Spermatogenic failure 48

Mendelian MONDO:0030846 Pathograph 13 Show in embeddings browser hereditary disease

Spermatogenic failure 48 is autosomal recessive male infertility caused by biallelic loss-of-function variants in M1AP, which encodes meiosis 1 associated protein, a germ-cell protein of unknown biochemical activity that binds the three components of the ZZS recombination complex (SHOC1, TEX11 and SPO16). Without M1AP, spermatocytes recruit less TEX11 to the chromosome axes, form fewer recombination intermediates and fewer class I crossovers, and most arrest at metaphase I and die. The arrest is partial rather than complete: a minority of cells finish meiosis, so affected men have non-obstructive azoospermia or, less often, cryptozoospermia or severe oligozoospermia, with rare round and elongated spermatids on biopsy. That residual spermatogenesis sets M1AP apart from the core ZZS genes, whose loss gives a complete early meiotic arrest, and it is why testicular sperm extraction is sometimes successful and one affected man has fathered a healthy child by ICSI. Testicular volume and testosterone are normal and there is no phenotype outside the testis. A recurrent frameshift, c.676dup (p.Trp226LeufsTer4), accounts for most reported cases, and M1AP is among the more frequently diagnosed single-gene causes of non-obstructive azoospermia.

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1
Inheritance
5
Pathophys.
1
Histopath.
5
Phenotypes
13
Pathograph
1
Genes
2
Medical Actions
2
Models
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Affected men are homozygous or compound heterozygous for M1AP variants, often from consanguineous families, and the variants segregate with infertility. The recurrent c.676dup frameshift predominates; splice-site variants, a homozygous single-exon (exon 2) deletion, and a missense variant segregating in one consanguineous family are also reported.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:32673564 SUPPORT Human Clinical
"Collectively, these findings demonstrate that mutations in M1AP are a relatively frequent cause of autosomal recessive severe spermatogenic failure and male infertility with strong clinical validity."
The founding multi-cohort study establishes autosomal recessive inheritance.
PMID:32017041 SUPPORT Human Clinical
"His parents and fertile brother were heterozygous for the mutation."
Heterozygous carriers in the family are unaffected, consistent with recessive inheritance.
PMID:38073178 SUPPORT Human Clinical
"We identified a pathogenic homozygous 10kb deletion encompassing exon two of the gene Meiosis 1-associated protein (M1AP) segregating with infertility in family 9"
A homozygous structural allele segregating with infertility in a consanguineous family, extending the allele spectrum beyond sequence-level variants.
⚙

Pathophysiology

5
M1AP Loss of Function
Mechanism confidence: Established
Biallelic frameshift, splice and exon-deletion variants remove or truncate M1AP. The only molecular activity demonstrated for M1AP is binding to the ZZS proteins SHOC1, TEX11 and SPO16, shown by co-immunoprecipitation for the mouse and the human proteins. Truncated M1AP proteins modelled on patient alleles no longer bind TEX11, so the disease alleles abolish the one activity the protein is known to have.
M1AP hgnc:25183 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves M1AP (hgnc:25183). hgnc:25183 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Germline biallelic truncating, splice and exon-deletion variants; the recurrent allele is c.676dup (p.Trp226LeufsTer4).
binding to the ZZS proteins SHOC1, TEX11 and SPO16 GO:0005515 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased binding to the ZZS proteins SHOC1, TEX11 and SPO16, annotated with protein binding (GO:0005515). GO:0005515 is a molecular function from the Gene Ontology.
Downstream
Reduced TEX11 Recruitment to Recombination Sites Without its binding partner M1AP, less TEX11 is recruited to the chromosome axes, while SHOC1 localisation is unchanged.
Show evidence (5 references)
PMID:32673564 SUPPORT Human Clinical
"This variant most likely results in a truncated protein as shown in vitro by heterologous expression of mutant M1AP."
Shows that the recurrent c.676dup allele produces a truncated protein.
PMID:32017041 SUPPORT Human Clinical
"The splice variant led to a lack of M1AP protein in the patient's spermatozoa."
Demonstrates absent M1AP protein in a patient carrying a homozygous splice variant.
PMID:36440627 SUPPORT Model Organism
"M1AP interacts with the mammalian ZZS (an acronym for yeast proteins Zip2-Zip4-Spo16) complex components, SHOC1, TEX11, and SPO16."
Establishes the binding partners of M1AP in mouse, the basis of the molecular-function binding on this node.
+ 2 more references
Reduced TEX11 Recruitment to Recombination Sites
Mechanism confidence: Established
M1AP localises to the chromosome axes of spermatocytes in a SPO16-dependent manner and colocalises with TEX11. Its loss leaves SHOC1 in place but reduces the TEX11 recruited to recombination intermediates, by about two thirds in the one human spermatocyte spread analysed. The ZZS complex is not abolished, which distinguishes this lesion from loss of SHOC1, TEX11 or SPO16 themselves, where TEX11 foci are absent.
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.
Downstream
Reduced Recombination Intermediates and Class I Crossovers TEX11 recruited by the ZZS complex stabilises recombination intermediates destined to become class I crossovers, so less TEX11 means fewer of both.
Show evidence (2 references)
PMID:40374915 SUPPORT Human Clinical
"M1AP deficiency significantly reduced the recruitment of TEX11 to the axes"
Direct measurement of reduced TEX11 foci in spermatocyte spreads from a man with biallelic M1AP loss of function.
PMID:36440627 SUPPORT Model Organism
"M1AP localizes to chromosomal axes in a SPO16-dependent manner and colocalizes with TEX11."
Places M1AP at the chromosome axes alongside TEX11, where the recruitment defect occurs.
Reduced Recombination Intermediates and Class I Crossovers
Mechanism confidence: Established
Early recombination proceeds: double-strand breaks form and are repaired, and homologous chromosomes synapse fully. What is reduced is the number of MSH5-marked recombination intermediates and of MLH1-marked class I crossovers. In the one human case quantified, MSH5 foci fell to about half and MLH1 foci to about 35 against 48 per spermatocyte, although every homologue pair still carried at least one crossover in the cell examined.
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.
reciprocal meiotic recombination GO:0007131 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased reciprocal meiotic recombination (GO:0007131). GO:0007131 is a biological process from the Gene Ontology.
Animal models
M1ap patient splice-variant knock-in mouse Mouse recapitulates Reproduces the reduction in recombination intermediates and crossovers.
Downstream
Metaphase I Arrest and Spermatocyte Apoptosis Spermatocytes with too few crossovers cannot align their chromosomes properly at metaphase I and are eliminated.
Show evidence (3 references)
PMID:40374915 SUPPORT Human Clinical
"Abolished M1AP led to a reduced number of recombination intermediates and class I crossover."
Human spermatocyte evidence for the recombination defect.
PMID:40374915 SUPPORT Human Clinical
"Interestingly, the complete repair of DSBs post-zygotene and the clear restriction of γH2AX to the XY body was only observed in controls and in men with LoF variants in M1AP."
Shows that double-strand break repair is intact, which places the defect at the crossover-designation step rather than earlier.
PMID:36440627 SUPPORT Model Organism
"The mutation abolishes M1AP foci on the chromosome axes, resulting in decreased recombination intermediates and crossovers in male mouse models."
Mice carrying the patient splice mutation reproduce the reduction in recombination intermediates and crossovers.
Metaphase I Arrest and Spermatocyte Apoptosis
Mechanism confidence: Established
Most spermatocytes progress through prophase I and arrest at metaphase I with misaligned chromosomes, then undergo apoptosis. The arrest is partial: some metaphase cells align correctly, escape apoptosis, and complete meiosis, so round and occasionally elongated spermatids are found. This partial metaphase I arrest differs from the early zygotene to pachytene arrest caused by loss of SHOC1, TEX11 or SPO16.
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. spermatocyte apoptosis GO:0006915 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased spermatocyte apoptosis, annotated with apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology.
Animal models
M1ap-deficient mouse Mouse recapitulates Reproduces the predominant metaphase I arrest with apoptosis seen in affected men.
Downstream
Severe Spermatogenic Failure Loss of most spermatocytes at metaphase I leaves few or no post-meiotic germ cells.
Spermatocyte maturation arrest The metaphase I arrest is what the pathologist reports as spermatocyte maturation arrest.
Show evidence (4 references)
PMID:40374915 SUPPORT Human Clinical
"Men with LoF variants in M1AP exhibited a predominant metaphase I arrest with rare haploid round or even elongated spermatids."
Defines the human arrest stage and its incompleteness.
PMID:40374915 SUPPORT Human Clinical
"This, together with the presence of post-meiotic cells, classified the arrest in men with M1AP LoF variants as a partial metaphase I arrest"
Classifies the arrest as partial metaphase I arrest.
PMID:36440627 SUPPORT Human Clinical
"Here, we report a homozygous M1AP splicing mutation (c.1074 + 2T > C) in patients with severe oligozoospermia owing to meiotic metaphase I arrest."
Independent human report of metaphase I arrest with a different allele.
+ 1 more reference
Severe Spermatogenic Failure
Mechanism confidence: Established
Seminiferous tubules contain spermatogonia and spermatocytes but few haploid cells, and only some tubules contain round spermatids. Sperm output ranges from none to very few. The conformance to the meiotic prophase failure module is at its spermatogenic-outcome node only: the M1AP lesion itself acts after prophase recombination has largely succeeded, and is not a pachytene checkpoint arrest.
spermatid CL:0000018 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves spermatid (CL:0000018). CL:0000018 is a cell type from the Cell Ontology.
spermatogenesis GO:0007283 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased spermatogenesis (GO:0007283). GO:0007283 is a biological process from the Gene Ontology.
Downstream
Non-obstructive azoospermia
Cryptozoospermia
Severe oligozoospermia
Male infertility
Show evidence (2 references)
PMID:40374915 SUPPORT Human Clinical
"In all analysed men with LoF variants in M1AP (N = 7), CREM-positive spermatids were observed however in significantly lower numbers than controls with an average of 0.50 ± 0.43 cell/tubule."
Quantifies how few haploid cells remain in M1AP-deficient testes.
PMID:32673564 SUPPORT Human Clinical
"The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed."
Summarises the range of spermatogenic output across the founding cohort.
✶

