Spermatogenic Failure 64

Mendelian MONDO:0030522 Pathograph 9 Show in embeddings browser Spermatogenic Failure Genetic Disease

Spermatogenic failure 64 (SPGF64) is autosomal recessive male infertility caused by biallelic variants in FBXO43, which encodes EMI2 (early meiotic inhibitor 2). EMI2 is a direct inhibitor of the anaphase-promoting complex/cyclosome (APC/C), the E3 ubiquitin ligase that drives meiotic cell cycle transitions. It is expressed mainly in germ cells. The phenotype depends on the allele. Homozygous or compound heterozygous truncating variants cause non-obstructive azoospermia: spermatocytes arrest in meiosis I and no spermatids form. In the first family, testicular tissue lacked FBXO43 and the arrest was placed in early diplotene of prophase I, the same stage at which Emi2 knockout mouse spermatocytes arrest. Missense variants have been reported with sperm in the ejaculate. One man with two C-terminal missense variants had macrozoospermia, defective chromatin condensation and raised sperm aneuploidy, and repeated ICSI cycles failed. An earlier family with a homozygous missense variant had teratozoospermia. The proposed explanation is a dosage series: the more an allele weakens FBXO43 binding to the APC/C, the earlier meiosis fails.

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👪

Inheritance

1
Autosomal recessive HP:0000007
Affected men carry biallelic FBXO43 variants. Both families with homozygous variants were consanguineous, and the two later probands were compound heterozygous.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:34595750 SUPPORT Human clinical
"we identified a homozygous nonsense mutation in FBXO43 c.1747C > T:p.Gln583X in two NOA brothers from a Chinese consanguineous family via whole-exome sequencing"
A homozygous truncating variant in affected brothers of a consanguineous family fits recessive inheritance.
PMID:42597893 SUPPORT Human clinical
"Two infertile patients carrying distinct compound heterozygous FBXO43 variants-missense mutations in a macrozoospermia case and truncating mutations in a nonobstructive azoospermia (NOA) case-were identified through whole-exome sequencing."
Two compound heterozygous probands add further biallelic cases.
⚙

Pathophysiology

4
Loss of FBXO43 Inhibition of the APC/C
FBXO43 (EMI2) binds the APC/C and holds its ubiquitin ligase activity in check during meiosis. In patient testis a homozygous nonsense allele removed the protein. Truncating and missense alleles both made FBXO43 less stable in transfected cells and broke its binding to APC3, the APC/C substrate-recognition subunit, while binding to APC2, APC6 and APC8 was kept. In Xenopus eggs, the C-terminal tail of EMI2 blocks the APC/C by occupying the APC10 site that the E2 enzyme Ube2S needs.
FBXO43 hgnc:28521 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FBXO43 (hgnc:28521). hgnc:28521 is a gene from the HUGO Gene Nomenclature Committee.
ubiquitin ligase inhibitor activity GO:1990948 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ubiquitin ligase inhibitor activity (GO:1990948). GO:1990948 is a molecular function from the Gene Ontology. anaphase-promoting complex binding GO:0010997 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased anaphase-promoting complex binding (GO:0010997). GO:0010997 is a molecular function from the Gene Ontology.
Downstream
Reduced Cdk1 Activity in Meiotic Prophase Spermatocytes Shown in knockout mice. Loss of Emi2 lowered Cdk1 activity in the testis without lowering Cdk1 or cyclin B1 protein. The step that connects the APC/C to Cdk1 here is not known.
Meiotic Chromosome Missegregation Proposed for hypomorphic alleles that leave enough FBXO43 for meiosis to finish. Weaker APC3 binding is thought to let the APC/C act too early or at the wrong time, so chromosomes segregate wrongly.
Show evidence (4 references)
PMID:34595750 SUPPORT Human clinical
"FBXO43 was absent from testicular tissue of the proband, and FBXO43-immunostaining signals were invisible in the affected seminiferous tubules."
The nonsense allele removes FBXO43 protein from patient testis.
PMID:34595750 SUPPORT In vitro / ex vivo
"In mouse testicular protein extracts, three subunits of the APC/C, including ANAPC2, ANAPC8 and ANAPC10, were validated to interact directly with FBXO43, whereas no interactions were detected for FBXO43 and SKP1."
FBXO43 binds APC/C subunits in testis extracts but not SKP1, so it acts as an APC/C binder rather than in an SCF ligase.
PMID:42597893 SUPPORT In vitro / ex vivo
"Mechanistically, all mutations reduced FBXO43 protein stability and disrupted its specific binding to the APC/C substrate recognition subunit APC3, whereas interactions with APC2/6/8 remained intact."
Patient truncating and missense alleles all lower FBXO43 stability and lose APC3 binding.
+ 1 more reference
Reduced Cdk1 Activity in Meiotic Prophase Spermatocytes
In Emi2 knockout spermatocytes, Cdk1 activity falls and its inhibitory Tyr15 phosphorylation rises. Raising Cdk1 activity with a knockin allele let some spermatocytes go past diplotene into metaphase, so low Cdk1 activity is part of the cause of the arrest.
primary spermatocyte CL:0000656 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves primary spermatocyte (CL:0000656). CL:0000656 is a cell type from the Cell Ontology.
Cdk1 kinase activity GO:0004693 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased Cdk1 kinase activity, annotated with cyclin-dependent protein serine/threonine kinase activity (GO:0004693). GO:0004693 is a molecular function from the Gene Ontology.
Animal models
Emi2 knockout mouse Mouse recapitulates The Cdk1 finding and its genetic rescue come only from this model.
Downstream
Meiotic Prophase I Arrest at Early Diplotene Partial rescue of the arrest by a Cdk1 knockin allele shows that low Cdk1 activity contributes to it.
Show evidence (1 reference)
PMID:28723571 SUPPORT Model organism
"Interestingly, decreased activity of Cdk1 in the absence of Emi2 was associated with increased Tyr15 inhibitory phosphorylation."
Describes how Cdk1 activity is lowered in Emi2-null testis.
Meiotic Prophase I Arrest at Early Diplotene
Spermatocytes stop in early diplotene of prophase I. Chromosomes do not condense and do not enter metaphase I, and the arrested cells die. Primary spermatocytes are present in the testis but no spermatids. Shown in patient testis and in Emi2 knockout mice.
primary spermatocyte CL:0000656 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves primary spermatocyte (CL:0000656). CL:0000656 is a cell type from the Cell Ontology.
male meiosis I GO:0007141 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased male meiosis I (GO:0007141). GO:0007141 is a biological process from the Gene Ontology.
Animal models
Emi2 knockout mouse Mouse recapitulates Knockout spermatocytes arrest in early diplotene, the stage reported in patient testis.
Downstream
Spermatocyte maturation arrest
Non-obstructive azoospermia With no spermatocyte completing meiosis, no sperm reach the ejaculate.
Show evidence (3 references)
PMID:34595750 SUPPORT Human clinical
"Furthermore, in humans, FBXO43 defects cause meiotic arrest within early diplotene of prophase I."
Places the human arrest in early diplotene.
PMID:28723571 SUPPORT Model organism
"In the absence of Emi2, spermatocytes arrest in early diplotene of prophase I."
The knockout mouse arrests at the same stage as the human testis.
PMID:28723571 SUPPORT Model organism
"indicating the inability of meiosis I chromosomes to undergo condensation and progress beyond diplotene in the absence of Emi2"
Absent phospho-histone H3 shows chromosomes fail to condense at the arrest point.
Meiotic Chromosome Missegregation
Reported in one man with two C-terminal missense variants. His spermatocytes completed meiosis, but his sperm had a raised rate of aneuploidy on FISH, together with poor chromatin condensation and histone retention. The missegregation itself happens in the meiotic divisions of spermatocytes; it is observed as aneuploidy in the sperm.
primary spermatocyte CL:0000656 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves primary spermatocyte (CL:0000656). CL:0000656 is a cell type from the Cell Ontology. sperm CL:0000019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves sperm (CL:0000019). CL:0000019 is a cell type from the Cell Ontology.
meiotic chromosome segregation GO:0045132 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased meiotic chromosome segregation (GO:0045132). GO:0045132 is a biological process from the Gene Ontology.
Downstream
Macrozoospermia The authors read the enlarged sperm heads, chromatin defects and aneuploidy together as signs of faulty meiotic division in the missense patient.
Show evidence (1 reference)
PMID:42597893 SUPPORT Human clinical
"Missense variants (NM_001029860, p.Pro641Leu/p.Arg660Gln) in the macrozoospermia patient allowed completion of meiosis but led to severe sperm head enlargement, chromatin condensation defects, and markedly elevated aneuploidy, resulting in repeated ICSI failure."
Missense alleles allow meiosis to finish but leave aneuploid sperm.
✶

