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.

• 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.

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.

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.