Histopathology

1
Partial metaphase I arrest with rare round spermatids
The discriminating testicular histology is a predominant meiotic arrest at metaphase I in which some tubules still contain CREM-positive round spermatids and occasionally elongated spermatids. Metaphase cells with correctly aligned chromosomes are present alongside aberrant ones. Loss of SHOC1, TEX11 or SPO16 instead gives a complete early arrest without haploid cells.
Show evidence (2 references)
PMID:40374915 SUPPORT Human Clinical
"One key difference between the cases was that only men with LoF variants in M1AP exhibited TUNEL-negative metaphase cells, round, and even elongated spermatids."
Distinguishes the M1AP histology from that of the core ZZS genes.
PMID:40374915 SUPPORT Human Clinical
"Only men with LoF variants in M1AP had CREM-positive round spermatids."
Haploid round spermatids are present in M1AP deficiency but not in ZZS deficiency.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Spermatogenic failure 48 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

5
Genitourinary 2
Non-obstructive azoospermia 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:32673564 SUPPORT Human Clinical
"The common phenotype between all affected men was NOA, but occasionally spermatids and rarely a few spermatozoa in the semen were observed."
Non-obstructive azoospermia was common to all affected men in the founding cohorts.
PMID:42324855 SUPPORT Human Clinical
"Five variants in ZZS complex-associated genes TEX11 and M1AP were identified from five NOA patients."
Independent Chinese NOA cohort in which M1AP variants were found.
Male infertility HP:0003251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Male infertility (HP:0003251). HP:0003251 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32673564 SUPPORT Human Clinical
"Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu), segregated with infertility in five men from a consanguineous Turkish family."
Infertility segregating with biallelic M1AP variants in a large family.
PMID:40374915 SUPPORT Human Clinical
"Clinical features were similar between men, including normal testicular volumes, normal luteinising hormone, follicle-stimulating hormone in the high range, and normal testosterone"
Shows that the disease is confined to spermatogenesis, with normal endocrine testicular function.
Other 3
Cryptozoospermia HP:0030974 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptozoospermia (HP:0030974). HP:0030974 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40374915 SUPPORT Human Clinical
"Interestingly, all three cryptozoospermic men were homozygous for the recurrent LoF variant in M1AP (c.676dup)."
Documents cryptozoospermia in men with biallelic M1AP loss of function.
Severe oligozoospermia HP:0034818 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe oligozoospermia (HP:0034818). HP:0034818 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32017041 SUPPORT Human Clinical
"Here, we report a homozygous splice-site mutation in M1AP (meiosis 1 associated protein; NM_138804, c.1435-1G>A) observed in a patient with SO from a consanguineous Han Chinese family."
Severe oligozoospermia (SO) in a man with a homozygous M1AP splice variant.
PMID:36440627 SUPPORT Human Clinical
"Here, we report a homozygous M1AP splicing mutation (c.1074 + 2T > C) in patients with severe oligozoospermia owing to meiotic metaphase I arrest."
A second family with severe oligozoospermia and a different splice allele.
Spermatocyte maturation arrest 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:40374915 SUPPORT Human Clinical
"Our study shows that pathogenic genetic variants in the human meiosis-associated gene M1AP result mainly in meiotic arrest at metaphase I, leading to male infertility."
Meiotic arrest at metaphase I is the characteristic testicular finding.
PMID:32673564 SUPPORT Human Clinical
"To address this gap, 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, encoding meiosis 1 associated protein, in three unrelated men."
M1AP variants were identified in men selected for meiotic arrest on biopsy.
🧬

Genetic Associations

1
M1AP
Gene: M1AP hgnc:25183 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is M1AP (hgnc:25183). hgnc:25183 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:32673564 SUPPORT Human Clinical
"Next, we screened four large cohorts of infertile men and identified three additional individuals carrying homozygous c.676dup and three carrying combinations of this and other likely causal variants in M1AP."
Replication of biallelic M1AP variants across independent infertility cohorts.
PMID:41401169 SUPPORT Human Clinical
"Of the 270 positive cases identified through ES testing, mutations in 262 genes were detected, with AR, TEX11, FANCM, TDRD9, PNLDC1, M1AP, FBXO15, and DMRT1 being the most frequently observed."
A meta-analysis of exome sequencing in non-obstructive azoospermia places M1AP among the most frequently diagnosed genes.
PMID:37459509 SUPPORT Model Organism
"M1AP (Meiosis 1–associated protein) is a conserved protein of unknown biochemical function but when knocked out in mice causes male (but not female) infertility associated primarily with meiotic metaphase I arrest"
Records that M1AP has no characterised biochemical activity, and that the knockout phenotype is male-specific.
💊

