSI can achieve
      live birth in a patient with genetically determined ZP1-mutant ZP-free oocytes.
  - reference: PMID:36476320
    reference_title: "Can successful pregnancy be achieved and predicted from patients with identified ZP mutations? A literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      If oocytes with ZP defects could be obtained from the affected patients, ICSI
      could be preferentially chosen instead of the traditional IVF, which may
      improve the probability of successful pregnancy via ART.
    explanation: >-
      Recommends ICSI over conventional IVF whenever ZP-defective oocytes can be
      retrieved from patients with ZP gene mutations.
- name: Oocyte Donation
  action_category: THERAPEUTIC
  description: >-
    For the majority of ZP1-mutant patients (~75 to 80%, particularly those carrying
    biallelic truncating, frameshift, or severe missense variants such as p.Arg366Gln)
    who present with genuine empty follicle syndrome or complete intra-follicular
    oocyte degeneration where no viable metaphase II oocytes can be recovered,
    autologous ICSI is not feasible and in vitro fertilization using donor oocytes
    is the definitive therapeutic option to achieve pregnancy.
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_phenotypes:
  - preferred_term: Female infertility
    term:
      id: HP:0008222
      label: Female infertility
  - preferred_term: Empty ovarian follicle
    term:
      id: HP:0031067
      label: Empty ovarian follicle
  evidence:
  - reference: PMID:36476320
    reference_title: "Can successful pregnancy be achieved and predicted from patients with identified ZP mutations? A literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      For patients with the most severe phenotypes of EFS caused by ZP gene mutations,
      the current optimal treatment choice would be egg donation.
    explanation: >-
      Establishes oocyte (egg) donation as the optimal treatment for patients with
      severe empty follicle syndrome caused by ZP gene mutations.
- name: Genetic Counseling
  description: >-
    Genetic counseling is recommended for affected women and their family members to
    explain autosomal recessive or sex-limited autosomal dominant inheritance, screen
    female siblings of reproductive age who may share pathogenic ZP1 variants, and
    guide reproductive decision-making between autologous ICSI attempts and oocyte
    donation to avoid repeated futile ovarian stimulation cycles.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:42060237
    reference_title: "A recurrent North African ZP1 variant and a literature review of genotype-phenotype correlations in ZP-related infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The recurrent ZP1 c.1097G > A p.(Arg366Gln) variant contributes to EFS in
      consanguineous North African families. Genetic diagnosis using targeted gene
      panels is valuable for personalized infertility care and counseling.
    explanation: >-
      Supports targeted genetic diagnosis and genetic counseling to guide
      personalized infertility care in families with ZP1 variants.
diagnosis:
- name: Genetic Testing (ZP1 Sequencing / Infertility Gene Panel / Exome Sequencing)
  description: >-
    Definitive molecular diagnosis is established by identifying biallelic (or
    pathogenic heterozygous) variants in ZP1 via whole-exome sequencing or targeted
    female infertility gene panel sequencing in women presenting with genuine empty
    follicle syndrome, degenerated/fragile oocytes, or zona pellucida-free oocytes
    upon transvaginal follicular aspiration despite normal ovarian reserve and
    hormonal response.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    Identification of homozygous, compound heterozygous, or pathogenic heterozygous
    variants in ZP1 (NM_207341.4). In patients of North African ancestry presenting
    with empty follicle syndrome or degenerated oocytes, targeted screening for the
    recurrent founder variant c.1097G>A p.(Arg366Gln) accounts for ~18% of OMD cases.
  evidence:
  - reference: PMID:35460069
    reference_title: "A recurrent ZP1 variant is responsible for oocyte maturation defect with degenerated oocytes in infertile females."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this cohort of North African OMD patients, whole exome sequencing permitted
      to diagnose 44% of the patients studied and to identify a new frequent ZP1
      variant.
    explanation: >-
      Demonstrates the diagnostic utility of whole-exome sequencing and targeted
      ZP1 variant detection in North African patients with oocyte maturation defect.
  - reference: PMID:33272616
    reference_title: "The critical role of ZP genes in female infertility characterized by empty follicle syndrome and oocyte degeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings not only reveal the critical roles of ZP genes but also pave the
      way for the efficient genetic diagnosis of females with GEFS and oocyte
      degeneration.
    explanation: >-
      Highlights the high diagnostic yield of ZP1 genetic testing in patients with
      GEFS and oocyte degeneration.
differential_diagnoses:
- name: Oocyte maturation defect 3 (ZP3-related zona pellucida defect / empty follicle syndrome)
  disease_term:
    preferred_term: oocyte maturation defect 3
    term:
      id: MONDO:0021574
      label: oocyte maturation defect 3
  description: >-
    Caused by heterozygous autosomal dominant variants in ZP3 (such as p.Ala134Thr,
    p.Ser173Cys, p.Arg254Gly, and p.Arg349Leu). Clinically overlaps with OOMD1 by
    presenting with genuine empty follicle syndrome, degenerated oocytes, or ZP-free
    oocytes, but follows strictly autosomal dominant inheritance rather than the
    predominantly autosomal recessive inheritance of ZP1-related OOMD1.
  distinguishing_features:
  - Heterozygous pathogenic variant in ZP3 (hgnc:13189) on genetic testing
  - Exclusively autosomal dominant mode of inheritance in reported human pedigrees
  evidence:
  - reference: PMID:33272616
    reference_title: "The critical role of ZP genes in female infertility characterized by empty follicle syndrome and oocyte degeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ZP1 variants were inherited in an autosomal recessive pattern; the ZP2 and
      ZP3 variants were inherited in an autosomal dominant pattern.
    explanation: >-
      Distinguishes ZP3-related oocyte maturation defect 3 from ZP1-related OOMD1
      by genetic locus and autosomal dominant inheritance.
- name: Oocyte maturation defect 6 (ZP2-related zona pellucida defect)
  disease_term:
    preferred_term: oocyte maturation defect 6
    term:
      id: MONDO:0032696
      label: oocyte maturation defect 6
  description: >-
    Caused by homozygous or compound heterozygous (and occasionally heterozygous)
    pathogenic variants in ZP2, encoding the primary sperm-binding component of the
    zona pellucida after cleavage rejuvenation. Presents with thin or absent zona
    pellucida, defective sperm binding in conventional IVF, or empty follicle syndrome,