Histopathology

1
Meiotic arrest on testicular biopsy
Primary spermatocytes are present but no spermatids, and FBXO43 staining is absent from the seminiferous tubules.
Show evidence (2 references)
PMID:42597893 SUPPORT Human clinical
"Although primary spermatocytes were present, no spermatids were detected, consistent with a histological picture suggestive of meiotic arrest."
Biopsy histology of the NOA proband.
PMID:34595750 SUPPORT Human clinical
"FBXO43 was absent from testicular tissue of the proband, and FBXO43-immunostaining signals were invisible in the affected seminiferous tubules."
Immunostaining shows no FBXO43 in patient tubules.
⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Spermatogenic Failure 64 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Non-obstructive azoospermia Reproductive HP:0011961 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Non-obstructive azoospermia (HP:0011961). HP:0011961 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34595750 SUPPORT Human clinical
"we identified a homozygous nonsense mutation in FBXO43 c.1747C > T:p.Gln583X in two NOA brothers from a Chinese consanguineous family via whole-exome sequencing"
Two brothers homozygous for a nonsense allele had non-obstructive azoospermia.
PMID:42597893 SUPPORT Human clinical
"Truncating mutations cause profound meiotic arrest and NOA"
A second, unrelated proband with truncating variants had NOA.
Spermatocyte maturation arrest Reproductive HP:0031039 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spermatocyte maturation arrest (HP:0031039). HP:0031039 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42597893 SUPPORT Human clinical
"Although primary spermatocytes were present, no spermatids were detected, consistent with a histological picture suggestive of meiotic arrest."
Biopsy of the NOA proband showed arrest at the spermatocyte stage.
PMID:34595750 SUPPORT Human clinical
"spermatocytes were unable to complete meiotic divisions without FBXO43 in humans"
Spermatocytes of the first family did not complete meiosis.
Macrozoospermia Reproductive HP:0025437 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrozoospermia (HP:0025437). HP:0025437 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42597893 SUPPORT Human clinical
"Proband P1 presented with macrozoospermia."
Reports macrozoospermia in the missense proband.
Reduced progressive sperm motility Reproductive HP:0034011 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced progressive sperm motility (HP:0034011). HP:0034011 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42597893 SUPPORT Human clinical
"The proportion of progressively motile sperm was only 13.56%, and the percentage of morphologically normal spermatozoa was 3.3%"
Semen analysis of the missense proband shows reduced progressive motility.
Decreased testicular size Reproductive HP:0008734 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased testicular size (HP:0008734). HP:0008734 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42597893 SUPPORT Human clinical
"Physical examination revealed bilateral testicular volumes of approximately 8-10 mL, which is below the adult reference range (10-15 mL)."
Examination of the NOA proband found testes smaller than the adult reference range.
Teratozoospermia Reproductive HP:0012864 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Teratozoospermia, annotated with Abnormal sperm morphology (HP:0012864). HP:0012864 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:30878252 SUPPORT Human clinical
"A novel homozygous nonsynonymous mutation (C1991T, p.G664D) in FBXO43 (F-box only protein 43) was observed in two brothers from a consanguineous Chinese family."
The affected brothers in this family were ascertained for teratozoospermia.
PMID:30878252 SUPPORT Human clinical
"The mutation in FBXO43 is a causative factor of male infertility and teratozoospermia."
The authors' conclusion links the homozygous missense variant to teratozoospermia.
PMID:42597893 SUPPORT BACKGROUND Human clinical
"the homozygous missense variant (p.Gly664Asp) leading to oligoasthenoteratozoospermia"
Restates the earlier family's phenotype as oligoasthenoteratozoospermia, of which teratozoospermia is one part.
🧬

Genetic Associations

1
FBXO43
Gene: FBXO43 hgnc:28521 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FBXO43 (hgnc:28521). hgnc:28521 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:34595750 SUPPORT Human clinical
"The results here demonstrate the pathogenicity of this loss-of-function mutation"
Patient genetics, absent testicular protein and the matching mouse phenotype support FBXO43 as causal.
PMID:42597893 SUPPORT Human clinical
"hypomorphic missense mutations permit meiotic completion but result in severe teratozoospermia with high aneuploidy"
Supports the allele-severity relationship recorded in the notes.
💊