Medical Actions

2
Testicular sperm extraction with intracytoplasmic sperm injection
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. NCIT:C185482
Platform: Other
Nothing restores spermatogenesis, but the arrest is incomplete, so sperm can sometimes be recovered from the ejaculate or by testicular sperm extraction and used for ICSI. One cohort reported a TESE success rate of 40%, and a multicentre study reported up to 50% for M1AP carriers. Of the four men in that cohort who attempted ICSI, one fathered a healthy, euploid child using ejaculated sperm; the other attempts failed at fertilisation or embryo development. Because few crossovers form, aneuploid sperm are a theoretical concern that has not been measured.
Show evidence (4 references)
PMID:40374915 SUPPORT Human Clinical
"The TESE success rate in our cohort was 40%, and we described one man who fathered a healthy, euploid child, thus showing that biallelic LoF variants in M1AP are compatible with fatherhood and, thereby, presenting a proof-of-principle."
Sperm retrieval succeeds in a minority of men and fatherhood by ICSI is possible.
PMID:40896145 SUPPORT Human Clinical
"the proportion of cases with successful sperm recovery is up to 50% for patients carrying M1AP LP/P mutations"
An independent multicentre study gives a sperm retrieval rate for M1AP carriers similar to the single-cohort figure, so a molecular diagnosis does not argue against attempting retrieval.
PMID:40374915 SUPPORT Human Clinical
"In an ICSI-TESE attempt by M2062 and his female partner, three oocytes were fertilised, but none developed to the blastocyst stage and a transfer was not possible."
Not every attempt succeeds; embryo development can fail after fertilisation.
+ 1 more reference
Genetic counselling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Counselling covers autosomal recessive recurrence risk for brothers, the possibility of sperm retrieval, and the open question of sperm aneuploidy.
Show evidence (2 references)
PMID:32017041 SUPPORT Human Clinical
"His parents and fertile brother were heterozygous for the mutation."
Heterozygous relatives are unaffected carriers, which is the basis for recessive recurrence-risk and carrier counselling in the family.
PMID:40374915 SUPPORT Human Clinical
"Segregation analysis showed the autosomal-recessive inheritance pattern of the frameshift variant c.676dup."
Family segregation confirming autosomal recessive transmission of the recurrent allele, which sets the recurrence risk for brothers.
🔬

Biochemical Markers

1
Serum follicle-stimulating hormone (Elevated (high range))
Show evidence (1 reference)
PMID:40374915 SUPPORT Human Clinical
"Clinical features were similar between men, including normal testicular volumes, normal luteinising hormone, follicle-stimulating hormone in the high range, and normal testosterone"
Reports FSH in the high range with normal LH and testosterone.
🔬

Diagnosis

4
Semen analysis
Repeated semen analysis shows azoospermia or cryptozoospermia. Azoospermia is only called once no sperm are found after centrifugation of the sample, which is also how cryptozoospermia, the presentation that still allows sperm to be used from the ejaculate, is distinguished from it.
Results: Azoospermia, or cryptozoospermia with sperm only in the centrifuged pellet.
Show evidence (2 references)
PMID:41401169 SUPPORT Human Clinical
"Among the various causes of male infertility, azoospermia is considered the most severe form, defined as the complete absence of spermatozoa in the ejaculate following centrifugation and subsequent microscopic evaluation of the specimen on two separate semen analyses"
Defines azoospermia by examination of the centrifuged ejaculate on two analyses.
PMID:40374915 SUPPORT Human Clinical
"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."
Semen analysis findings in the M1AP and ZZS-gene cohort; the three cryptozoospermic men all carried M1AP variants.
Karyotype and Y-chromosome microdeletion analysis
Both tests come before gene-level testing and exclude the commonest genetic causes of non-obstructive azoospermia. Men with M1AP-related disease have a normal 46,XY karyotype and no AZF deletion.
karyotyping NCIT:C16768 NCI Thesaurus (NCIT)
Results: Normal 46,XY karyotype with no AZF microdeletion.
Show evidence (2 references)
PMID:40896145 SUPPORT Human Clinical
"Current genetic diagnostic tests for NOA include karyotyping and Y chromosome azoospermia factor (AZF) microdeletion analysis."
Names the two standard genetic tests that precede gene-level testing.
PMID:42324855 SUPPORT Human Clinical
"WES were conducted in genomic DNA from all the patients with a normal karyotype (46, XY) and no Y chromosome microdeletions."
In the cohort where M1AP variants were found, exome sequencing was done only after karyotype and Y-microdeletion testing were normal.
Testicular biopsy
Histology from a biopsy or sperm-extraction procedure shows the partial metaphase I arrest with rare round spermatids described under histopathology. It points to a meiotic gene but does not name one.
testicular biopsy NCIT:C15189 NCI Thesaurus (NCIT)
Results: Predominant metaphase I arrest with rare round and elongated spermatids.
Show evidence (1 reference)
PMID:40374915 SUPPORT Human Clinical
"Testicular biopsies originating from testicular sperm retrieval (TESE) procedures were available in 20 of the selected cases and used for histological evaluation of spermatogenic differentiation."
Histology in this cohort came from TESE material, so the biopsy and the retrieval attempt are usually one procedure.
M1AP molecular genetic testing
Exome sequencing or an exome-based infertility gene panel finds the recurrent c.676dup frameshift and other sequence variants. A homozygous deletion of exon 2 found in a Pakistani family was missed by exome sequencing and detected only by genome sequencing with copy-number calling, so a negative exome does not exclude M1AP disease.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic M1AP variants.
Show evidence (2 references)
PMID:32673564 SUPPORT Human Clinical
"To address this gap, 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"
Exome sequencing detects the recurrent frameshift allele.
PMID:38073178 SUPPORT Human Clinical
"On the positive side, the identification of the 10kb M1AP deletion, affecting a single exon, was a direct result of the WGS approach, as this causal mutation would have been missed with standard WES."
The exon-2 deletion needs genome sequencing or copy-number analysis; exome sequencing alone would miss it.
⚖️

Clinical Burden

Moderate
The burden is reproductive and psychosocial. There is no systemic disease and no effect on virilisation or testosterone. The cost is the prospect of biological parenthood without assisted reproduction, with a minority of men able to father children through sperm retrieval and ICSI.
🐁

Animal Models

2
M1ap-deficient mouse
The first M1ap knockout. Males are infertile or severely oligozoospermic with a predominant metaphase I arrest; females have normal ovaries.
Species
Mouse
Genotype
M1ap null
Publication
PMID:23269666
Pathograph links
Metaphase I Arrest and Spermatocyte Apoptosis recapitulates fidelity: high observes: cellular Reproduces the predominant metaphase I arrest with apoptosis seen in affected men.
Limitations: The mouse also shows progressive tubular degeneration to a Sertoli cell-only picture, which has not been described as typical of the human disease.
Show evidence (1 reference)
PMID:23269666 SUPPORT Model Organism
"Although some germ cells arrested at the zygotene/pachytene stages, most cells advanced to metaphase I before arresting and entering apoptosis."
Shows the model reproduces the metaphase I arrest node.
Show evidence (1 reference)
PMID:23269666 SUPPORT Model Organism
"Whereas females had histologically normal ovaries, males exhibited reduced testicular size and a myriad of tubular defects, which led to severe oligozoospermia and infertility."
The knockout phenotype is male-specific infertility.
M1ap patient splice-variant knock-in mouse
Mice carrying the splice mutation found in patients, used to establish M1AP's interaction with the ZZS complex and its effect on TEX11 recruitment and crossover formation.
Species
Mouse
Genotype
M1ap knock-in of the human c.1074+2T>C splice mutation, homozygous
Publication
PMID:36440627
Pathograph links
Reduced Recombination Intermediates and Class I Crossovers recapitulates fidelity: high observes: cellular Reproduces the reduction in recombination intermediates and crossovers.
Limitations: The mechanism is established in mouse spermatocytes; the human evidence for the same step comes from a spermatocyte spread of a single man.
Show evidence (1 reference)
PMID:36440627 SUPPORT Model Organism
"The mutation abolishes M1AP foci on the chromosome axes, resulting in decreased recombination intermediates and crossovers in male mouse models."
Shows the model reproduces the recombination node.
Show evidence (1 reference)
PMID:36440627 SUPPORT Model Organism
"M1AP shows cytoplasmic localization in fetal oocytes and is dispensable for fertility and crossover formation in female mice."
Records the sex difference: the model affects male but not female fertility.
{ }

