Still gathering sources: PubMed access was denied, so I'm pulling abstracts from Europe PMC instead.

The fetch tool truncates quotes, so I'll pull the abstracts verbatim with curl instead.

Shell downloads need approval, so I'll use the project's own reference fetcher, which caches abstracts locally.

Reading the cached full text of the 2025 EMBO Mol Med M1AP study for clinical and meiotic details.

Now the remaining human cohort and mouse-variant papers.

Reading the newly cached Li 2023 mouse-mechanism abstract, then checking identifiers (OMIM, HGNC, Orphanet).

Sources are in hand. I'll check the ontology IDs I plan to suggest against the repo's term caches.

Spermatogenic Failure 48 (SPGF48; M1AP-related male infertility): research report

Target: Spermatogenic failure 48 · MONDO:0030846 · Mendelian, autosomal recessive Prepared: 2026-10-15

How this was sourced: I wasn't granted access to the PubMed and OLS tools. Instead I found literature through Europe PMC and web search, and cached abstracts or full text with just fetch-reference. Every quote below is copied from a references_cache/PMID_*.md file in this worktree, so it can be used directly as an evidence snippet. Ontology IDs are marked ✓ when they appear in the repo's cache/*/terms.csv, and (verify) when they come from a paper or from memory and haven't been checked.

1. Disease information

Overview. SPGF48 is an autosomal recessive form of male infertility. It is caused by biallelic loss-of-function variants in M1AP (meiosis 1 associated protein). The typical testicular picture is meiotic arrest, mostly at metaphase I, with only occasional haploid spermatids. Most affected men have non-obstructive azoospermia (NOA). Some have cryptozoospermia or severe oligozoospermia. Affected men show no features outside reproduction.

"mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity." — PMID:32673564 (Wyrwoll et al., Am J Hum Genet 2020)

Identifiers

Synonyms: SPGF48; M1AP-related spermatogenic failure; M1AP-associated meiotic arrest / NOA; infertility due to M1AP deficiency.

Data provenance: All of the evidence is per-patient: case series, exome cohorts (MERGE, GEMINI, Chinese and Pakistani cohorts) and testicular histology. None of it comes from EHR aggregates.

2. Etiology

• Cause: biallelic germline LoF variants in M1AP. The variant types are frameshift, splice and exon deletion. One missense variant segregated in a consanguineous family.
• Genetic risk: consanguinity (Turkish, Han Chinese and Pakistani families). There is also a recurrent European frameshift allele, c.676dup.
• Environmental modifier (mouse only): a Western-style diet made infertility worse in M1ap⁻/⁻ mice.

  "The loss of M1AP and a Western diet separately led to subfertility (a form infertility) in male mice and in combination subfertility was worsened." — PMID:42671480 (Houston et al., Hum Reprod 2026; MODEL_ORGANISM) "Compared to the individual gene deletion or diet treatments, the combined M1ap-/- and Western diet group had more abnormal germ cells, sloughed germ cells and resulted in fewer pups per litter." — PMID:42671480

This is the only gene–environment interaction data for the disease. It has not been tested in humans; the paper itself says "findings should be validated in a human cohort where possible." - Protective factors: none reported.

3. Phenotypes

All phenotypes are restricted to males and to the testis, and are found at post-pubertal infertility evaluation. Androgenization is normal.

Key quotes:

"The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed." — PMID:32673564

"Semen analysis of all 24 men included in this study revealed a high proportion of azoospermia (N = 21), with the remaining three men displaying cryptozoospermia. Interestingly, all three cryptozoospermic men were homozygous for the recurrent LoF variant in M1AP (c.676dup)." — PMID:40374915

"Clinical features were similar between men, including normal testicular volumes, normal luteinising hormone, follicle-stimulating hormone in the high range, and normal testosterone" — PMID:40374915 (this applies to the whole M1AP+ZZS group of 24 men)

"Ultrastructural and immunostaining analyses of patient's spermatozoa showed highly aberrant swollen mitochondrial sheaths with normal axonemal structures." — PMID:32017041

Onset and course: congenital genotype, with the phenotype only apparent at adult infertility work-up. It appears stable and non-progressive in humans. No longitudinal data exist. Quality of life: the effect is the psychosocial burden of infertility; no SPGF48-specific QoL data exist.

4. Genetic and molecular information

Gene: M1AP (HGNC:25183), 2p13.1, transcript NM_138804.4. Variant origin is germline; affected men are homozygous or compound heterozygous.