Medical Actions

2
ICSI with preimplantation genetic testing for aneuploidy
Action: intracytoplasmic sperm injectionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is intracytoplasmic sperm injection (NCIT:C185482). NCIT:C185482 is a clinical intervention from the NCI Thesaurus. Ontology label: Intracytoplasmic Sperm Injection NCIT:C185482
Platform: Other
Where sperm are present, as with missense genotypes, ICSI is possible, but in the one reported man repeated cycles failed and the only pregnancy miscarried, in line with his high sperm aneuploidy. The authors recommend preimplantation genetic testing for aneuploidy to select embryos. No therapy restores meiosis.
Show evidence (2 references)
PMID:42597893 SUPPORT Human clinical
"The macrozoospermia patient experienced repeated ICSI failure and early pregnancy loss, consistent with the high sperm aneuploidy detected in our study and prior reports"
Reports the ICSI outcome in the missense proband.
PMID:42597893 SUPPORT Human clinical
"Based on the identified mutation-specific risks, preimplantation genetic testing for aneuploidy (PGT-A) is recommended for affected couples to improve embryo selection and optimize ART outcomes."
The authors' recommendation for embryo selection; it is not a tested outcome.
Donor sperm insemination
Action: donor sperm inseminationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is donor sperm insemination, annotated with Artificial Insemination (NCIT:C16739). NCIT:C16739 is a clinical intervention from the NCI Thesaurus. Ontology label: Artificial Insemination NCIT:C16739
Platform: Other
For men with truncating genotypes, meiosis does not complete and endogenous sperm production is very unlikely, so donor sperm is the route to pregnancy. The man with truncating variants used donor-sperm insemination after biopsy showed meiotic arrest. The authors also suggest donor gametes where loss-of-function carriers have poor reproductive outcomes.
Show evidence (2 references)
PMID:42597893 SUPPORT Human clinical
"These findings collectively indicated an extremely low likelihood of endogenous sperm production. The patient ultimately proceeded with donor-sperm insemination."
The NOA proband with truncating variants used donor sperm.
PMID:42597893 SUPPORT Human clinical
"For carriers of loss-of-function variants with poor reproductive outcomes, donor gametes may be preferable."
The authors' recommendation; it is not a tested outcome.
🔬

Diagnosis

2
Semen analysis
Repeated semen analysis separates the two presentations. Truncating genotypes give azoospermia, confirmed by finding no sperm in a centrifuged pellet. Missense genotypes give sperm in the ejaculate with poor motility and abnormal morphology, including macrozoospermia. Normal-looking counts do not predict reproductive outcome.
semen analysis NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:42597893 SUPPORT Human clinical
"Azoospermia was diagnosed based on at least three independent semen analyses, with confirmation by the absence of spermatozoa after centrifugation and microscopic evaluation of semen pellets."
Describes how azoospermia was established in the study.
Whole-exome sequencing
Finds the biallelic FBXO43 variants. All reported probands were identified by exome sequencing. The authors recommend including meiosis genes such as FBXO43 in the genetic workup of severe male infertility.
whole-exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:42597893 SUPPORT Human clinical
"Two infertile patients carrying distinct compound heterozygous FBXO43 variants-missense mutations in a macrozoospermia case and truncating mutations in a nonobstructive azoospermia (NOA) case-were identified through whole-exome sequencing."
Both probands in this study were found by exome sequencing.
PMID:42597893 SUPPORT Human clinical
"support the inclusion of meiosis-related genes such as FBXO43 in genetic evaluation of severe male infertility"
The authors recommend testing FBXO43 in severe male infertility.
⚖️

Clinical Burden

Moderate
The effect is reproductive only. No systemic features have been reported in affected men. The cost is loss of biological fertility, and for men with sperm present, failed ICSI cycles and pregnancy loss.
🐁

Animal Models

1
Emi2 knockout mouse
Male and female knockouts are viable but sterile. Male germ-cell-specific deletion with Stra8-Cre gives the same sterility, so the defect is intrinsic to germ cells.
Species
Mouse
Genotype
Emi2 (Fbxo43) null, exon 3 floxed and deleted
Publication
PMID:28723571
Pathograph links
Meiotic Prophase I Arrest at Early Diplotene recapitulates fidelity: high observes: cellular Knockout spermatocytes arrest in early diplotene, the stage reported in patient testis.
Limitations: A null allele models the truncating genotypes only. It says nothing about the missense alleles that let meiosis finish.
Show evidence (1 reference)
PMID:28723571 SUPPORT Model organism
"Male and female Emi2 knockout mice are viable but sterile, indicating that Emi2 is essential for meiosis but dispensable for embryonic development and mitotic cell divisions."
Supports the knockout as a model of the meiotic defect.
Reduced Cdk1 Activity in Meiotic Prophase Spermatocytes recapitulates fidelity: unknown observes: molecular The Cdk1 finding and its genetic rescue come only from this model.
Limitations: Cdk1 activity has not been measured in patient testis.
Show evidence (1 reference)
PMID:28723571 SUPPORT Model organism
"This arrest is associated with decreased Cdk1 activity and was partially rescued by a knockin mouse model of elevated Cdk1 activity."
The knockout shows the reduced Cdk1 activity, and the knockin rescue ties it to the arrest.
{ }

Source YAML

click to show 
name: Spermatogenic Failure 64
creation_date: "2026-10-21T00:00:00Z"
category: Mendelian
synonyms:
- SPGF64
- spermatogenic failure 64
- FBXO43-related male infertility
- EMI2-related spermatogenic failure
description: >-
  Spermatogenic failure 64 (SPGF64) is autosomal recessive male infertility
  caused by biallelic variants in FBXO43, which encodes EMI2 (early meiotic
  inhibitor 2). EMI2 is a direct inhibitor of the anaphase-promoting
  complex/cyclosome (APC/C), the E3 ubiquitin ligase that drives meiotic cell
  cycle transitions. It is expressed mainly in germ cells.