Source YAML

click to show 
name: Spermatogenic failure 48
creation_date: "2026-10-15T00:00:00Z"
description: >-
  Spermatogenic failure 48 is autosomal recessive male infertility caused by
  biallelic loss-of-function variants in M1AP, which encodes meiosis 1
  associated protein, a germ-cell protein of unknown biochemical activity that
  binds the three components of the ZZS recombination complex (SHOC1, TEX11 and
  SPO16). Without M1AP, spermatocytes recruit less TEX11 to the chromosome axes,
  form fewer recombination intermediates and fewer class I crossovers, and most
  arrest at metaphase I and die. The arrest is partial rather than complete: a
  minority of cells finish meiosis, so affected men have non-obstructive
  azoospermia or, less often, cryptozoospermia or severe oligozoospermia, with
  rare round and elongated spermatids on biopsy. That residual spermatogenesis
  sets M1AP apart from the core ZZS genes, whose loss gives a complete early
  meiotic arrest, and it is why testicular sperm extraction is sometimes
  successful and one affected man has fathered a healthy child by ICSI.
  Testicular volume and testosterone are normal and there is no phenotype
  outside the testis. A recurrent frameshift, c.676dup (p.Trp226LeufsTer4),
  accounts for most reported cases, and M1AP is among the more frequently
  diagnosed single-gene causes of non-obstructive azoospermia.
notes: >-
  No GeneReviews chapter covers M1AP or spermatogenic failure 48. Female
  meiosis is not addressed by this entry: M1ap-deficient female mice are
  fertile, and no biallelic M1AP variants have been reported in women, so a
  female phenotype is neither curated nor excluded.
category: Mendelian
parents:
- hereditary disease
synonyms:
- SPGF48
- M1AP-related spermatogenic failure
- M1AP-related male infertility
disease_term:
  preferred_term: Spermatogenic failure 48
  term:
    id: MONDO:0030846
    label: spermatogenic failure 48
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected men are homozygous or compound heterozygous for M1AP variants,
    often from consanguineous families, and the variants segregate with
    infertility. The recurrent c.676dup frameshift predominates; splice-site
    variants, a homozygous single-exon (exon 2) deletion, and a missense variant
    segregating in one consanguineous family are also reported.
  evidence:
  - reference: PMID:32673564
    reference_title: "Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Collectively, these findings demonstrate that mutations in M1AP are a
      relatively frequent cause of autosomal recessive severe spermatogenic
      failure and male infertility with strong clinical validity.
    explanation: >-
      The founding multi-cohort study establishes autosomal recessive
      inheritance.
  - reference: PMID:32017041
    reference_title: "An M1AP homozygous splice-site mutation associated with severe oligozoospermia in a consanguineous family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His parents and fertile brother were heterozygous for the mutation.
    explanation: >-
      Heterozygous carriers in the family are unaffected, consistent with
      recessive inheritance.
  - reference: PMID:38073178
    reference_title: "Genome sequencing of Pakistani families with male infertility identifies deleterious genotypes in SPAG6, CCDC9, TKTL1, TUBA3C, and M1AP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a pathogenic homozygous 10kb deletion encompassing exon two
      of the gene Meiosis 1-associated protein (M1AP) segregating with
      infertility in family 9
    explanation: >-
      A homozygous structural allele segregating with infertility in a
      consanguineous family, extending the allele spectrum beyond
      sequence-level variants.
pathophysiology:
- name: M1AP Loss of Function
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    Biallelic frameshift, splice and exon-deletion variants remove or truncate
    M1AP. The only molecular activity demonstrated for M1AP is binding to the
    ZZS proteins SHOC1, TEX11 and SPO16, shown by co-immunoprecipitation for
    the mouse and the human proteins. Truncated M1AP proteins modelled on
    patient alleles no longer bind TEX11, so the disease alleles abolish the
    one activity the protein is known to have.
  notes: >-
    The molecular function is bound to GO:0005515 protein binding because that
    is the activity the literature demonstrates and nothing more specific is
    supported. On 2026-10-15 QuickGO returned only GO:0005515 protein binding
    and GO:0042802 identical protein binding as molecular-function annotations
    for UniProtKB:Q8TC57, and PMID:37459509 describes M1AP as a conserved
    protein of unknown biochemical function. GO:0044877 protein-containing
    complex binding was considered and not used: PMID:40374915 shows each ZZS
    protein binding M1AP independently in pairwise co-expression, not binding to
    an assembled complex. An adaptor-activity term was also not used, since
    reduced TEX11 recruitment shows M1AP is needed for recruitment but not that
    it bridges TEX11 to another molecule. Unlike interaction-screen hits, these
    bindings are targeted experiments, and their loss is the disease mechanism.
  genes:
  - preferred_term: M1AP
    term:
      id: hgnc:25183
      label: M1AP
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    description: >-
      Germline biallelic truncating, splice and exon-deletion variants; the
      recurrent allele is c.676dup (p.Trp226LeufsTer4).
  molecular_functions:
  - preferred_term: binding to the ZZS proteins SHOC1, TEX11 and SPO16
    modifier: DECREASED
    term:
      id: GO:0005515
      label: protein binding
  evidence:
  - reference: PMID:32673564
    reference_title: "Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This variant most likely results in a truncated protein as shown in vitro
      by heterologous expression of mutant M1AP.
    explanation: >-
      Shows that the recurrent c.676dup allele produces a truncated protein.
  - reference: PMID:32017041
    reference_title: "An M1AP homozygous splice-site mutation associated with severe oligozoospermia in a consanguineous family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The splice variant led to a lack of M1AP protein in the patient's
      spermatozoa.
    explanation: >-
      Demonstrates absent M1AP protein in a patient carrying a homozygous splice
      variant.
  - reference: PMID:36440627
    reference_title: "M1AP interacts with the mammalian ZZS complex and promotes male meiotic recombination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      M1AP interacts with the mammalian ZZS (an acronym for yeast proteins
      Zip2-Zip4-Spo16) complex components, SHOC1, TEX11, and SPO16.
    explanation: >-
      Establishes the binding partners of M1AP in mouse, the basis of the
      molecular-function binding on this node.
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A subsequent Western blot showed that human M1AP binds specifically to
      each of the three human ZZS complex components
    explanation: >-
      Confirms the same binding for the human proteins by co-immunoprecipitation
      in transfected HEK293T cells.
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We demonstrated that the deletion of the last 97 amino acids of M1AP (~
      18% of the protein) is already sufficient to completely abolish the
      binding of M1AP and TEX11 implying that for the protein-protein
      interaction the full-length protein of M1AP is mandatory.
    explanation: >-
      Shows that truncation abolishes TEX11 binding, linking the loss-of-function
      alleles to loss of the binding activity.
  downstream:
  - target: Reduced TEX11 Recruitment to Recombination Sites
    causal_link_type: DIRECT
    description: >-
      Without its binding partner M1AP, less TEX11 is recruited to the
      chromosome axes, while SHOC1 localisation is unchanged.
    evidence:
    - reference: PMID:36440627
      reference_title: "M1AP interacts with the mammalian ZZS complex and promotes male meiotic recombination."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Ablation of M1AP does not alter SHOC1 localization but reduces the
        recruitment of TEX11 to recombination intermediates.
      explanation: >-
        Mouse evidence that M1AP loss reduces TEX11 recruitment specifically.
- name: Reduced TEX11 Recruitment to Recombination Sites
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    M1AP localises to the chromosome axes of spermatocytes in a SPO16-dependent
    manner and colocalises with TEX11. Its loss leaves SHOC1 in place but
    reduces the TEX11 recruited to recombination intermediates, by about two
    thirds in the one human spermatocyte spread analysed. The ZZS complex is not
    abolished, which distinguishes this lesion from loss of SHOC1, TEX11 or
    SPO16 themselves, where TEX11 foci are absent.
  cell_types:
  - preferred_term: primary spermatocyte
    term:
      id: CL:0000656
      label: primary spermatocyte
  evidence:
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      M1AP deficiency significantly reduced the recruitment of TEX11 to the axes
    explanation: >-
      Direct measurement of reduced TEX11 foci in spermatocyte spreads from a
      man with biallelic M1AP loss of function.
  - reference: PMID:36440627
    reference_title: "M1AP interacts with the mammalian ZZS complex and promotes male meiotic recombination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      M1AP localizes to chromosomal axes in a SPO16-dependent manner and
      colocalizes with TEX11.
    explanation: >-
      Places M1AP at the chromosome axes alongside TEX11, where the recruitment
      defect occurs.
  downstream:
  - target: Reduced Recombination Intermediates and Class I Crossovers
    causal_link_type: DIRECT
    description: >-
      TEX11 recruited by the ZZS complex stabilises recombination intermediates
      destined to become class I crossovers, so less TEX11 means fewer of both.
    evidence:
    - reference: PMID:40374915
      reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We propose that M1AP is functionally linked to the regulation of SHOC1,
        TEX11, and SPO16, thereby affecting recombination stability,
        processing, and class I crossover resolution.
      explanation: >-
        The authors' model linking M1AP's effect on the ZZS proteins to
        recombination and crossover outcome; stated as a proposal.
- name: Reduced Recombination Intermediates and Class I Crossovers
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    Early recombination proceeds: double-strand breaks form and are repaired,
    and homologous chromosomes synapse fully. What is reduced is the number of
    MSH5-marked recombination intermediates and of MLH1-marked class I
    crossovers. In the one human case quantified, MSH5 foci fell to about half
    and MLH1 foci to about 35 against 48 per spermatocyte, although every
    homologue pair still carried at least one crossover in the cell examined.
  cell_types:
  - preferred_term: primary spermatocyte
    term:
      id: CL:0000656
      label: primary spermatocyte
  biological_processes:
  - preferred_term: reciprocal meiotic recombination
    modifier: DECREASED
    term:
      id: GO:0007131
      label: reciprocal meiotic recombination
  evidence:
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Abolished M1AP led to a reduced number of recombination intermediates and
      class I crossover.
    explanation: >-
      Human spermatocyte evidence for the recombination defect.
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, the complete repair of DSBs post-zygotene and the clear
      restriction of γH2AX to the XY body was only observed in controls and in
      men with LoF variants in M1AP.
    explanation: >-
      Shows that double-strand break repair is intact, which places the defect
      at the crossover-designation step rather than earlier.
  - reference: PMID:36440627
    reference_title: "M1AP interacts with the mammalian ZZS complex and promotes male meiotic recombination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The mutation abolishes M1AP foci on the chromosome axes, resulting in
      decreased recombination intermediates and crossovers in male mouse models.
    explanation: >-
      Mice carrying the patient splice mutation reproduce the reduction in
      recombination intermediates and crossovers.
  downstream:
  - target: Metaphase I Arrest and Spermatocyte Apoptosis
    causal_link_type: DIRECT
    description: >-
      Spermatocytes with too few crossovers cannot align their chromosomes
      properly at metaphase I and are eliminated.
    evidence:
    - reference: PMID:40374915
      reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In contrast, LoF variants in M1AP led to a metaphase I arrest, where
        early meiotic recombination was completed while the total number of
        recombination intermediates and the final recombination products, the
        meiotic class I crossover events, was reduced.
      explanation: >-
        Connects the reduced crossover number to the metaphase I arrest in the
        same men.
    - reference: PMID:23269666
      reference_title: "Meiosis I arrest abnormalities lead to severe oligozoospermia in meiosis 1 arresting protein (M1ap)-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        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.
      explanation: >-
        In the M1ap knockout mouse, failed crossover formation is what prevents
        metaphase I chromosome alignment.
- name: Metaphase I Arrest and Spermatocyte Apoptosis
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    Most spermatocytes progress through prophase I and arrest at metaphase I
    with misaligned chromosomes, then undergo apoptosis. The arrest is partial:
    some metaphase cells align correctly, escape apoptosis, and complete
    meiosis, so round and occasionally elongated spermatids are found. This
    partial metaphase I arrest differs from the early zygotene to pachytene
    arrest caused by loss of SHOC1, TEX11 or SPO16.
  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
  - preferred_term: spermatocyte apoptosis
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Men with LoF variants in M1AP exhibited a predominant metaphase I arrest
      with rare haploid round or even elongated spermatids.
    explanation: >-
      Defines the human arrest stage and its incompleteness.
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This, together with the presence of post-meiotic cells, classified the
      arrest in men with M1AP LoF variants as a partial metaphase I arrest
    explanation: >-
      Classifies the arrest as partial metaphase I arrest.
  - reference: PMID:36440627
    reference_title: "M1AP interacts with the mammalian ZZS complex and promotes male meiotic recombination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a homozygous M1AP splicing mutation (c.1074 + 2T > C) in
      patients with severe oligozoospermia owing to meiotic metaphase I arrest.
    explanation: >-
      Independent human report of metaphase I arrest with a different allele.
  - reference: PMID:23269666
    reference_title: "Meiosis I arrest abnormalities lead to severe oligozoospermia in meiosis 1 arresting protein (M1ap)-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Although some germ cells arrested at the zygotene/pachytene stages, most
      cells advanced to metaphase I before arresting and entering apoptosis.
    explanation: >-
      The knockout mouse shows the same predominant metaphase I arrest followed
      by apoptosis.
  downstream:
  - target: Severe Spermatogenic Failure
    causal_link_type: DIRECT
    description: >-
      Loss of most spermatocytes at metaphase I leaves few or no post-meiotic
      germ cells.
  - target: Spermatocyte maturation arrest
    causal_link_type: DIRECT
    description: >-
      The metaphase I arrest is what the pathologist reports as spermatocyte
      maturation arrest.
- name: Severe Spermatogenic Failure
  biological_scale: TISSUE
  role: central_effector
  mechanism_confidence: ESTABLISHED
  conforms_to: "meiotic_prophase_failure#Spermatogenic Arrest and Non-Obstructive Azoospermia"
  description: >-
    Seminiferous tubules contain spermatogonia and spermatocytes but few
    haploid cells, and only some tubules contain round spermatids. Sperm output
    ranges from none to very few. The conformance to the meiotic prophase
    failure module is at its spermatogenic-outcome node only: the M1AP lesion
    itself acts after prophase recombination has largely succeeded, and is not
    a pachytene checkpoint arrest.
  cell_types:
  - preferred_term: spermatid
    term:
      id: CL:0000018
      label: spermatid
  biological_processes:
  - preferred_term: spermatogenesis
    modifier: DECREASED
    term:
      id: GO:0007283
      label: spermatogenesis
  evidence:
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all analysed men with LoF variants in M1AP (N = 7), CREM-positive
      spermatids were observed however in significantly lower numbers than
      controls with an average of 0.50 ± 0.43 cell/tubule.
    explanation: >-
      Quantifies how few haploid cells remain in M1AP-deficient testes.
  - reference: PMID:32673564
    reference_title: "Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The common phenotype between all affected men was NOA, but occasionally
      spermatids and rarely a few spermatozoa in the semen were observed.
    explanation: >-
      Summarises the range of spermatogenic output across the founding cohort.
  downstream:
  - target: Non-obstructive azoospermia
    causal_link_type: DIRECT
  - target: Cryptozoospermia
    causal_link_type: DIRECT
  - target: Severe oligozoospermia
    causal_link_type: DIRECT
  - target: Male infertility
    causal_link_type: DIRECT
phenotypes:
- category: Reproductive
  name: Non-obstructive azoospermia
  description: >-
    Absence of sperm in the ejaculate from a testicular cause. The commonest
    presentation, seen in most reported men.
  phenotype_term:
    preferred_term: Non-obstructive azoospermia
    term:
      id: HP:0011961
      label: Non-obstructive azoospermia
  evidence:
  - reference: PMID:32673564
    reference_title: "Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The common phenotype between all affected men was NOA, but occasionally
      spermatids and rarely a few spermatozoa in the semen were observed.
    explanation: >-
      Non-obstructive azoospermia was common to all affected men in the
      founding cohorts.
  - reference: PMID:42324855
    reference_title: "Variants in ZZS Complex-Associated Genes TEX11 and M1AP Are Responsible for Male Infertility and Nonobstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five variants in ZZS complex-associated genes TEX11 and M1AP were
      identified from five NOA patients.
    explanation: >-
      Independent Chinese NOA cohort in which M1AP variants were found.
- category: Reproductive
  name: Cryptozoospermia
  description: >-
    A few sperm found only after centrifugation of the ejaculate. In one
    cohort, all three cryptozoospermic men carried the recurrent c.676dup
    allele homozygously.
  phenotype_term:
    preferred_term: Cryptozoospermia
    term:
      id: HP:0030974
      label: Cryptozoospermia
  evidence:
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, all three cryptozoospermic men were homozygous for the