    and is differentiated from OOMD1 by molecular testing of ZP2.
  distinguishing_features:
  - Pathogenic variants in ZP2 (hgnc:13188) identified on exome or gene panel sequencing
  evidence:
  - reference: PMID:30810869
    reference_title: "Novel mutations in ZP1, ZP2, and ZP3 cause female infertility due to abnormal zona pellucida formation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Previous studies have identified mutations in ZP1, ZP2, and ZP3 that lead to
      female infertility caused by oocyte degeneration, empty follicle syndrome, or
      in vitro fertilization failure.
    explanation: >-
      Demonstrates that ZP1, ZP2, and ZP3 mutations produce overlapping zona
      pellucida defects that require molecular genetic testing to distinguish.
- name: Oocyte maturation defect 2 (TUBB8-related oocyte maturation arrest)
  disease_term:
    preferred_term: oocyte maturation defect 2
    term:
      id: MONDO:0021573
      label: oocyte maturation defect 2
  description: >-
    Caused by heterozygous or biallelic variants in the primate-specific beta-tubulin
    isotype gene TUBB8 (curated in kb/disorders/TUBB8-related_Oocyte_Maturation_Defect.yaml).
    Unlike OOMD1, where the primary defect lies in the extracellular zona pellucida
    coat while meiotic spindle assembly can proceed to metaphase II, TUBB8-related
    OOMD2 primarily disrupts meiotic spindle assembly and arrests oocytes at
    metaphase I within an intact zona pellucida.
  distinguishing_features:
  - Intact zona pellucida surrounding metaphase I-arrested oocytes with disorganized or absent meiotic spindles
  - Pathogenic variants in TUBB8 (hgnc:20773)
  evidence:
  - reference: PMID:26789871
    reference_title: "Mutations in TUBB8 and Human Oocyte Meiotic Arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified seven mutations in the primate-specific gene TUBB8 that were
      responsible for oocyte meiosis I arrest in 7 of the 24 families. TUBB8
      expression is unique to oocytes and the early embryo, in which this gene
      accounts for almost all the expressed β-tubulin.
    explanation: >-
      Establishes that TUBB8 mutations cause oocyte meiosis I arrest via spindle
      disruption rather than primary zona pellucida extracellular matrix loss.
animal_models:
- name: Zp1 p.I390fs404X homozygous knock-in rat (Zp1MT/MT)
  species: Rattus norvegicus
  genotype: Zp1 p.I390fs404X homozygous knock-in (Zp1MT/MT)
  background: Sprague-Dawley
  genes:
  - preferred_term: ZP1
    term:
      id: hgnc:13187
      label: ZP1
  publication: PMID:33624742
  description: >-
    Rats knocked in for the human frameshift mutation Zp1 p.I390fs404X (Zp1MT/MT)
    closely phenocopy human OOMD1 because rats, like humans, express four zona
    pellucida glycoproteins (ZP1, ZP2, ZP3, and ZP4). Homozygous Zp1MT/MT female
    rats completely lack a zona pellucida around growing oocytes due to intracellular
    retention of mutant ZP1 and impeded incorporation of ZP3 and ZP4, ovulate
    drastically fewer eggs (1–2 naked eggs versus ~21 in wild-type controls), fail
    in vitro fertilization, and exhibit complete female infertility.
  modeled_mechanisms:
  - target: ZP1 Loss-of-Function and Cytoplasmic Co-Sequestration of Zona Pellucida Glycoproteins
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Homozygous Zp1MT/MT rat oocytes retain mutant ZP1 intracellularly and fail
      to incorporate ZP3 and ZP4 into an extracellular zona pellucida.
  evidence:
  - reference: PMID:33624742
    reference_title: "Mutant Zp1 impedes incorporation of ZP3 and ZP4 in the zona pellucida, resulting in zona absence and female infertility in rats†."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The ovaries of homozygous (Zp1MT/MT) females possessed both growing and fully
      grown oocytes; the oocytes completely lacked a ZP, but ZP1 was detectable
      inside the cytoplasm. Only 1-2 eggs were recovered from oviducts of
      superovulated Zp1MT/MT females, while an average of 21 eggs were recovered from
      superovulated Zp1WT/WT per female. The eggs of Zp1MT/MT females were not
      surrounded by a ZP and lost their fertilization capacity in vitro. Zp1MT/MT
      females mated with wild-type males failed to become pregnant.
    explanation: >-
      Demonstrates that the Zp1 knock-in rat model recapitulates human ZP1-related
      absence of the zona pellucida, cytoplasmic ZP1 retention, severe reduction
      in ovulated eggs, IVF failure, and complete female infertility.
- name: ZP1 CRISPR/Cas9 loss-of-function cynomolgus macaque (#ZP1-2)
  species: Macaca fascicularis
  genotype: ZP1 CRISPR/Cas9 loss-of-function mutant (#ZP1-2)
  background: Cynomolgus macaque
  genes:
  - preferred_term: ZP1
    term:
      id: hgnc:13187
      label: ZP1
  publication: PMID:40923306
  description: >-
    First non-human primate model of ZP1 deficiency, generated by CRISPR/Cas9 editing
    in cynomolgus macaques. The ZP1-mutant female macaque (#ZP1-2) exhibited oocytes
    with thin, irregular, or completely absent zona pellucida, markedly reduced
    in vitro maturation (IVM) and blastocyst formation rates after ICSI, disrupted
    granulosa-oocyte transcriptomic signaling in late antral follicles, and oocyte
    mitochondrial swelling associated with SOD2 downregulation.
  modeled_mechanisms:
  - target: Impaired Cumulus-Oocyte Complex Organization and Granulosa-Oocyte Crosstalk
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Recapitulates ZP absence/thinning and disrupted oocyte-granulosa signaling
      in late antral follicles of a non-human primate with a four-ZP-subunit matrix.
  evidence:
  - reference: PMID:40923306
    reference_title: "Abnormal zona pellucida and follicular development in ZP1-mutant macaques."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Following sexual maturation, oocytes retrieved from #ZP1-2 through
      superovulation exhibited a marked increase in zona pellucida-deficient oocytes
      and a significant reduction in maturation rates compared to controls.
      Integrated analyses, including immunofluorescence staining, transmission
      electron microscopy, transcriptomic profiling of oocytes, and histopathological
      examination of ovarian tissue, revealed disrupted folliculogenesis and oocyte
      anomalies consistent with phenotypes observed in human empty follicle syndrome.
    explanation: >-
      Establishes the cynomolgus macaque CRISPR ZP1 model showing ZP-deficient
      oocytes, disrupted folliculogenesis, and reduced oocyte maturation consistent
      with human empty follicle syndrome.
- name: Zp1-null knockout mouse (Zp1tm/tm)
  species: Mus musculus
  genotype: Zp1-/- (Zp1tm/tm null)
  background: C57BL/6
  genes:
  - preferred_term: ZP1
    term:
      id: hgnc:13187
      label: ZP1
  publication: PMID:10433913
  description: >-
    Unlike humans and rats, mice possess only three functional zona pellucida genes
    (Zp1, Zp2, and Zp3, with Zp4 pseudogenized). Homozygous Zp1-null female mice
    still assemble a loosely organized, porous zona pellucida matrix composed of