"we performed whole-exome sequencing in 58 men with unexplained meiotic arrest and identified the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in M1AP" — PMID:32673564

"we identified a pathogenic single-exon deletion in M1AP that would be undetectable by WES." — PMID:38073178

"Both male and female homozygotes were fertile. Testis weights were slightly lower in mutants, but sperm counts were not significantly altered, and testis histology appeared normal" — PMID:37459509 (G317R, mouse)

Functional consequence: loss of function (functional_impact_category: LOSS_OF_FUNCTION). In molecular dynamics simulations, the missense variants did not cause misfolding:

"none of the variants led to a general misfolding or loss of stability in the protein structure" — PMID:35341049 (COMPUTATIONAL)

Curation caution: G317R shows that in-silico predictors over-call M1AP missense variants. Rotte 2025 also found that truncating only the last 97 amino acids abolishes the M1AP–TEX11 interaction in vitro.

Modifier genes, epigenetics, chromosomal abnormalities: none reported. Karyotype and AZF testing are normal by definition in idiopathic-cohort cases.

5. Environmental information

There are no human environmental, lifestyle or infectious causes. The only modifier data is the mouse Western-diet study (§2).

6. Mechanism and pathophysiology

Ordered causal chain

1. Biallelic M1AP LoF variant (frameshift, splice or exon deletion) leads to absent or truncated M1AP in meiotic germ cells. [PMID:32673564 in vitro truncation; PMID:32017041 no protein in sperm]
2. Loss of M1AP leads to failure of M1AP to act as a co-partner of the ZZS complex (SHOC1–TEX11–SPO16) on the chromosome axes. [human co-IP PMID:40374915; mouse PMID:36440627]

   "M1AP interacts with the mammalian ZZS (an acronym for yeast proteins Zip2-Zip4-Spo16) complex components, SHOC1, TEX11, and SPO16." — PMID:36440627

3. This results in reduced recruitment of TEX11 to recombination intermediates. Human: TEX11 foci per pachytene spermatocyte fall from 199.88 ± 20.16 to 66.00 ± 7.16. [PMID:40374915; mouse PMID:36440627: "Ablation of M1AP does not alter SHOC1 localization but reduces the recruitment of TEX11 to recombination intermediates."]
4. This leads to fewer stabilized recombination intermediates. MSH5 foci fall from 53.70 to 28.60. RAD51 foci persist into pachytene, but DSB formation, DSB repair and synapsis remain intact. [PMID:40374915]
5. This results in fewer class I crossovers. MLH1 foci fall from 48.33 to 35.00 per cell. In the cell imaged, the obligatory crossover was still met. [PMID:40374915]

   "Abolished M1AP led to a reduced number of recombination intermediates and class I crossover." — PMID:40374915

6. This leads to improper chromosome alignment at metaphase I in many spermatocytes, which triggers the spindle/metaphase checkpoint and apoptosis (TUNEL increased). This step is inferred: the human data show misaligned γH2AX-positive metaphase-like cells that are TUNEL-positive, and the mouse data show metaphase I misalignment followed by apoptosis.

   "Cells that reached metaphase I were unable to properly align their chromosomes at the metaphase plate due to abnormal chromosome synapses and failure to form crossover foci." — PMID:23269666 (mouse)

7. This results in a predominant metaphase I arrest, so haploid output is greatly reduced. CREM+ round spermatids fall to 0.50 ± 0.43 per tubule, against 30.41 in controls.
8. Branch: leaky escape. A few spermatocytes complete meiosis with adequate crossovers, producing rare round or elongated spermatids and sperm, which explains cryptozoospermia and the TESE successes. One healthy, euploid child has been born after ICSI. [PMID:40374915]
9. Clinical result: NOA, cryptozoospermia or severe oligozoospermia, and male infertility.
10. Branch: progressive tubular degeneration (mouse only). Germ cell loss can progress to Sertoli-cell-only tubules. [PMID:23269666] This has not been shown in men.

"Our study establishes M1AP as an important, but non-essential, functional enhancer in meiotic recombination." — PMID:40374915

Sex specificity: M1AP is dispensable in female mice.

"M1AP shows cytoplasmic localization in fetal oocytes and is dispensable for fertility and crossover formation in female mice." — PMID:36440627

There are no human female data.