      recurrent LoF variant in M1AP (c.676dup).
    explanation: >-
      Documents cryptozoospermia in men with biallelic M1AP loss of function.
- category: Reproductive
  name: Severe oligozoospermia
  description: >-
    A very low but detectable sperm count, reported in Chinese families with
    homozygous M1AP splice variants.
  phenotype_term:
    preferred_term: Severe oligozoospermia
    term:
      id: HP:0034818
      label: Severe oligozoospermia
  evidence:
  - reference: PMID:32017041
    reference_title: "An M1AP homozygous splice-site mutation associated with severe oligozoospermia in a consanguineous family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a homozygous splice-site mutation in M1AP (meiosis 1
      associated protein; NM_138804, c.1435-1G>A) observed in a patient with SO
      from a consanguineous Han Chinese family.
    explanation: >-
      Severe oligozoospermia (SO) in a man with a homozygous M1AP splice variant.
  - reference: PMID:36440627
    reference_title: "M1AP interacts with the mammalian ZZS complex and promotes male meiotic recombination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a homozygous M1AP splicing mutation (c.1074 + 2T > C) in
      patients with severe oligozoospermia owing to meiotic metaphase I arrest.
    explanation: >-
      A second family with severe oligozoospermia and a different splice
      allele.
- category: Reproductive
  name: Spermatocyte maturation arrest
  description: >-
    Testicular biopsy shows spermatogenesis arrested at the spermatocyte
    stage, specifically a partial metaphase I arrest with rare round
    spermatids.
  phenotype_term:
    preferred_term: Spermatocyte maturation arrest
    term:
      id: HP:0031039
      label: Spermatocyte maturation arrest
  evidence:
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study shows that pathogenic genetic variants in the human
      meiosis-associated gene M1AP result mainly in meiotic arrest at metaphase
      I, leading to male infertility.
    explanation: >-
      Meiotic arrest at metaphase I is the characteristic testicular finding.
  - reference: PMID:32673564
    reference_title: "Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To address this gap, 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, encoding meiosis 1
      associated protein, in three unrelated men.
    explanation: >-
      M1AP variants were identified in men selected for meiotic arrest on
      biopsy.
- category: Reproductive
  name: Male infertility
  description: >-
    Infertility is the presenting complaint and the whole clinical burden.
    Testicular volume, luteinising hormone and testosterone are normal, and
    follicle-stimulating hormone is in the high range.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:32673564
    reference_title: "Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, a homozygous missense variant, c.1166C>T (p.Pro389Leu),
      segregated with infertility in five men from a consanguineous Turkish
      family.
    explanation: >-
      Infertility segregating with biallelic M1AP variants in a large family.
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features were similar between men, including normal testicular
      volumes, normal luteinising hormone, follicle-stimulating hormone in the
      high range, and normal testosterone
    explanation: >-
      Shows that the disease is confined to spermatogenesis, with normal
      endocrine testicular function.
biochemical:
- name: Serum follicle-stimulating hormone
  presence: Elevated (high range)
  biomarker_term:
    preferred_term: follicle-stimulating hormone
    term:
      id: NCIT:C181076
      label: Follicle-Stimulating Hormone
  loinc_term:
    id: LOINC:15067-2
    label: Follitropin [Units/volume] in Serum or Plasma
  notes: >-
    FSH is in the high range while luteinising hormone and testosterone are
    normal, the expected pattern when spermatogenesis fails but Leydig cell
    function is intact. The source reports this for its whole cohort of men
    with M1AP or ZZS-gene loss of function, not for M1AP carriers separately.
  evidence:
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features were similar between men, including normal testicular
      volumes, normal luteinising hormone, follicle-stimulating hormone in the
      high range, and normal testosterone
    explanation: >-
      Reports FSH in the high range with normal LH and testosterone.
genetic:
- name: M1AP
  notes: >-
    M1AP (meiosis 1 associated protein; previous symbol C2orf65) lies on 2p13.
    It is among the more frequently identified single-gene causes in exome
    studies of non-obstructive azoospermia. The recurrent c.676dup frameshift
    accounts for most reported alleles. Missense variants need caution: a
    p.Gly317Arg variant reported in a man with meiotic arrest did not impair
    fertility when modelled in mice.
  gene_term:
    preferred_term: M1AP
    term:
      id: hgnc:25183
      label: M1AP
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:32673564
    reference_title: "Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Next, we screened four large cohorts of infertile men and identified three
      additional individuals carrying homozygous c.676dup and three carrying
      combinations of this and other likely causal variants in M1AP.
    explanation: >-
      Replication of biallelic M1AP variants across independent infertility
      cohorts.
  - reference: PMID:41401169
    reference_title: "Diagnostic yield of exome sequencing in nonobstructive azoospermia (NOA): A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 270 positive cases identified through ES testing, mutations in 262
      genes were detected, with AR, TEX11, FANCM, TDRD9, PNLDC1, M1AP, FBXO15,
      and DMRT1 being the most frequently observed.
    explanation: >-
      A meta-analysis of exome sequencing in non-obstructive azoospermia places
      M1AP among the most frequently diagnosed genes.
  - reference: PMID:37459509
    reference_title: "In vivo versus in silico assessment of potentially pathogenic missense variants in human reproductive genes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      M1AP (Meiosis 1–associated protein) is a conserved protein of unknown
      biochemical function but when knocked out in mice causes male (but not
      female) infertility associated primarily with meiotic metaphase I arrest
    explanation: >-
      Records that M1AP has no characterised biochemical activity, and that
      the knockout phenotype is male-specific.
histopathology:
- name: Partial metaphase I arrest with rare round spermatids
  description: >-
    The discriminating testicular histology is a predominant meiotic arrest at
    metaphase I in which some tubules still contain CREM-positive round
    spermatids and occasionally elongated spermatids. Metaphase cells with
    correctly aligned chromosomes are present alongside aberrant ones. Loss of
    SHOC1, TEX11 or SPO16 instead gives a complete early arrest without haploid
    cells.
  evidence:
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One key difference between the cases was that only men with LoF variants
      in M1AP exhibited TUNEL-negative metaphase cells, round, and even
      elongated spermatids.
    explanation: >-
      Distinguishes the M1AP histology from that of the core ZZS genes.
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only men with LoF variants in M1AP had CREM-positive round spermatids.
    explanation: >-
      Haploid round spermatids are present in M1AP deficiency but not in ZZS
      deficiency.
diagnosis:
- name: Semen analysis
  description: >-
    Repeated semen analysis shows azoospermia or cryptozoospermia. Azoospermia
    is only called once no sperm are found after centrifugation of the sample,
    which is also how cryptozoospermia, the presentation that still allows
    sperm to be used from the ejaculate, is distinguished from it.
  results: Azoospermia, or cryptozoospermia with sperm only in the centrifuged pellet.
  evidence:
  - reference: PMID:41401169
    reference_title: "Diagnostic yield of exome sequencing in nonobstructive azoospermia (NOA): A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the various causes of male infertility, azoospermia is considered
      the most severe form, defined as the complete absence of spermatozoa in
      the ejaculate following centrifugation and subsequent microscopic
      evaluation of the specimen on two separate semen analyses
    explanation: >-
      Defines azoospermia by examination of the centrifuged ejaculate on two
      analyses.
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Semen analysis findings in the M1AP and ZZS-gene cohort; the three
      cryptozoospermic men all carried M1AP variants.
- name: Karyotype and Y-chromosome microdeletion analysis
  description: >-
    Both tests come before gene-level testing and exclude the commonest
    genetic causes of non-obstructive azoospermia. Men with M1AP-related
    disease have a normal 46,XY karyotype and no AZF deletion.
  diagnosis_term:
    preferred_term: karyotyping
    term:
      id: NCIT:C16768
      label: Karyotyping
  results: Normal 46,XY karyotype with no AZF microdeletion.
  evidence:
  - reference: PMID:40896145
    reference_title: "Genetic determinants of testicular sperm extraction outcomes: insights from a large multicentre study of men with non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Current genetic diagnostic tests for NOA include karyotyping and Y
      chromosome azoospermia factor (AZF) microdeletion analysis.
    explanation: >-
      Names the two standard genetic tests that precede gene-level testing.
  - reference: PMID:42324855