    mZP2 and mZP3, with ectopic clusters of granulosa cells trapped in the perivitelline
    space. Zp1-null female mice remain fertile with reduced litter sizes (~50% of
    wild-type) due to fragile cleavage-stage embryos and precocious hatching in the
    oviduct, making the mouse knock-out a milder structural phenotype than the
    truncating/missense ZP1 mutations seen in humans and knock-in rats.
  modeled_mechanisms:
  - target: Failure of ZP1-N1 Disulfide Cross-Linking and Zona Pellucida Extracellular Matrix Assembly
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Demonstrates loss of ZP1 filament cross-linking and porous ZP architecture,
      but mice retain an uncross-linked ZP2/ZP3 coat and remain subfertile rather
      than completely sterile.
  evidence:
  - reference: PMID:10433913
    reference_title: "Abnormal zonae pellucidae in mice lacking ZP1 result in early embryonic loss."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Although a zona pellucida composed of ZP2 and ZP3 was formed around growing
      Zp1(tm/tm) oocytes, the matrix was more loosely organized than zonae around
      normal oocytes. In some Zp1 null follicles, this structural abnormality
      resulted in ectopic clusters of granulosa cells, lodged between the zona matrix
      and the oolemma, that perturbed normal folliculogenesis. Comparable numbers of
      eggs were ovulated from Zp1 null females and normal females following hormonal
      stimulation. However, after mating with males, fewer two-cell embryos were
      recovered from Zp1 null females, and their litters were significantly smaller
      than those produced by normal mice.
    explanation: >-
      Characterizes the Zp1-null mouse model, showing a loosely organized ZP2/ZP3
      matrix, ectopic perivitelline granulosa cells, and reduced fertility due to
      early embryonic loss.
experimental_models:
- name: HeLa, CHO, and HEK293T Mammalian Heterologous ZP Co-Expression and Secretion Systems
  experimental_model_type: CELL_LINE
  cell_source: HeLa, Chinese hamster ovary (CHO), and HEK293T mammalian cell lines
  culture_system: Transient plasmid transfection and conditioned-medium secretion assay
  publication: PMID:24670168
  description: >-
    Transient co-transfection of wild-type and patient-derived mutant human ZP1
    constructs alongside ZP2, ZP3, and ZP4 in HeLa, Chinese hamster ovary (CHO),
    or HEK293T cells, coupled with confocal immunofluorescence, co-immunoprecipitation,
    and conditioned-medium immunoblotting. Used to assay intracellular ER retention,
    dominant-negative or recessive co-sequestration of ZP3/ZP4, ZP1-N1 homodimerization,
    and secretion into the culture medium.
  modeled_mechanisms:
  - target: ZP1 Loss-of-Function and Cytoplasmic Co-Sequestration of Zona Pellucida Glycoproteins
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Directly reproduces intracellular retention of mutant ZP1 and co-sequestration
      of wild-type ZP3/ZP4 in cultured mammalian cells.
  evidence:
  - reference: PMID:24670168
    reference_title: "Mutant ZP1 in familial infertility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro studies showed that defective ZP1 proteins and normal ZP3 proteins
      colocalized throughout the cells and were not expressed at the cell surface,
      suggesting that the aberrant ZP1 results in the sequestration of ZP3 in the
      cytoplasm, thereby preventing the formation of the zona pellucida around the
      oocyte.
    explanation: >-
      Demonstrates in HeLa cells that mutant ZP1 colocalizes with and sequesters
      ZP3 in the cytoplasm, preventing cell-surface expression.
  - reference: PMID:31300655
    reference_title: "Molecular basis of egg coat cross-linking sheds light on ZP1-associated female infertility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Importantly, this conclusion can be extended to the mammalian homologue of the
      protein because, mirroring full-length hZP1 (Fig. 1b, left panel), a construct
      corresponding to hZP1-N1 is also secreted as a homodimer linked by
      intermolecular disulphide(s) (Fig. 2i).
    explanation: >-
      Uses mammalian cell secretion and cross-linking assays to demonstrate that
      human ZP1-N1 is secreted as an intermolecular disulfide-linked homodimer.
datasets: []
discussions:
- discussion_id: oomd1_species_zp_composition_divergence
  prompt: >-
    Why do human patients and Zp1-knock-in rats with ZP1 mutations exhibit complete
    absence of the zona pellucida or empty follicle syndrome, whereas Zp1-null
    knockout mice assemble a loosely organized ZP2/ZP3 coat and remain subfertile?
  kind: HUMAN_MODEL_MISMATCH
  status: RESOLVED
  attaches_to:
  - animal_models#Zp1 p.I390fs404X homozygous knock-in rat (Zp1MT/MT)
  - animal_models#Zp1-null knockout mouse (Zp1tm/tm)
  - pathophysiology#ZP1 Loss-of-Function and Cytoplasmic Co-Sequestration of Zona Pellucida Glycoproteins
  rationale: >-
    Humans, macaques, and rats express four zona pellucida glycoproteins (ZP1, ZP2,
    ZP3, ZP4), whereas mice have a pseudogenized Zp4 gene and express only three
    subunits (mZP1, mZP2, mZP3). Furthermore, human and rat truncating or missense
    ZP1 mutant proteins accumulate in the oocyte cytoplasm and actively bind and
    sequester ZP3 and ZP4 intracellularly, blocking their secretion and preventing
    any extracellular ZP matrix assembly, whereas complete Zp1 null alleles in mice
    allow unimpeded secretion of mZP2 and mZP3 to form an uncross-linked matrix.
  evidence:
  - reference: PMID:33624742
    reference_title: "Mutant Zp1 impedes incorporation of ZP3 and ZP4 in the zona pellucida, resulting in zona absence and female infertility in rats†."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Studies in 293T cells showed that mutant Zp1 resulted in a truncated ZP1
      protein, which might be intracellularly sequestered and interacted with
      wild-type ZP3 or ZP4.
    explanation: >-
      Demonstrates in HEK293T cells that truncated mutant ZP1 is intracellularly
      sequestered and interacts with wild-type ZP3 and ZP4.
  - reference: PMID:33624742
    reference_title: "Mutant Zp1 impedes incorporation of ZP3 and ZP4 in the zona pellucida, resulting in zona absence and female infertility in rats†."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results suggest that the Zp1 point mutation led to infertility and loss of
      the ZP in oocytes in rats.
    explanation: >-
      Confirms in the knock-in rat model that the Zp1 mutation leads to complete
      loss of the zona pellucida in oocytes and female infertility.
notes: >-
  Nosology and cross-species note: MONDO:0014342 ('female infertility due to zona
  pellucida defect', OMIM:615774, OOMD1) specifically denotes ZP1-related zona
  pellucida defect / empty follicle syndrome. Related zona pellucida disorders
  caused by ZP3 (MONDO:0021574, OOMD3, OMIM:617712) and ZP2 (MONDO:0032696, OOMD6,
  OMIM:618353) have distinct MONDO entries and are cross-referenced in
  differential_diagnoses.