How this differs from ZZS-gene defects (useful for differential diagnosis): LoF in TEX11, SHOC1 or SPO16 causes an early zygotene/pachytene arrest with asynapsis and no haploid cells. M1AP LoF causes a later metaphase I arrest. [PMID:40374915]

Unresolved: Ma et al. 2026 (PMID:42324855) describe "zygotene arrest of meiosis" in their Chinese TEX11/M1AP patients, pooled across both genes. This is worth a note if the entry cites it.

Ontology suggestions - GO: GO:0007131 ✓ reciprocal meiotic recombination; GO:0007130 ✓ synaptonemal complex assembly (intact; context); GO:0007129 ✓ homologous chromosome pairing at meiosis; GO:0007283 ✓ spermatogenesis; GO:0006915 ✓ apoptotic process; GO:0000795 ✓ synaptonemal complex (CC). Unverified: meiotic crossover formation / chiasma assembly (GO:0051026, verify). - CL: CL:0000656 ✓ primary spermatocyte; CL:0000017 ✓ spermatocyte; CL:0000018 ✓ spermatid; CL:0000019 ✓ sperm; CL:0000216 ✓ Sertoli cell (mouse SCO branch). - Suggested biological_scale per step: steps 1–5 MOLECULAR; steps 6–7 CELLULAR; step 9 ORGANISM.

Omics: human testis scRNA-seq shows M1AP mRNA "in all stages of meiosis with strong mRNA abundance during early prophase I (leptotene, zygotene)" (PMID:40374915, re-analysis of Di Persio 2021). No proteomic or metabolomic data exist.

7. Anatomical structures affected

• Organ: testis (UBERON:0000473 ✓). Seminiferous tubule (UBERON:0001343 ✓). The reproductive system only. The disease is non-syndromic.
• Cells: primary spermatocytes (main defect); spermatids and sperm (reduced); Sertoli cells are spared but exposed in the mouse SCO branch.
• Subcellular: meiotic chromosome axes and synaptonemal complex (GO:0000795 ✓), recombination nodules, and the metaphase I spindle. In one human case, the sperm mitochondrial sheath (GO:0097226 ✓).
• Laterality: bilateral.

8. Temporal development

The defect is congenital (germline) but shows itself only after puberty, when spermatogenesis starts. Onset is insidious, since the condition has no symptoms beyond infertility. The course is stable and lifelong, with no remission. The mouse shows tubular degeneration over time. The mouse diet study compared 10–12-week and 26–28-week animals but reported its outcomes by diet rather than by age.

9. Inheritance and population

• Inheritance: autosomal recessive (HP:0000007, verify). Penetrance in males is complete for infertility, but expressivity is variable: azoospermia, cryptozoospermia, or rare TESE-retrievable sperm.
• Sex-limited: only males are affected. Female homozygotes are presumed fertile on mouse evidence (HP:0008210? not applicable; better to note sex-limited expression in description).
• Frequency: Wyrwoll 2020 found the c.676dup homozygote in 3 of 58 men with unexplained meiotic arrest. This is a frequent monogenic cause within that subgroup. c.676dup has a gnomAD v4.1 MAF of 0.003327, which suggests a European founder or recurrent allele. Treat any implied carrier frequency of about 1 in 150 as an inference that hasn't been published.
• Founder effects and consanguinity: recurrent European c.676dup; homozygous splice variants and the exon-2 deletion in consanguineous Turkish, Han Chinese and Pakistani families.
• Prevalence: not documented (prevalence_class: NOT_YET_DOCUMENTED). NOA affects about 1% of men (PMID:42324855 background), and SPGF48 is a small fraction of that.

10. Diagnostics

• Semen analysis: azoospermia or cryptozoospermia, confirmed on centrifuged pellet.
• Hormones: FSH high-normal or elevated; LH and testosterone normal. LOINC FSH serum code is 15067-2 (verify in cache before binding).
• Exclusion work-up: karyotype and AZF microdeletion testing are normal.
• Histology (TESE/biopsy): predominant meiotic (metaphase I) arrest, with aligned metaphase cells plus misaligned TUNEL-positive ones, and rare CREM+ round spermatids. Staining panel used: PAS/H&E, CREM, γH2AX, H3S10p, TUNEL. Research-grade spermatocyte spreads: SYCP1/3, MLH1, MSH5, TEX11.
• Genetic testing: an exome-based male infertility panel including M1AP.
• c.676dup is easily detected by WES.
• WGS or CNV analysis is needed for exon deletions (PMID:38073178).
• Splice variants need RNA or minigene confirmation (PMID:40374915).
• Be cautious calling missense variants pathogenic (PMID:37459509).
• Differential diagnosis:
• TEX11 (X-linked), SHOC1, SPO16: early arrest, no spermatids.
• Other meiotic NOA genes: SYCE1, MSH4, STAG3, MEIOB.
• Klinefelter syndrome and AZFa/b deletions: excluded by karyotype and Y-microdeletion testing.
• Sertoli-cell-only syndrome.
• Screening: none. Cascade counseling of brothers, and carrier testing of partners in consanguineous unions.