    reference_title: "Variants in ZZS Complex-Associated Genes TEX11 and M1AP Are Responsible for Male Infertility and Nonobstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES were conducted in genomic DNA from all the patients with a normal
      karyotype (46, XY) and no Y chromosome microdeletions.
    explanation: >-
      In the cohort where M1AP variants were found, exome sequencing was done
      only after karyotype and Y-microdeletion testing were normal.
- name: Testicular biopsy
  description: >-
    Histology from a biopsy or sperm-extraction procedure shows the partial
    metaphase I arrest with rare round spermatids described under
    histopathology. It points to a meiotic gene but does not name one.
  diagnosis_term:
    preferred_term: testicular biopsy
    term:
      id: NCIT:C15189
      label: Biopsy Procedure
  results: Predominant metaphase I arrest with rare round and elongated spermatids.
  evidence:
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Testicular biopsies originating from testicular sperm retrieval (TESE)
      procedures were available in 20 of the selected cases and used for
      histological evaluation of spermatogenic differentiation.
    explanation: >-
      Histology in this cohort came from TESE material, so the biopsy and the
      retrieval attempt are usually one procedure.
- name: M1AP molecular genetic testing
  description: >-
    Exome sequencing or an exome-based infertility gene panel finds the
    recurrent c.676dup frameshift and other sequence variants. A homozygous
    deletion of exon 2 found in a Pakistani family was missed by exome
    sequencing and detected only by genome sequencing with copy-number
    calling, so a negative exome does not exclude M1AP disease.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: Biallelic pathogenic M1AP variants.
  evidence:
  - reference: PMID:32673564
    reference_title: "Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To address this gap, 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
    explanation: >-
      Exome sequencing detects the recurrent frameshift allele.
  - reference: PMID:38073178
    reference_title: "Genome sequencing of Pakistani families with male infertility identifies deleterious genotypes in SPAG6, CCDC9, TKTL1, TUBA3C, and M1AP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On the positive side, the identification of the 10kb M1AP deletion,
      affecting a single exon, was a direct result of the WGS approach, as this
      causal mutation would have been missed with standard WES.
    explanation: >-
      The exon-2 deletion needs genome sequencing or copy-number analysis;
      exome sequencing alone would miss it.
animal_models:
- name: M1ap-deficient mouse
  species: Mouse
  genotype: M1ap null
  publication: PMID:23269666
  description: >-
    The first M1ap knockout. Males are infertile or severely oligozoospermic
    with a predominant metaphase I arrest; females have normal ovaries.
  modeled_mechanisms:
  - target: Metaphase I Arrest and Spermatocyte Apoptosis
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Reproduces the predominant metaphase I arrest with apoptosis seen in
      affected men.
    limitations: >-
      The mouse also shows progressive tubular degeneration to a Sertoli
      cell-only picture, which has not been described as typical of the human
      disease.
    evidence:
    - reference: PMID:23269666
      reference_title: "Meiosis I arrest abnormalities lead to severe oligozoospermia in meiosis 1 arresting protein (M1ap)-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Although some germ cells arrested at the zygotene/pachytene stages, most
        cells advanced to metaphase I before arresting and entering apoptosis.
      explanation: >-
        Shows the model reproduces the metaphase I arrest node.
  evidence:
  - reference: PMID:23269666
    reference_title: "Meiosis I arrest abnormalities lead to severe oligozoospermia in meiosis 1 arresting protein (M1ap)-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Whereas females had histologically normal ovaries, males exhibited
      reduced testicular size and a myriad of tubular defects, which led to
      severe oligozoospermia and infertility.
    explanation: >-
      The knockout phenotype is male-specific infertility.
- name: M1ap patient splice-variant knock-in mouse
  species: Mouse
  genotype: M1ap knock-in of the human c.1074+2T>C splice mutation, homozygous
  publication: PMID:36440627
  description: >-
    Mice carrying the splice mutation found in patients, used to establish
    M1AP's interaction with the ZZS complex and its effect on TEX11
    recruitment and crossover formation.
  modeled_mechanisms:
  - target: Reduced Recombination Intermediates and Class I Crossovers
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      Reproduces the reduction in recombination intermediates and crossovers.
    limitations: >-
      The mechanism is established in mouse spermatocytes; the human evidence
      for the same step comes from a spermatocyte spread of a single man.
    evidence:
    - reference: PMID:36440627
      reference_title: "M1AP interacts with the mammalian ZZS complex and promotes male meiotic recombination."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The mutation abolishes M1AP foci on the chromosome axes, resulting in
        decreased recombination intermediates and crossovers in male mouse
        models.
      explanation: >-
        Shows the model reproduces the recombination node.
  evidence:
  - reference: PMID:36440627
    reference_title: "M1AP interacts with the mammalian ZZS complex and promotes male meiotic recombination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      M1AP shows cytoplasmic localization in fetal oocytes and is dispensable
      for fertility and crossover formation in female mice.
    explanation: >-
      Records the sex difference: the model affects male but not female
      fertility.
treatments:
- name: Testicular sperm extraction with intracytoplasmic sperm injection
  description: >-
    Nothing restores spermatogenesis, but the arrest is incomplete, so sperm
    can sometimes be recovered from the ejaculate or by testicular sperm
    extraction and used for ICSI. One cohort reported a TESE success rate of
    40%, and a multicentre study reported up to 50% for M1AP carriers. Of the
    four men in that cohort who attempted ICSI, one fathered a healthy,
    euploid child using ejaculated sperm; the other attempts failed at
    fertilisation or embryo development. Because few crossovers form, aneuploid sperm are a
    theoretical concern that has not been measured.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Intracytoplasmic Sperm Injection
    term:
      id: NCIT:C185482
      label: Intracytoplasmic Sperm Injection
  evidence:
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The TESE success rate in our cohort was 40%, and we described one man who
      fathered a healthy, euploid child, thus showing that biallelic LoF
      variants in M1AP are compatible with fatherhood and, thereby, presenting a
      proof-of-principle.
    explanation: >-
      Sperm retrieval succeeds in a minority of men and fatherhood by ICSI is
      possible.
  - reference: PMID:40896145
    reference_title: "Genetic determinants of testicular sperm extraction outcomes: insights from a large multicentre study of men with non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the proportion of cases with successful sperm recovery is up to 50% for
      patients carrying M1AP LP/P mutations
    explanation: >-
      An independent multicentre study gives a sperm retrieval rate for M1AP
      carriers similar to the single-cohort figure, so a molecular diagnosis
      does not argue against attempting retrieval.
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In an ICSI-TESE attempt by M2062 and his female partner, three oocytes
      were fertilised, but none developed to the blastocyst stage and a
      transfer was not possible.
    explanation: >-
      Not every attempt succeeds; embryo development can fail after
      fertilisation.
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four of the ten men with LoF variants in M1AP tried to conceive via ICSI.
    explanation: >-
      The denominator for the ICSI outcomes: four attempting couples, one live
      birth.
- name: Genetic counselling
  description: >-
    Counselling covers autosomal recessive recurrence risk for brothers, the
    possibility of sperm retrieval, and the open question of sperm aneuploidy.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:32017041
    reference_title: "An M1AP homozygous splice-site mutation associated with severe oligozoospermia in a consanguineous family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His parents and fertile brother were heterozygous for the mutation.
    explanation: >-
      Heterozygous relatives are unaffected carriers, which is the basis for
      recessive recurrence-risk and carrier counselling in the family.
  - reference: PMID:40374915
    reference_title: "Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Segregation analysis showed the autosomal-recessive inheritance pattern
      of the frameshift variant c.676dup.
    explanation: >-
      Family segregation confirming autosomal recessive transmission of the
      recurrent allele, which sets the recurrence risk for brothers.
clinical_burden:
  burden_level: MODERATE
  rationale: >-
    The burden is reproductive and psychosocial. There is no systemic disease
    and no effect on virilisation or testosterone. The cost is the prospect of
    biological parenthood without assisted reproduction, with a minority of
    men able to father children through sperm retrieval and ICSI.
📚