📚

References & Deep Research

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Female Infertility Due to Zona Pellucida Defect (OOMD1; ZP1-related): Research Report

claude-haiku-4-5-20251001, claude-opus-5-5 22 citations 2026-10-14T15:52:48.824203

Female Infertility Due to Zona Pellucida Defect (OOMD1; ZP1-related): Research Report

Target: MONDO:0014342 · OMIM 615774 · ORPHA:404466 · Category: Mendelian Report date: 2026-10-14

How to read the citations. I took the direct quotes marked "abstract quote" from abstracts already cached in this repository's references_cache/, or from the existing draft entry kb/disorders/Female_Infertility_Due_To_Zona_Pellucida_Defect.yaml, which has passed snippet validation. Claims marked [unverified] came from web search or memory and need a PMID lookup with just fetch-reference before they are used as evidence. Some ontology IDs are marked "ID to look up"; I was not able to source those IDs, so I did not write them.

Tooling note. The PubMed, OLS and bgpt MCP connectors in this session need authorization through claude.ai connector settings, and I could not use them here. OMIM returned HTTP 403. Identifiers were confirmed through NCBI MedGen instead.

1. Disease Information

Overview. The disorder is an autosomal recessive form of primary female infertility, with a smaller autosomal dominant arm. It is caused mainly by pathogenic variants in ZP1, which encodes zona pellucida glycoprotein 1. ZP1 cross-links the filaments of the zona pellucida (ZP), the extracellular coat around the oocyte.

Affected women otherwise look reproductively normal: normal karyotype, menarche, menstrual cycles, hormone levels, ovarian reserve and tubal/uterine anatomy. The defect only shows up during ART cycles. Retrieval then yields one of three things: - no oocytes at all (genuine empty follicle syndrome, GEFS); - shrivelled, degenerated oocytes; - mature MII oocytes with no ZP, or a very thin one, which fail conventional IVF.

"Here we describe a form of infertility with an autosomal recessive mode of inheritance, characterized by abnormal eggs that lack a zona pellucida. We identified a homozygous frameshift mutation in ZP1 in six family members." — Huang et al., NEJM 2014, PMID:24670168 (abstract quote)

Identifiers (from NCBI MedGen C4014291, MedGen UID 862728):

Resource	ID
MONDO	MONDO:0014342
OMIM	615774 (gene ZP1, OMIM 195000 [verify])
Orphanet	ORPHA:404466
MedGen	C4014291
Gene locus	ZP1, 11q12.2; HGNC hgnc:13187
ICD-10 / ICD-11	No specific code. Nearest are N97.x (female infertility) and ICD-11 GA31 (female infertility) [verify]
MeSH	No specific descriptor. Nearest are "Infertility, Female" and "Zona Pellucida"

Synonyms: oocyte maturation defect 1 (OOMD1); oocyte/zygote/embryo maturation arrest 1 (OZEMA1); ZP1-related empty follicle syndrome; ZP1-related zona pellucida defect; zona-free oocytes, familial.