  The phenotype depends on the allele. Homozygous or compound heterozygous
  truncating variants cause non-obstructive azoospermia: spermatocytes arrest
  in meiosis I and no spermatids form. In the first family, testicular tissue
  lacked FBXO43 and the arrest was placed in early diplotene of prophase I,
  the same stage at which Emi2 knockout mouse spermatocytes arrest. Missense
  variants have been reported with sperm in the ejaculate. One man with two
  C-terminal missense variants had macrozoospermia, defective chromatin
  condensation and raised sperm aneuploidy, and repeated ICSI cycles failed.
  An earlier family with a homozygous missense variant had teratozoospermia.
  The proposed explanation is a dosage series: the more an allele weakens
  FBXO43 binding to the APC/C, the earlier meiosis fails.
disease_term:
  preferred_term: spermatogenic failure 64
  term:
    id: MONDO:0030522
    label: spermatogenic failure 64
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  MONDO cross-references the phenotype as OMIM 619696. MONDO records FBXO43 as
  its only causal gene and no descendant terms. Biallelic FBXO43 variants also
  cause female infertility with early embryonic arrest (PMID:34052850). MONDO
  lists that as a separate disease, oocyte maturation defect 12
  (MONDO:0030523), so it is not part of this entry. The reported male cases are
  few: two brothers with a homozygous missense variant (PMID:30878252), two
  brothers with a homozygous nonsense variant (PMID:34595750), two unrelated
  men with compound heterozygous variants (PMID:42597893), and one case in an
  exome series whose abstract does not give the phenotype (PMID:41932285). The
  stage of arrest is reported differently. The primary human and mouse studies
  give early diplotene of prophase I (PMID:34595750, PMID:28723571). The
  background section of PMID:42597893 says metaphase I. This entry follows the
  primary studies. The same 2019 study found four heterozygous FBXO43 carriers
  among 124 further men with teratozoospermia (PMID:30878252); single
  heterozygous variants do not fit recessive inheritance, so they are not
  counted as cases here. The deep-research report in research/ found no
  further patients.
inheritance:
- name: Autosomal recessive
  description: >-
    Affected men carry biallelic FBXO43 variants. Both families with
    homozygous variants were consanguineous, and the two later probands were
    compound heterozygous.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:34595750
    reference_title: "A homozygous loss-of-function mutation in FBXO43 causes human non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a homozygous nonsense mutation in FBXO43 c.1747C > T:p.Gln583X in two NOA brothers from a Chinese consanguineous family via whole-exome sequencing"
    explanation: A homozygous truncating variant in affected brothers of a consanguineous family fits recessive inheritance.
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two infertile patients carrying distinct compound heterozygous FBXO43 variants-missense mutations in a macrozoospermia case and truncating mutations in a nonobstructive azoospermia (NOA) case-were identified through whole-exome sequencing."
    explanation: Two compound heterozygous probands add further biallelic cases.
pathophysiology:
- name: Loss of FBXO43 Inhibition of the APC/C
  description: >-
    FBXO43 (EMI2) binds the APC/C and holds its ubiquitin ligase activity in
    check during meiosis. In patient testis a homozygous nonsense allele
    removed the protein. Truncating and missense alleles both made FBXO43
    less stable in transfected cells and broke its binding to APC3, the APC/C
    substrate-recognition subunit, while binding to APC2, APC6 and APC8 was
    kept. In Xenopus eggs, the C-terminal tail of EMI2 blocks the APC/C by
    occupying the APC10 site that the E2 enzyme Ube2S needs.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: FBXO43
    term:
      id: hgnc:28521
      label: FBXO43
  molecular_functions:
  - preferred_term: ubiquitin ligase inhibitor activity
    modifier: DECREASED
    term:
      id: GO:1990948
      label: ubiquitin ligase inhibitor activity
  - preferred_term: anaphase-promoting complex binding
    modifier: DECREASED
    term:
      id: GO:0010997
      label: anaphase-promoting complex binding
  downstream:
  - target: Reduced Cdk1 Activity in Meiotic Prophase Spermatocytes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Shown in knockout mice. Loss of Emi2 lowered Cdk1 activity in the testis
      without lowering Cdk1 or cyclin B1 protein. The step that connects the
      APC/C to Cdk1 here is not known.
    evidence:
    - reference: PMID:28723571
      reference_title: "Emi2 Is Essential for Mouse Spermatogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In the absence of Emi2 in testes, we observed the decreased activity of Cdk1."
      explanation: Links loss of Emi2 to reduced Cdk1 activity in the mouse testis.
  - target: Meiotic Chromosome Missegregation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed for hypomorphic alleles that leave enough FBXO43 for meiosis to
      finish. Weaker APC3 binding is thought to let the APC/C act too early or
      at the wrong time, so chromosomes segregate wrongly.
    evidence:
    - reference: PMID:42597893
      reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Loss of APC3 binding likely impairs APC/C inhibition, disturbing meiotic chromosome segregation in a mutation-severity-dependent manner."
      explanation: The authors infer missegregation from lost APC3 binding in cell assays together with patient sperm aneuploidy; the link is a stated model, not a direct measurement.
  evidence:
  - reference: PMID:34595750
    reference_title: "A homozygous loss-of-function mutation in FBXO43 causes human non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FBXO43 was absent from testicular tissue of the proband, and FBXO43-immunostaining signals were invisible in the affected seminiferous tubules."
    explanation: The nonsense allele removes FBXO43 protein from patient testis.
  - reference: PMID:34595750
    reference_title: "A homozygous loss-of-function mutation in FBXO43 causes human non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In mouse testicular protein extracts, three subunits of the APC/C, including ANAPC2, ANAPC8 and ANAPC10, were validated to interact directly with FBXO43, whereas no interactions were detected for FBXO43 and SKP1."
    explanation: FBXO43 binds APC/C subunits in testis extracts but not SKP1, so it acts as an APC/C binder rather than in an SCF ligase.
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mechanistically, all mutations reduced FBXO43 protein stability and disrupted its specific binding to the APC/C substrate recognition subunit APC3, whereas interactions with APC2/6/8 remained intact."
    explanation: Patient truncating and missense alleles all lower FBXO43 stability and lose APC3 binding.
  - reference: PMID:24770399
    reference_title: "Emi2 mediates meiotic MII arrest by competitively inhibiting the binding of Ube2S to the APC/C."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Significantly, Emi2 and Ube2S bind commonly to the APC/C catalytic subunit APC10 via their similar C-terminal tails."
    explanation: Gives the biochemical mechanism of APC/C inhibition by EMI2, worked out in Xenopus egg extracts rather than spermatocytes.
- name: Reduced Cdk1 Activity in Meiotic Prophase Spermatocytes
  description: >-
    In Emi2 knockout spermatocytes, Cdk1 activity falls and its inhibitory
    Tyr15 phosphorylation rises. Raising Cdk1 activity with a knockin allele
    let some spermatocytes go past diplotene into metaphase, so low Cdk1
    activity is part of the cause of the arrest.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: primary spermatocyte
    term:
      id: CL:0000656
      label: primary spermatocyte
  molecular_functions:
  - preferred_term: Cdk1 kinase activity
    modifier: DECREASED
    term:
      id: GO:0004693
      label: cyclin-dependent protein serine/threonine kinase activity
  downstream:
  - target: Meiotic Prophase I Arrest at Early Diplotene
    causal_link_type: DIRECT
    description: >-
      Partial rescue of the arrest by a Cdk1 knockin allele shows that low
      Cdk1 activity contributes to it.
    evidence:
    - reference: PMID:28723571
      reference_title: "Emi2 Is Essential for Mouse Spermatogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This arrest is associated with decreased Cdk1 activity and was partially rescued by a knockin mouse model of elevated Cdk1 activity."
      explanation: Genetic rescue in mice links low Cdk1 activity to the meiotic arrest.
  evidence:
  - reference: PMID:28723571
    reference_title: "Emi2 Is Essential for Mouse Spermatogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Interestingly, decreased activity of Cdk1 in the absence of Emi2 was associated with increased Tyr15 inhibitory phosphorylation."