11. Outcome and prognosis

Life expectancy and general health are normal; infertility is the only morbidity. Sperm retrieval prognosis depends on the gene and is better than for most meiotic-arrest genes:

"the proportion of cases with successful sperm recovery is up to 50% for patients carrying M1AP LP/P mutations, as classified using the diagnostic method, which is the same likelihood observed in idiopathic NOA cases" — PMID:40896145 (Riera-Escamilla et al., Hum Reprod Open 2025)

"A positive TESE result was only seen in men with LoF variants in M1AP (N = 4)." — PMID:40374915

ICSI results in Rotte 2025: - 4 men attempted ICSI; 1 live birth: a healthy, euploid boy from ejaculated sperm after 3 cycles. - 3 men failed, including a total fertilization failure.

"Medically assisted reproduction resulted in the birth of a healthy child, offering the possibility of fatherhood to men with LoF variants in M1AP." — PMID:40374915

The child is an obligate heterozygous carrier.

12. Treatment

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

therapeutic_modality: SURGERY (TESE); BEHAVIORAL (counseling, diet). No pharmacotherapy, gene therapy or clinical trials were found. No registered NCT trials are specific to M1AP.

13. Prevention

There is no primary prevention for the affected man. Prevention options: - carrier testing of partners and relatives, especially in consanguineous families - PGT or prenatal testing is technically possible but rarely indicated for a condition limited to male fertility - tertiary: early genotype-informed counseling before TESE

14. Other species

M1ap is a conserved vertebrate gene; the mouse ortholog is M1ap (MGI, formerly D6Mm5e). No naturally occurring animal disease was found; I didn't search OMIA in depth.

15. Model organisms

"Although some germ cells arrested at the zygotene/pachytene stages, most cells advanced to metaphase I before arresting and entering apoptosis." — PMID:23269666

A possible HUMAN_MODEL_MISMATCH discussion: knockout mice keep producing some sperm (severe oligozoospermia), while most men are azoospermic. Also, mouse spermatogenesis is about ten times more efficient per gram of testis (PMID:40896145 discussion).

Notes for building the KB entry

• References now cached (untracked files in this worktree): PMID 32673564, 40374915, 42671480, 35341049, 23269666, 38073178, 42324855, 37459509, 36440627, 34498060, 36259570, 32017041. PMID 40896145 was already present. Commit the ones the entry cites and prune the rest.
• Not yet validated: HGNC:25183, and every ID marked "(verify)", including HP:0031039, the cryptozoospermia HP term, the GO crossover term and the NCIT TESE/ICSI terms. Run just validate-terms after binding them.
• Evidence source:
• Rotte 2025 combines human histology (HUMAN_CLINICAL) with co-IP/minigene work (IN_VITRO). Split those into separate evidence items.
• Gerlevik 2022 is COMPUTATIONAL.
• Arango 2013, Li 2023 (mouse parts), Houston 2026 and Ding 2023 are MODEL_ORGANISM.
• Not found, so the entry should say so rather than fill the slot: a ClinGen record, an Orphanet-specific code, prevalence, human QoL data, and any human environmental modifier.

Sources: PubMed records retrieved via Europe PMC and the local reference cache (DOIs: 10.1016/j.ajhg.2020.06.010; 10.1038/s44321-025-00244-0; 10.15252/embr.202255778; 10.1095/biolreprod.111.098673; 10.1111/cge.13712; 10.1111/andr.13570; 10.1111/andr.70291; 10.1073/pnas.2219925120; 10.7717/peerj.12947; 10.1093/humrep/deag130; 10.1093/hropen/hoaf049; 10.1093/humupd/dmab030); HGNC M1AP record; PMC7413853; UroToday summary of Wyrwoll 2020.

Reference Validation

Checked with linkml-reference-validator 0.3.0.

All extracted references resolved successfully.

Term Validation

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

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

• HP:0008210 (1 mention) - HP does not contain this term

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.