Nosology caveat. OMIM 615774 and MONDO:0014342 are ZP1-specific. The overlapping ZP2 and ZP3 disorders have their own entries: - ZP3: OOMD3 / OZEMA3, OMIM 617712, MONDO:0021574 - ZP2: OOMD6 / OZEMA6, OMIM 618353, MONDO:0032696

ZP4-related thin-zona infertility currently has no OMIM phenotype entry [verify]. A dismech entry should keep ZP1 as the defining gene and handle ZP2, ZP3 and ZP4 as differentials or a grouping, not lump them in.

Data provenance. All knowledge comes from aggregated case reports and small cohorts, mostly Chinese and North African. There are no registry or EHR-scale data.

2. Etiology

Primary cause. Germline pathogenic ZP1 variants. Inheritance is mostly biallelic (homozygous or compound heterozygous), with a minority of heterozygous variants that appear to act in a dominant-negative way.

Genetic risk factors: - Consanguinity. The index family was a consanguineous Chinese pedigree (PMID:24670168), and the North African founder families are also consanguineous (PMID:42060237). - Founder variant ZP1 c.1097G>A p.(Arg366Gln) in North African populations (PMID:35460069, PMID:42060237).

"The recurrent ZP1 c.1097G > A p.(Arg366Gln) variant contributes to EFS in consanguineous North African families." — PMID:42060237 (abstract quote) - Paternally transmitted heterozygous variants with sex-limited expression, for example ZP1 p.Tyr262Cys (PMID:38966008). Carrier fathers are fertile.

Environmental risk factors: none known. The disorder is fully genetic. Maternal age and stimulation protocol affect ART outcome but do not cause the zona defect.

Protective factors / gene–environment interactions: none described.

Modifiers. Phenotype severity (EFS vs ZP-free MII oocytes) depends on variant type and location. Truncating and splice variants lean toward EFS or degeneration. Some missense variants (for example in the ZP-N1 domain) allow retrieval of ZP-free MII oocytes (PMID:36476320; PMID:42060237). No modifier genes have been identified.

3. Phenotypes

Phenotype	Type	Onset	Frequency	Suggested HPO
Primary female infertility	Clinical sign	Adult (found when trying to conceive)	Obligate (100%)	HP:0008222 Female infertility
Absent zona pellucida (ZP-free oocytes)	Laboratory/ART finding	Found at oocyte retrieval	Common. About 20–25% of ZP1 patients yield ZP-free MII oocytes [count from PMID:36476320 review — check text]	"Absent zona pellucida" (term exists; listed in MedGen), ID to look up
Thin or irregular zona pellucida	ART finding	Retrieval	Occasional	"Abnormal zona pellucida morphology" or similar, ID to look up
Empty follicle syndrome (no oocytes despite normal follicle growth and hCG/E2)	ART finding	Retrieval	Most frequent ZP1 presentation (EFS plus degeneration ≈ 75%+ of reported ZP1 cases)	Look up an HPO term for empty follicle syndrome. None may exist; if so, bind to Female infertility and keep the detail in `preferred_term`
Degenerated, shrivelled or dark oocytes	ART finding	Retrieval	Frequent	"Oocyte degeneration"-type term, ID to look up
Failure of fertilization in conventional IVF	ART finding	ART	Universal when ZP-free oocytes are inseminated by IVF	"Fertilization failure"-type term, ID to look up
Normal menstrual cycle, hormones, AMH	Negative findings	—	Typical	— (diagnostic context)

Key quotes:

"All the oocytes from ZP1-associated patients appeared shriveled and dark indicating that the abnormal ZP1 protein induced oocyte death and degeneration." — PMID:35460069

"Sixty-nine mutations of the ZP genes were reported in 87 patients with different clinical phenotypes, including empty follicle syndrome (EFS), ZP-free oocytes (ZFO), ZP-thin oocytes (ZTO), degenerated and immature oocytes. The phenotypes of patients were influenced by the types and location of the mutations." — Zhang et al. 2022 review, PMID:36476320

Severity, progression and quality of life. The phenotype is stable and lifelong. There are no systemic or somatic features. The burden is psychosocial: repeated failed stimulation cycles, cost, and infertility distress. No disease-specific QoL studies exist. Generic FertiQoL data on infertility apply.

4. Genetic / Molecular Information

Causal gene: ZP1 (hgnc:13187; 12 exons; 638-aa type I membrane glycoprotein). Its domains run from N- to C-terminus: signal peptide, ZP-N1 (the cross-linking domain), proline-rich linker, trefoil (P-type) domain, bipartite ZP module (ZP-N and ZP-C), consensus furin cleavage site, transmembrane domain and cytoplasmic tail.

Variant spectrum.

"A total of 47 ZP1 mutations have been reported in 19 pieces of literature … Mutations are distributed in all 12 exons of ZP1 gene … including 13 nonsense mutations, 16 missense mutations, seven splicing mutations and 11 frameshift mutations" — PMID:36476320

Notable variants (transcript NM_207341):

Variant	Domain	Zygosity / inheritance	Phenotype	Source
c.1169_1176del, p.Ile390Thrfs*16 (I390fs404X)	ZP module	Homozygous, AR	ZP-free oocytes; the original family	PMID:24670168
c.1097G>A, p.Arg366Gln	ZP-N	Homozygous; North African founder	Degenerated oocytes / EFS	PMID:35460069, PMID:42060237
p.Trp83Arg	ZP-N1	Compound heterozygous / heterozygous	Blocks ZP1-N1 homodimerization	PMID:31300655
c.326G>A, p.Arg109His	ZP-N1	Heterozygous	ZP-free oocytes; live birth after ICSI	PMID:32573113
p.Tyr262Cys	Trefoil	Heterozygous, paternally inherited	Abnormal ZP formation	PMID:38966008
Compound heterozygous pairs in sisters	various	AR	EFS	PMID:31292994
20 ZP1 variants (in a cohort of 35 GEFS/degeneration patients)	various	AR	GEFS / degeneration	PMID:33272616

Classification and frequency. Most variants are reported as pathogenic or likely pathogenic in the original papers. ClinVar curation is sparse and there is no ClinGen gene–disease validity curation [verify via just list-gene-validity/CGGV cache]. Variants are rare or absent in gnomAD. The Arg366Gln carrier frequency in North African populations has not been formally estimated.