    explanation: Describes how Cdk1 activity is lowered in Emi2-null testis.
- name: Meiotic Prophase I Arrest at Early Diplotene
  description: >-
    Spermatocytes stop in early diplotene of prophase I. Chromosomes do not
    condense and do not enter metaphase I, and the arrested cells die.
    Primary spermatocytes are present in the testis but no spermatids. Shown
    in patient testis and in Emi2 knockout mice.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: primary spermatocyte
    term:
      id: CL:0000656
      label: primary spermatocyte
  biological_processes:
  - preferred_term: male meiosis I
    modifier: DECREASED
    term:
      id: GO:0007141
      label: male meiosis I
  downstream:
  - target: Spermatocyte maturation arrest
    causal_link_type: DIRECT
  - target: Non-obstructive azoospermia
    causal_link_type: DIRECT
    description: >-
      With no spermatocyte completing meiosis, no sperm reach the ejaculate.
    evidence:
    - reference: PMID:42597893
      reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "abolished the C-terminal functional domain and caused meiotic arrest with complete absence of mature sperm"
      explanation: Links the truncating genotype through meiotic arrest to absent sperm.
  evidence:
  - reference: PMID:34595750
    reference_title: "A homozygous loss-of-function mutation in FBXO43 causes human non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, in humans, FBXO43 defects cause meiotic arrest within early diplotene of prophase I."
    explanation: Places the human arrest in early diplotene.
  - reference: PMID:28723571
    reference_title: "Emi2 Is Essential for Mouse Spermatogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the absence of Emi2, spermatocytes arrest in early diplotene of prophase I."
    explanation: The knockout mouse arrests at the same stage as the human testis.
  - reference: PMID:28723571
    reference_title: "Emi2 Is Essential for Mouse Spermatogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "indicating the inability of meiosis I chromosomes to undergo condensation and progress beyond diplotene in the absence of Emi2"
    explanation: Absent phospho-histone H3 shows chromosomes fail to condense at the arrest point.
- name: Meiotic Chromosome Missegregation
  description: >-
    Reported in one man with two C-terminal missense variants. His
    spermatocytes completed meiosis, but his sperm had a raised rate of
    aneuploidy on FISH, together with poor chromatin condensation and
    histone retention. The missegregation itself happens in the meiotic
    divisions of spermatocytes; it is observed as aneuploidy in the sperm.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: primary spermatocyte
    term:
      id: CL:0000656
      label: primary spermatocyte
  - preferred_term: sperm
    term:
      id: CL:0000019
      label: sperm
  biological_processes:
  - preferred_term: meiotic chromosome segregation
    modifier: DECREASED
    term:
      id: GO:0045132
      label: meiotic chromosome segregation
  downstream:
  - target: Macrozoospermia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The authors read the enlarged sperm heads, chromatin defects and
      aneuploidy together as signs of faulty meiotic division in the
      missense patient.
    evidence:
    - reference: PMID:42597893
      reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Together, these findings demonstrate that sperm from P1 exhibit a typical macrozoospermia phenotype accompanied by impaired nuclear maturation, defective chromatin condensation, and chromosome segregation errors, collectively indicating severe defects in meiotic progression and chromatin remodeling."
      explanation: Ties the macrozoospermia to chromosome segregation errors in the same patient.
  evidence:
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Missense variants (NM_001029860, p.Pro641Leu/p.Arg660Gln) in the macrozoospermia patient allowed completion of meiosis but led to severe sperm head enlargement, chromatin condensation defects, and markedly elevated aneuploidy, resulting in repeated ICSI failure."
    explanation: Missense alleles allow meiosis to finish but leave aneuploid sperm.
phenotypes:
- category: Reproductive
  name: Non-obstructive azoospermia
  description: >-
    No sperm in the ejaculate, caused by failed spermatogenesis. Seen with
    truncating FBXO43 genotypes.
  phenotype_term:
    preferred_term: Non-obstructive azoospermia
    term:
      id: HP:0011961
      label: Non-obstructive azoospermia
  evidence:
  - reference: PMID:34595750
    reference_title: "A homozygous loss-of-function mutation in FBXO43 causes human non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a homozygous nonsense mutation in FBXO43 c.1747C > T:p.Gln583X in two NOA brothers from a Chinese consanguineous family via whole-exome sequencing"
    explanation: Two brothers homozygous for a nonsense allele had non-obstructive azoospermia.
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Truncating mutations cause profound meiotic arrest and NOA"
    explanation: A second, unrelated proband with truncating variants had NOA.
- category: Reproductive
  name: Spermatocyte maturation arrest
  description: >-
    Testicular histology shows primary spermatocytes but no spermatids.
  phenotype_term:
    preferred_term: Spermatocyte maturation arrest
    term:
      id: HP:0031039
      label: Spermatocyte maturation arrest
  evidence:
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although primary spermatocytes were present, no spermatids were detected, consistent with a histological picture suggestive of meiotic arrest."
    explanation: Biopsy of the NOA proband showed arrest at the spermatocyte stage.
  - reference: PMID:34595750
    reference_title: "A homozygous loss-of-function mutation in FBXO43 causes human non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "spermatocytes were unable to complete meiotic divisions without FBXO43 in humans"
    explanation: Spermatocytes of the first family did not complete meiosis.
- category: Reproductive
  name: Macrozoospermia
  description: >-
    Large-headed sperm with poor chromatin condensation and raised
    aneuploidy, reported in one man with compound heterozygous missense
    variants. Repeated ICSI cycles gave one pregnancy, which miscarried.
  phenotype_term:
    preferred_term: Macrozoospermia
    term:
      id: HP:0025437
      label: Macrozoospermia
  evidence:
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Proband P1 presented with macrozoospermia."
    explanation: Reports macrozoospermia in the missense proband.
- category: Reproductive
  name: Reduced progressive sperm motility
  description: >-
    Reported in the man with compound heterozygous missense variants, whose
    sperm concentration was within the reference range. Only 13.56% of his
    sperm were progressively motile.
  phenotype_term:
    preferred_term: Reduced progressive sperm motility
    term:
      id: HP:0034011
      label: Reduced progressive sperm motility
  evidence:
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proportion of progressively motile sperm was only 13.56%, and the percentage of morphologically normal spermatozoa was 3.3%"
    explanation: Semen analysis of the missense proband shows reduced progressive motility.
- category: Reproductive
  name: Decreased testicular size
  description: >-
    Reported in the man with truncating variants and azoospermia, whose
    testes measured about 8-10 mL on each side.
  phenotype_term:
    preferred_term: Decreased testicular size
    term:
      id: HP:0008734
      label: Decreased testicular size
  evidence:
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical examination revealed bilateral testicular volumes of approximately 8-10 mL, which is below the adult reference range (10-15 mL)."
    explanation: Examination of the NOA proband found testes smaller than the adult reference range.
- category: Reproductive
  name: Teratozoospermia
  description: >-
    Abnormal sperm morphology in two brothers homozygous for the missense
    variant p.Gly664Asp. The abstract does not describe the morphology
    further, and that report had no functional data. A later paper describes
    the same family's phenotype as oligoasthenoteratozoospermia, which adds
    low sperm count and reduced motility.
  phenotype_term:
    preferred_term: Teratozoospermia
    term:
      id: HP:0012864
      label: Abnormal sperm morphology
  evidence:
  - reference: PMID:30878252
    reference_title: "A novel homozygous FBXO43 mutation associated with male infertility and teratozoospermia in a consanguineous Chinese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel homozygous nonsynonymous mutation (C1991T, p.G664D) in FBXO43 (F-box only protein 43) was observed in two brothers from a consanguineous Chinese family."
    explanation: The affected brothers in this family were ascertained for teratozoospermia.
  - reference: PMID:30878252
    reference_title: "A novel homozygous FBXO43 mutation associated with male infertility and teratozoospermia in a consanguineous Chinese family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation in FBXO43 is a causative factor of male infertility and teratozoospermia."
    explanation: The authors' conclusion links the homozygous missense variant to teratozoospermia.
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "the homozygous missense variant (p.Gly664Asp) leading to oligoasthenoteratozoospermia"
    explanation: Restates the earlier family's phenotype as oligoasthenoteratozoospermia, of which teratozoospermia is one part.
genetic:
- name: FBXO43
  notes: >-
    FBXO43 encodes EMI2, also called XErp1, a paralogue of EMI1 (FBXO5). Its
    C-terminal region, including the zinc-binding region, carries the APC/C
    inhibitory function. Reported male alleles are p.Gln583* (homozygous),
    p.Gly664Asp (homozygous), p.Trp532*/p.Ser577Leufs*11 and
    p.Pro641Leu/p.Arg660Gln (both compound heterozygous). Truncating alleles
    go with azoospermia and missense alleles with sperm present.
  gene_term:
    preferred_term: FBXO43
    term:
      id: hgnc:28521
      label: FBXO43
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:34595750
    reference_title: "A homozygous loss-of-function mutation in FBXO43 causes human non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The results here demonstrate the pathogenicity of this loss-of-function mutation"
    explanation: Patient genetics, absent testicular protein and the matching mouse phenotype support FBXO43 as causal.
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypomorphic missense mutations permit meiotic completion but result in severe teratozoospermia with high aneuploidy"
    explanation: Supports the allele-severity relationship recorded in the notes.
histopathology:
- name: Meiotic arrest on testicular biopsy
  description: >-
    Primary spermatocytes are present but no spermatids, and FBXO43 staining
    is absent from the seminiferous tubules.
  evidence:
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although primary spermatocytes were present, no spermatids were detected, consistent with a histological picture suggestive of meiotic arrest."
    explanation: Biopsy histology of the NOA proband.
  - reference: PMID:34595750
    reference_title: "A homozygous loss-of-function mutation in FBXO43 causes human non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FBXO43 was absent from testicular tissue of the proband, and FBXO43-immunostaining signals were invisible in the affected seminiferous tubules."
    explanation: Immunostaining shows no FBXO43 in patient tubules.
animal_models:
- name: Emi2 knockout mouse
  species: Mouse
  genotype: Emi2 (Fbxo43) null, exon 3 floxed and deleted
  publication: PMID:28723571
  description: >-
    Male and female knockouts are viable but sterile. Male germ-cell-specific
    deletion with Stra8-Cre gives the same sterility, so the defect is
    intrinsic to germ cells.
  modeled_mechanisms:
  - target: Meiotic Prophase I Arrest at Early Diplotene
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Knockout spermatocytes arrest in early diplotene, the stage reported in
      patient testis.
    limitations: >-
      A null allele models the truncating genotypes only. It says nothing
      about the missense alleles that let meiosis finish.
    evidence:
    - reference: PMID:28723571
      reference_title: "Emi2 Is Essential for Mouse Spermatogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Male and female Emi2 knockout mice are viable but sterile, indicating that Emi2 is essential for meiosis but dispensable for embryonic development and mitotic cell divisions."
      explanation: Supports the knockout as a model of the meiotic defect.
  - target: Reduced Cdk1 Activity in Meiotic Prophase Spermatocytes
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: MOLECULAR
    description: >-
      The Cdk1 finding and its genetic rescue come only from this model.
    limitations: >-
      Cdk1 activity has not been measured in patient testis.
    evidence:
    - reference: PMID:28723571
      reference_title: "Emi2 Is Essential for Mouse Spermatogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This arrest is associated with decreased Cdk1 activity and was partially rescued by a knockin mouse model of elevated Cdk1 activity."
      explanation: The knockout shows the reduced Cdk1 activity, and the knockin rescue ties it to the arrest.
diagnosis:
- name: Semen analysis
  description: >-
    Repeated semen analysis separates the two presentations. Truncating
    genotypes give azoospermia, confirmed by finding no sperm in a centrifuged
    pellet. Missense genotypes give sperm in the ejaculate with poor motility
    and abnormal morphology, including macrozoospermia. Normal-looking counts
    do not predict reproductive outcome.
  diagnosis_term:
    preferred_term: semen analysis
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Azoospermia was diagnosed based on at least three independent semen analyses, with confirmation by the absence of spermatozoa after centrifugation and microscopic evaluation of semen pellets."
    explanation: Describes how azoospermia was established in the study.
- name: Whole-exome sequencing
  description: >-
    Finds the biallelic FBXO43 variants. All reported probands were
    identified by exome sequencing. The authors recommend including meiosis
    genes such as FBXO43 in the genetic workup of severe male infertility.
  diagnosis_term:
    preferred_term: whole-exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two infertile patients carrying distinct compound heterozygous FBXO43 variants-missense mutations in a macrozoospermia case and truncating mutations in a nonobstructive azoospermia (NOA) case-were identified through whole-exome sequencing."
    explanation: Both probands in this study were found by exome sequencing.
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "support the inclusion of meiosis-related genes such as FBXO43 in genetic evaluation of severe male infertility"
    explanation: The authors recommend testing FBXO43 in severe male infertility.
treatments:
- name: ICSI with preimplantation genetic testing for aneuploidy
  description: >-
    Where sperm are present, as with missense genotypes, ICSI is possible,
    but in the one reported man repeated cycles failed and the only
    pregnancy miscarried, in line with his high sperm aneuploidy. The
    authors recommend preimplantation genetic testing for aneuploidy to
    select embryos. No therapy restores meiosis.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: intracytoplasmic sperm injection
    term:
      id: NCIT:C185482
      label: Intracytoplasmic Sperm Injection
  evidence:
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The macrozoospermia patient experienced repeated ICSI failure and early pregnancy loss, consistent with the high sperm aneuploidy detected in our study and prior reports"
    explanation: Reports the ICSI outcome in the missense proband.
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on the identified mutation-specific risks, preimplantation genetic testing for aneuploidy (PGT-A) is recommended for affected couples to improve embryo selection and optimize ART outcomes."
    explanation: The authors' recommendation for embryo selection; it is not a tested outcome.
- name: Donor sperm insemination
  description: >-
    For men with truncating genotypes, meiosis does not complete and
    endogenous sperm production is very unlikely, so donor sperm is the
    route to pregnancy. The man with truncating variants used donor-sperm
    insemination after biopsy showed meiotic arrest. The authors also
    suggest donor gametes where loss-of-function carriers have poor
    reproductive outcomes.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: donor sperm insemination
    term:
      id: NCIT:C16739
      label: Artificial Insemination
  evidence:
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings collectively indicated an extremely low likelihood of endogenous sperm production. The patient ultimately proceeded with donor-sperm insemination."
    explanation: The NOA proband with truncating variants used donor sperm.
  - reference: PMID:42597893
    reference_title: "Mutation Severity of FBXO43 Determines Spermatogenic Outcome and Informs Precision ART Strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For carriers of loss-of-function variants with poor reproductive outcomes, donor gametes may be preferable."
    explanation: The authors' recommendation; it is not a tested outcome.
clinical_burden:
  burden_level: MODERATE
  rationale: >-
    The effect is reproductive only. No systemic features have been reported
    in affected men. The cost is loss of biological fertility, and for men
    with sperm present, failed ICSI cycles and pregnancy loss.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Record notes