Origin and function. All variants are germline. The functional consequence is loss of function: truncation, absent secretion, or loss of ZP1-N1 dimerization. Some heterozygous missense and frameshift alleles are proposed to act dominant-negatively, by trapping wild-type ZP2, ZP3 and ZP4 inside the cell (PMID:24670168; PMID:33272616; PMID:32573113). Strictly, heterozygous causality rests on a few families and in-vitro data, so treat it as moderate evidence.

Related ZP genes (differential/allelic group): - ZP3, heterozygous p.Ala134Thr. Autosomal dominant EFS with paternal transmission (Chen et al., AJHG 2017, PMID:28886344 [verify]). A homozygous ZP3 EFS variant has also been reported (Front Genet 2023, PMC10613883). - ZP2. Biallelic variants cause a thin ZP that cannot bind sperm (Dai et al. 2019 [PMID to verify]). A ZP2 loss-of-function variant has been modelled in humans and rats (PMC10244809). - ZP4. Heterozygous loss-of-function variants were found in 3 of 26 women with thin, irregular ZP (about 11%); ICSI pregnancies were achieved (summarized in PMID:36476320). - Combined cohorts:

"We identified zona pellucida (ZP) gene variants in 18 individuals, which included 20 variants in the ZP1 gene, two variants in the ZP2 gene, and one previously reported recurrent variant in the ZP3 gene. The women carrying ZP variants constituted 51.43% of the GEFS cohort." — PMID:33272616

Epigenetics and chromosomal abnormalities: none reported. Karyotype is normal (46,XX).

5. Environmental Information

Not applicable. No toxin, lifestyle or infectious contribution is known. Note that acquired, iatrogenic "false" EFS (for example from a faulty hCG trigger) is a non-genetic phenocopy and has to be excluded clinically (see §10).

6. Mechanism / Pathophysiology

Ordered causal chain

Germline ZP1 variant: truncating, splice, or missense in ZP-N1, trefoil or ZP module.
This leads to loss of secreted ZP1. Mutant ZP1 is misfolded or truncated and is retained in the oocyte cytoplasm / ER instead of being secreted (shown in HeLa, CHO and 293T cells, and in rat oocytes).

"secretion of hZP1Mut is completely abolished" — PMID:31300655 (in vitro)
Branch A (mainly truncating and dominant-negative alleles). Retained mutant ZP1 binds and co-sequesters wild-type ZP3 and ZP4, and possibly ZP2, inside the cell, so they cannot be exported.

"the aberrant ZP1 results in the sequestration of ZP3 in the cytoplasm, thereby preventing the formation of the zona pellucida around the oocyte." — PMID:24670168 (in vitro)

Branch B (ZP-N1 missense alleles). ZP1 is secreted but cannot form the disulfide-bonded ZP1-N1 homodimer, so ZP2/ZP3/ZP4 filaments are not cross-linked. Human ZP4 cannot substitute.

"W83R … significantly reduces its ability to form disulphide-bonded homodimers … the mutation leads to lack of the ZP by hindering human ZP filament cross-linking." — PMID:31300655 (in vitro, structural) 4. Both branches result in failed ZP matrix assembly or maintenance. The ZP is absent, very thin, or fragile around growing oocytes. Human ovarian histology shows a thin, ZP1-lacking ZP in preantral follicles (PMID:31734689; one case). 5. Branch point at the antral transition. - 5a. If the matrix is lost or unstable in antral follicles, cumulus–oocyte complex (COC) organization and transzonal oocyte–granulosa communication fail. [Partly inferred] Human histology supports the COC defect (PMID:31734689). The mechanism through communication loss is hypothesized (PMID:36476320). In macaques, ZP1 loss causes oxidative stress, SOD2 downregulation, mitochondrial swelling and autophagy (PMID:40923306; model organism). - 5a → 6a. These changes lead to oocyte degeneration in the follicle, or to fragile oocytes that rupture during aspiration. Clinically this is GEFS or degenerated oocytes. - 5b. If oocytes survive to MII, they lack the ZP sperm-binding matrix. ZP2-N terminus binding, the ZP-induced acrosome reaction, and the zona block to polyspermy are all missing. - 5b → 6b. This leads to fertilization failure in conventional IVF. ICSI bypasses it (§12). 6. Clinical endpoint: primary female infertility (obligate).

Upstream vs downstream. Steps 1–3 are molecular and oocyte-intrinsic. Step 4 is extracellular matrix. Steps 5–6 are follicular and gamete-level.

Suggested terms: - GO BP (validated in the draft YAML): extracellular matrix assembly GO:0085029; protein secretion GO:0009306; protein retention in ER lumen GO:0006621; ovarian follicle development GO:0001541; oocyte development GO:0048599; female gamete generation GO:0007292. Also worth looking up: "binding of sperm to zona pellucida", "egg coat formation", "acrosome reaction". - GO CC: extracellular matrix GO:0031012; endoplasmic reticulum GO:0005783. Look up "egg coat" for the zona pellucida itself. - GO MF: extracellular matrix structural constituent GO:0005201. - CL: oocyte CL:0000023; primary oocyte CL:0000654; granulosa cell CL:0000501. Look up cumulus cell. - Biochemical: no metabolic or immune involvement. This is a structural ECM glycoprotein defect. - Omics: macaque single-oocyte transcriptomics showed disrupted granulosa–oocyte signalling (PMID:40923306). There are no human omics datasets.

7. Anatomical Structures Affected

Organ: ovary, UBERON:0000992 (primary; the only organ affected). No secondary organ involvement. Body system: female reproductive.
Tissue: ovarian follicle (look up the UBERON ID), cumulus oophorus, and the zona pellucida ECM.
Cells: oocyte, primary oocyte, granulosa/cumulus cells.
Subcellular: oocyte ER/secretory pathway (retention) and the extracellular egg coat.
Laterality: bilateral (all oocytes affected).