MONDO cross-references the phenotype as OMIM 619696. MONDO records FBXO43 as its only causal gene and no descendant terms. Biallelic FBXO43 variants also cause female infertility with early embryonic arrest (PMID:34052850). MONDO lists that as a separate disease, oocyte maturation defect 12 (MONDO:0030523), so it is not part of this entry. The reported male cases are few: two brothers with a homozygous missense variant (PMID:30878252), two brothers with a homozygous nonsense variant (PMID:34595750), two unrelated men with compound heterozygous variants (PMID:42597893), and one case in an exome series whose abstract does not give the phenotype (PMID:41932285). The stage of arrest is reported differently. The primary human and mouse studies give early diplotene of prophase I (PMID:34595750, PMID:28723571). The background section of PMID:42597893 says metaphase I. This entry follows the primary studies. The same 2019 study found four heterozygous FBXO43 carriers among 124 further men with teratozoospermia (PMID:30878252); single heterozygous variants do not fit recessive inheritance, so they are not counted as cases here. The deep-research report in research/ found no further patients.

Claude Code ▸
Spermatogenic Failure 64 (SPGF64; FBXO43): Research Report
claude-haiku-5-5, claude-sonnet-5-5 12 citations 2026-10-24T04:53:02.809473

Spermatogenic Failure 64 (SPGF64; FBXO43): Research Report

Scope and caveat. The sources are search-result summaries and abstracts, not full texts. OMIM and PMC returned "proxy refused the connection." I could not independently confirm the journal or PMID for the Wu/Liu paper, the 2021 female paper, the 2017 mouse paper, or the 2026 paper's details beyond what the summaries said. I marked every such item as unverified. Verify each quote and PMID with just fetch-reference before using it as a snippet.

1. Disease information

SPGF64 (OMIM:619696, MONDO:0030522) is an autosomal recessive male infertility disorder caused by biallelic variants in FBXO43 (HGNC symbol FBXO43; this repository writes the CURIE as lowercase hgnc:, and I did not look up the numeric ID). FBXO43 is also called EMI2 or XErp1. The gene encodes an F-box protein that inhibits the anaphase-promoting complex/cyclosome (APC/C).

  • MedGen describes the phenotype as oligoasthenoteratozoospermia or non-obstructive azoospermia (NOA). Some patients have absent sperm from meiotic arrest at the diplotene stage. Others have low sperm counts, reduced progressive motility and enlarged amorphous sperm heads (MedGen).
  • The same MedGen entry notes that FBXO43 variants also cause female infertility with early embryonic arrest. That is a separate disease (OZEMA12; see MalaCards).
  • Disease Ontology: DOID:0112353 (DO).
  • Synonym: SPGF64.
  • I did not look up Orphanet, ICD or MeSH identifiers. The data come from aggregated disease resources and case reports, not EHR.

2. Etiology

  • Cause: biallelic (homozygous or compound heterozygous) FBXO43 variants. No environmental or infectious cause is established.
  • Risk factors: consanguinity (a homozygous family was consanguineous). I found no modifier genes, protective variants, or gene–environment data.

3. Phenotypes

All phenotypes are male-specific. No frequencies were retrievable beyond the case counts below.

Phenotype Suggested HPO term (verify by lookup) Source
Non-obstructive azoospermia Azoospermia (HP:0000027) NOA patient with truncating variants
Teratozoospermia Teratozoospermia (HP:0012864) Two brothers with p.G664D
Macrozoospermia, large sperm heads Macrozoospermia (HP:0034305) 2026 patient with p.Pro641Leu/p.Arg660Gln
Oligoasthenoteratozoospermia, reduced progressive motility Oligoasthenoteratozoospermia (HP:0034307) MedGen
Male infertility Male infertility (HP:0003251) All
Aneuploid sperm, chromatin condensation defects none identified 2026 patient
  • Onset and course: onset is at reproductive age, and the condition is non-progressive as far as reported. Patients present with infertility, and I found no extragonadal features.
  • Quality of life: I found no data.

4. Genetic and molecular information

  • Gene: FBXO43 (transcript NM_001029860 was used in the 2026 report).
  • Variants reported:
  • Homozygous p.G664D (C1991T) in two brothers with teratozoospermia. It was absent from 1000 Genomes, ExAC and 200 fertile controls. Screening of 124 additional cases found four with heterozygous FBXO43 mutations, which do not establish causation (Ma et al., Fertil Steril 2019;111:909–917, PMID:30878252, per an Atlas Genetics listing).
  • A homozygous loss-of-function variant in NOA (Wu H, Liu M et al.; PMID:34595750 per MalaCards/DO). The journal was not confirmed. A search summary suggested Clin Genet, and the DOI contains cge.14069.
  • Two unrelated compound heterozygotes (Xiao et al. 2026, Hum Mutat, PMID:42597893; PMC). The macrozoospermia patient carried two missense variants, p.Pro641Leu and p.Arg660Gln. The NOA patient carried a nonsense variant (p.Trp532*) and a frameshift. Per the abstract, "all four variants" reduced protein stability and disrupted APC3 binding (stability and binding per the EMJ summary; see EMJ).
  • Cohort: the 2026 study sequenced 118 asthenoteratozoospermia patients and 626 NOA patients and found two such compound heterozygotes.
  • Genotype–phenotype: truncating variants cause profound meiotic arrest and NOA. Hypomorphic C-terminal missense variants allow meiosis to finish but give macrozoospermia and high aneuploidy, and repeated ICSI failure.
  • Mechanism class: loss of function (complete or partial). Origin is germline.
  • Epigenetic and chromosomal abnormalities: none reported.

5. Environmental information

None known.

6. Mechanism and pathophysiology

Causal chain (steps 1–3 are demonstrated, step 4 is partly inferred, and step 5 is inferred from the 2026 report):

  1. Biallelic FBXO43 variants cause loss of, or reduced, protein stability (demonstrated in vitro).
  2. This leads to loss of APC/C inhibition, with disrupted binding of FBXO43 to APC3 for C-terminal missense variants (demonstrated in vitro).
  3. This results in failed meiotic progression. In mouse Emi2 knockout, spermatocytes arrest at early diplotene of prophase I, associated with reduced Cdk1 activity. The arrest was partially rescued by a knock-in mouse with elevated Cdk1 activity (Gopinathan et al., Cell Rep 2017; PMID not verified; see search summary).
  4. In humans with truncating variants, this causes meiotic arrest and absent mature sperm, producing NOA (testis analysis in the 2026 NOA patient suggested meiotic arrest, per EMJ).

  5. Branch: with hypomorphic missense variants, meiosis completes but with defective chromatin condensation, enlarged sperm heads and aneuploidy. This gives macrozoospermia or teratozoospermia and ICSI failure.

  6. Cell types: spermatocyte (CL:0000017), spermatid (CL:0000018).

  7. GO suggestions (verify by lookup): meiotic cell cycle (GO:0051321), negative regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle, and the APC/C complex (GO:0005680).
  8. Note on naming: the mouse male arrest is early diplotene of prophase I, not metaphase II. Metaphase II arrest (cytostatic factor) is the oocyte role.
  9. Omics: not available.

7. Anatomical structures

  • Primary: testis (UBERON:0000473), seminiferous tubule.
  • Cell level: spermatocytes and spermatids.
  • Subcellular: nucleus and APC/C.
  • Female involvement: early embryonic arrest from separate FBXO43 variants (OZEMA12).

8. Temporal development

Present from puberty or adulthood as infertility. It is stable.

9. Inheritance and population

  • Inheritance: autosomal recessive (OMIM). GeneBe lists evidence as limited.
  • Consanguinity: observed in the Chinese homozygous family.
  • Populations: all reports I found are from Chinese cohorts. Prevalence, incidence and carrier frequency are not available.
  • Sex: male-limited for SPGF64.

10. Diagnostics

  • Semen analysis: azoospermia, or macrozoospermia and teratozoospermia.
  • Testis findings: meiotic arrest on histology (inferred from the NOA patient).
  • Genetic testing: WES or a gene panel including FBXO43. WES in 744 men identified the cases above.
  • Differential: AURKC-related macrozoospermia (a literature item turned up in search), other meiotic-arrest genes, and other causes of NOA.
  • Screening: none established.

11. Prognosis

Fertility is the only reported outcome. Macrozoospermia with high aneuploidy led to repeated ICSI failure. Survival and morbidity data are not available.

12. Treatment

  • No disease-specific therapy.
  • Assisted reproduction: ICSI failed repeatedly in the macrozoospermia patient. The 2026 title mentions precision ART strategies, but I did not read the details.
  • Suggested NCIT terms (verify): intracytoplasmic sperm injection and genetic counseling (NCIT:C15240).
  • Trials: none found.

13. Prevention

Genetic counseling and, for carriers, prenatal or preimplantation testing. Nothing else applies.

14. Other species

  • Orthologs: mouse Fbxo43 (MGI:1926053, Alliance). The Xenopus ortholog is XErp1.
  • Natural disease and breed: not searched.

15. Model organisms

  • Emi2/Fbxo43 knockout mouse: both sexes are sterile as adults. The male arrest is at early diplotene and is partially rescued by elevated Cdk1 activity (Gopinathan et al. 2017; also see Emi2 is essential for mouse spermatogenesis).
  • Fidelity: the null phenotype resembles the human NOA/meiotic-arrest end. It does not model hypomorphic macrozoospermia.
  • Evidence classes: human clinical (Ma 2019, Wu/Liu, 2026 cohort), in vitro (stability and APC3 binding), model organism (mouse).

Gaps and verification list

  • Confirm PMID:34595750 (journal and title) and the Gopinathan 2017 PMID.
  • Read the full OMIM entry 619696 and the 2026 full text for exact quotes.
  • Look up the HPO, GO, CL and UBERON IDs above before binding them.
  • The 2019 paper's heterozygous findings in 4 of 124 cases are not strong support for causation.

Sources: - MedGen SPGF64 - Alliance MGI:1926053 - EMJ summary - Xiao 2026, PubMed - Xiao 2026, PMC - Emi2 essential for spermatogenesis - Mouse Emi2 article (PMC7974383) - Atlas Genetics Oncology FBXO43 - MalaCards OZEMA12 - Disease Ontology DOID:0112353 - Ma 2019, ScienceDirect - Wu/Liu, Wiley

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome Count
References checked 6
Resolved 4
Unresolved (possible confabulation) 0
Unverifiable 2
References weighed for topical relevance 4
On topic 4
Off topic 0

4 of 6 references resolved; the rest could not be looked up either way.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 15
Resolved 13
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 7
Terms named correctly 2
Terms named as a different term 2
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0034305 (1 mention) - the report calls it "Macrozoospermia"; HP calls it 2:1 atrioventricular block
  • HP:0034307 (1 mention) - the report calls it "Oligoasthenoteratozoospermia"; HP calls it Elevated left ventricular end-diastolic diameter

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0012864 (1 mention) - the report calls it "Teratozoospermia"; HP calls it Abnormal sperm morphology, and lists "Teratozoospermia" among its other names
  • CL:0000017 (1 mention) - the report calls it "Cell types: spermatocyte"; CL calls it spermatocyte**
  • UBERON:0000473 (1 mention) - the report calls it "Primary: testis"; UBERON calls it testis**

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM, MGI.