8. Temporal Development

Onset: the molecular defect is present from oocyte growth, which is fetal/prepubertal for primordial follicles and pubertal onward for growth. It is clinically silent until adulthood, when infertility is investigated or ART is attempted.
Course: stable and lifelong. No stages and no remission.
Critical window: the preantral→antral follicle transition, when the ZP must be assembled and maintained (PMID:31734689).

9. Inheritance and Population

Inheritance: autosomal recessive (HP:0000007) is the main mode. A minority is autosomal dominant (HP:0000006) with sex-limited expression: male carriers, homozygous or heterozygous, are fertile.

"The ZP1 variants were inherited in an autosomal recessive pattern; the ZP2 and ZP3 variants were inherited in an autosomal dominant pattern." — PMID:33272616
Penetrance: complete in homozygous females, as far as reported. Penetrance of heterozygous alleles is uncertain.
Expressivity: variable (EFS vs degeneration vs ZP-free MII), correlated with genotype.
Founder effect: p.Arg366Gln in North Africa (Algeria/Tunisia/Morocco [country breakdown to verify]).
Consanguinity: a major contributor in reported families.
Prevalence: unknown in the general population; ultra-rare (ORPHA lists no estimate [verify]). In enriched cohorts:
ZP gene variants in 18/35 (51.4%) of Chinese GEFS/degeneration patients (PMID:33272616);
homozygous ZP1 p.Arg366Gln in 5/27 (18.5%) of North African oocyte-maturation-defect patients (PMID:35460069);
a 2025 BJOG retrospective study of 12 Chinese women with EFS or degenerated oocytes found rare ZP variants [PMID to verify].
Underlying context: GEFS itself is reported in roughly 0.016–0.07% of IVF cycles [verify].
Sex ratio: female-only phenotype.

10. Diagnostics

Clinical and laboratory work-up:
Normal FSH, LH, E2 and AMH; normal antral follicle count; normal follicular growth on ultrasound during stimulation.
At retrieval: no oocytes, degenerated oocytes, or ZP-free/thin-ZP oocytes, seen under light microscopy (polarized-light ZP imaging can quantify thickness).
Exclude "false EFS" by confirming adequate serum hCG or LH on trigger day.
Histology (research only): ZP1 immunostaining of ovarian tissue shows a thin ZP lacking ZP1 (PMID:31734689).
Genetic testing (definitive). Use whole-exome sequencing, or a female-infertility / oocyte-maturation-defect panel covering ZP1, ZP2, ZP3, ZP4, TUBB8, PATL2, WEE2, PANX1, BTG4, TLE6, NLRP family genes and others.

"In this cohort of North African OMD patients, whole exome sequencing permitted to diagnose 44% of the patients studied and to identify a new frequent ZP1 variant." — PMID:35460069

Targeted testing for p.Arg366Gln is reasonable in North African patients. Microarray, karyotype, FISH, mtDNA and repeat testing are not relevant beyond confirming 46,XX. - Diagnostic ICSI. A small test ICSI can reveal the embryo-development potential of ZP-free oocytes (PMID:32847637). - NCIT: Genetic Testing NCIT:C15709. LOINC has no disease-specific assay. - Differential diagnosis: - OOMD3 (ZP3; AD) - OOMD6 (ZP2; thin ZP with sperm-binding failure) - ZP4 thin zona - OOMD2 (TUBB8; MI arrest with an intact ZP; PMID:26789871) - PATL2 (GV arrest; PMID:35460069 contrasts it with ZP1) - WEE2 (fertilization failure, intact ZP) - iatrogenic false EFS - diminished ovarian reserve / POI (abnormal AMH and FSH) - Screening: none at population level. Cascade testing of sisters is reasonable. Carrier screening is possible in founder populations but not established.

11. Outcome / Prognosis

Survival, life expectancy and mortality are not affected. There is no systemic morbidity.
The outcome is infertility with autologous oocytes. Prognosis depends on genotype and phenotype:

"Three patients with ZP1 mutations, two with ZP2 mutations, and three with ZP4 mutations had successful pregnancies through Intracytoplasmic sperm injection (ICSI) from ZFO or ZTO." — PMID:36476320

The same review built a pregnancy-prediction model (AUC 0.898) from mutation type and location [verify the figure in the full text]. - Poor-prognosis predictors: biallelic truncating ZP1 variants, EFS, and fully degenerated oocytes. Patients in this group usually need oocyte donation. - Complications: repeated futile stimulation cycles, OHSS risk with re-stimulation, and psychological burden.

12. Treatment

There is no disease-modifying therapy. Management is reproductive.

Intervention	Rationale / outcome	NCIT
ICSI of ZP-free/thin-ZP MII oocytes	Bypasses ZP-dependent sperm binding. Live births reported for ZP1 (PMID:32573113, PMID:32847637), ZP2 and ZP4. Requires careful handling and individual microdrop culture of zona-free embryos.	NCIT:C185482 Intracytoplasmic Sperm Injection
Low-pressure follicular aspiration / modified retrieval	Reduces rupture of fragile ZP-free oocytes (described in ZP4 and ZP1 reports [verify source])	Surgical/retrieval procedure; ID to look up
Diagnostic (test) ICSI	Assesses embryo potential before a full cycle (PMID:32847637)	NCIT:C185482
Oocyte donation	The only option for EFS or complete degeneration	Look up an NCIT oocyte-donation / ART term
Genetic counseling	Explains AR and sex-limited AD inheritance, sister testing, and avoiding futile cycles (PMID:42060237)	NCIT:C15240

Embryo transfer: zona-free embryos are fragile, so blastocyst-stage transfer is preferred.
Pharmacogenomics, gene/cell/RNA therapies: none. No clinical trials were found on ClinicalTrials.gov for ZP1 [search not exhaustive].
Experimental idea (not in human use): artificial zona or ZP-substitute matrices.

13. Prevention

Primary: none. The disease is genetic.
Secondary: genotype-guided ART planning. Women with prior EFS, degenerated oocytes or ZP-free oocytes should be offered ZP-gene testing before repeat cycles. They should go straight to ICSI rather than IVF, or to donation when the genotype predicts EFS (PMID:32573113; PMID:36476320; 2025 BJOG study).
Counseling: cascade testing of female siblings, especially in consanguineous or North African families. PGT for future generations is theoretically possible, but no one has reported it and there is little rationale because the phenotype is only infertility.
Vaccination / public health: not applicable.

14. Other Species / Natural Disease

OMIA: "Infertility, ZP1-related" in Macaca fascicularis (NCBITaxon:9541), OMIA 003005-9541. This entry records the engineered model (PMID:40923306), not natural disease.
No naturally occurring ZP1 disease is documented in companion animals or livestock [OMIA search for other species advised].
Comparative biology: ZP gene composition differs across species, and this explains the phenotypes seen in models:
humans, macaques and rats have four ZP proteins (ZP1–4);
in mice, Zp4 is a pseudogene (three proteins);
birds and fish have different ZP repertoires.

The ZP1-N1 cross-linking cysteine is conserved from chicken to human (PMID:31300655). - Orthologs: mouse Zp1 (MGI), rat Zp1 (RGD), macaque ZP1. Look up the NCBI Gene IDs. - Transmission/zoonosis: not applicable.

15. Model Organisms

Model	Genotype	Recapitulation	Ref
Rat (Rattus norvegicus, Sprague-Dawley)	Homozygous Zp1 knock-in of human I390fs404X	High. Complete ZP absence, cytoplasmic ZP1, 1–2 vs ~21 eggs ovulated, IVF failure, sterility.	PMID:33624742
Cynomolgus macaque	CRISPR ZP1 loss-of-function (#ZP1-2)	High (primate, 4-ZP). ZP-deficient oocytes, low IVM and blastocyst rates, disrupted folliculogenesis, mitochondrial swelling, SOD2 down. Single animal.	PMID:40923306
Mouse	Zp1-null (Zp1 tm/tm)	Partial. Loose, porous ZP2/ZP3 zona; ectopic granulosa cells; subfertile, with smaller litters from early embryo loss.	PMID:10433913
Mouse Zp2-null / Zp3-null	Knockout	No ZP, sterile; models the ZP2/ZP3 differentials	Rankin et al. 1996/2001 [PMIDs to look up]
Rat Zp2 model	Loss-of-function variant	ZP2 differential	PMC10244809
Cell lines (HeLa, CHO, HEK293T)	Co-transfected WT/mutant ZP1 ± ZP2/3/4	Moderate. Retention, co-sequestration, dimerization and secretion assays.	PMID:24670168, 31300655, 33272616, 32573113

Human–model mismatch. The mouse knockout is milder because mice lack ZP4, and a null allele (unlike a retained truncated protein) does not trap partner ZPs. The rat and macaque are the preferred models. This fits a HUMAN_MODEL_MISMATCH discussion, which the draft YAML already carries.
Resources: MGI, RGD, IMPC (check for a Zp1 line), OMIA.

Key gaps and cautions for curation

Population prevalence: none exists. Record it as unknown and use only cohort-enriched frequencies.
Heterozygous ZP1 causality rests on very few families. Mark the AD claim with moderate confidence.
The step from ZP loss to degeneration (oocyte–cumulus communication, oxidative stress) is supported only by human hypothesis and one macaque model. Edges for it should carry directness: INDIRECT or MODEL_ORGANISM evidence.
HPO IDs for "Absent zona pellucida", empty follicle syndrome and oocyte degeneration need lookup. Do not write them from memory.
[unverified] PMIDs for Chen 2017 AJHG (ZP3), Dai 2019 (ZP2), the 2025 BJOG cohort, and Rankin's Zp2/Zp3 knockouts need confirmation with just fetch-reference.
Draft YAML check: the existing YAML uses the deprecated percentage prevalence field and updated_date. Migrate both to structured prevalence (measure_type: UNKNOWN / cohort fraction) before PR.

Sources

Huang HL et al. NEJM 2014, PMID:24670168
Sun L et al. 2021, PMID:33272616
Zhang Z et al. 2022 review, PMID:36476320 — PMC9730648
Loeuillet C et al. 2022, PMID:35460069; North African ZP1 follow-up, PMID:42060237
Nishio S et al. 2019 (ZP1 cross-linking), PMID:31300655
Sun Y et al. 2019 (compound heterozygous sisters), PMID:31292994
Cao Q et al. 2020 (ZP1/ZP3 heterozygous), PMID:32573113
Dai C et al. 2019 / Zhou Z et al. 2019, PMID:30810869
Case report, ovarian histology, PMID:31734689
Diagnostic ICSI case report, PMID:32847637
ZP1-Y262C, PMID:38966008 — Frontiers Genet 2024
Rat Zp1 knock-in, PMID:33624742; macaque ZP1, PMID:40923306 — Zool Res PDF, OMIA 003005-9541
Rankin T et al. 1999 (Zp1-null mouse), PMID:10433913
Feng R et al. 2016 (TUBB8), PMID:26789871
NCBI MedGen C4014291
NORD entry
ZP3 homozygous EFS case, Front Genet 2023
ZP2 loss of function in humans and rats
BJOG 2025 ZP variant study (EBSCO record)
AlphaGalileo summary
News-Medical, 2026-09-08
Other search results consulted: PMC7822995, PMC9107549, PMC7642144, PMC7412702, PMC7336750, J Assist Reprod Genet 2022, J Ovarian Res 2025, PMC7492330, eLife ZP, ZP2 IVF failure, GTR ZP1

Female_Infertility_Due_To_Zona_Pellucida_Defect

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Female Infertility Due to Zona Pellucida Defect (OOMD1; ZP1-related): Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Key gaps and cautions for curation

Sources