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)

Create: Spermatogenic_Failure_48 (M1AP) · 2026-10-15T15:42:21Z · View source

New entry for spermatogenic failure 48 (MONDO:0030846), autosomal recessive M1AP-related meiotic arrest. Lump/split: curated as a DISEASE entry (single gene, own MONDO term; no subtypes). Deep research: claude_code provider report committed under research/ (14/14 references resolved, 1/1 quote valid; term validation flagged HP:0008210 as unresolved, which is not used). just preflight-dr was not run because no local MONDO build is available. Pathograph: M1AP Loss of Function (GO:0005515 protein binding, DECREASED, the only molecular activity demonstrated; QuickGO on 2026-10-15 listed only GO:0005515 and GO:0042802 for UniProtKB:Q8TC57) -> reduced TEX11 recruitment -> reduced recombination intermediates and class I crossovers -> metaphase I arrest and apoptosis -> severe spermatogenic failure (conforms to meiotic_prophase_failure#Spermatogenic Arrest and Non-Obstructive Azoospermia) -> NOA, cryptozoospermia, severe oligozoospermia, male infertility; arrest also reaches spermatocyte maturation arrest. Validation: just validate, validate-terms, count-verified-snippets (44/44 at time of writing), check-causal-targets, check-entity-refs, check-duplicate-keys, check-genereviews (NO_CHAPTER), check_gene_activity_grounding --against-ref origin/main.

Claude Code ▸
Spermatogenic Failure 48 (SPGF48; M1AP-related male infertility): research report
claude-haiku-5-5, claude-opus-5-5 3 citations 2026-10-15T15:37:31.181290

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

Resource ID Note
MONDO MONDO:0030846 "spermatogenic failure 48" in the draft entry
OMIM (phenotype) 619108 taken from Houston et al. 2021 Table (PMID:34498060): "M1AP | 2p13.1 | Non-obstructive azoospermia; OMIM:619108 | AR | 12 | Moderate". I didn't fetch the OMIM page itself.
OMIM (gene) 619098 HGNC REST record; also PMID:36259570 table
HGNC HGNC:25183 (write as hgnc:25183) HGNC REST: symbol M1AP; previous symbol C2orf65; aliases SPATA37, D6Mm5e; location 2p13.1; Entrez 130951; Ensembl ENSG00000159374; UniProt Q8TC57. Not yet in cache/hgnc/terms.csv.
Orphanet no SPGF48-specific ORPHA code found none in the local ORPHA cache. The broader NOA/spermatogenic failure groupings would apply.
ICD-10 / ICD-11 N46.01 / N46.0 (azoospermia, organic causes), GB04.0 (verify) no disease-specific code
MeSH Azoospermia (D053713); Infertility, Male (D007248) (verify)
ClinGen GDV no record found (no CGGV_* cache and no hit in cache/clingen/gene_validity.csv) Houston 2021 systematic review rates the gene–disease link "Moderate". Leave gene_disease_validity absent; that review is not a GenCC source.

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.

Phenotype Suggested HPO Frequency / detail Evidence
Non-obstructive azoospermia HP:0011961 ✓ Non-obstructive azoospermia most common: 7/10 LoF men in Rotte 2025 PMID:32673564, PMID:40374915
Cryptozoospermia Cryptozoospermia (verify HP ID; not in cache) 3/10 in Rotte 2025, all c.676dup homozygotes PMID:40374915
Severe oligozoospermia HP:0000798 ✓ Oligozoospermia (preferred_term "severe oligozoospermia") Chinese families (c.1435-1G>A; c.1074+2T>C) PMID:32017041, PMID:36440627
Male infertility HP:0000789 ✓ Infertility 100% all
Meiotic arrest (spermatocyte arrest), predominantly metaphase I HP:0031038 ✓ Spermatogenesis maturation arrest. Rotte 2025 itself cites HP:0031039 (verify label; not cached) all biopsied cases PMID:40374915
Rare round/elongated spermatids descriptive; part of the arrest phenotype round spermatids in 7/7 stained; elongated in 6 PMID:40374915
Elevated FSH (high-normal range) HP:0008232 ✓ Elevated circulating follicle stimulating hormone level "follicle-stimulating hormone in the high range" PMID:40374915
Normal testicular volume, LH and testosterone (negative findings; no HP binding needed) PMID:40374915
Swollen, abnormal sperm mitochondrial sheath HP:0012868 ✓ Abnormal sperm tail morphology (coarse); GO:0097226 ✓ sperm mitochondrial sheath single case (Tu 2020) PMID:32017041

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.

Variant (NM_138804.4) Type Population / zygosity Source
c.676dup p.(Trp226LeufsTer4) frameshift; recurrent; truncated protein in vitro European (German, Dutch, Portuguese, UK, US). gnomAD v4.1 MAF 0.003327 PMID:32673564, PMID:40374915
c.1166C>T p.(Pro389Leu) missense; homozygous; 5 affected men consanguineous Turkish family PMID:32673564
c.1073_1074+10del p.(Leu358Glnfs*58) splice; the minigene assay showed aberrant splicing; MAF 0.00006815 M3609 PMID:40374915
c.1074+2T>C splice; homozygous; abolishes M1AP axis foci (mouse knock-in) Chinese patients with severe oligozoospermia PMID:36440627
c.1435-1G>A splice; homozygous; no M1AP protein in sperm consanguineous Han Chinese family PMID:32017041
~10 kb deletion of exon 2 CNV, homozygous; WES can't detect it consanguineous Pakistani family PMID:38073178
Further variants (2 genes, 5 patients total) rare or absent in databases; reduced M1AP mRNA Chinese NOA cohort (n=108) PMID:42324855
c.949G>A p.(Gly317Arg) (rs140179344) missense. Likely benign: a mouse knock-in was fertile. It was found in trans with c.676dup US NOA case PMID:37459509

"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:

Intervention NCIT suggestion Notes
Testicular sperm extraction (micro-TESE) NCIT:C15329 ✓ Surgical Procedure (preferred_term "testicular sperm extraction"); a specific NCIT TESE term isn't verified ~50% retrieval (PMID:40896145)
ICSI / medically assisted reproduction (verify NCIT term) 1 live birth among 4 couples (PMID:40374915)
Cryopreservation of ejaculated sperm (cryptozoospermic men) (verify) the successful case used ejaculated sperm
Genetic counseling NCIT:C15240 ✓ Genetic Counseling
Lifestyle/diet optimization NCIT:C15447 Dietary Intervention (verify) mouse rationale only (PMID:42671480); no human evidence
Donor sperm / adoption alternatives

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

Model Phenotype Fidelity to human SPGF48 Source
M1ap⁻/⁻ mouse (Arango 2013) reduced testis size, severe oligozoospermia, infertility; mostly metaphase I arrest and apoptosis, some zygotene/pachytene arrest; progression to SCO-like tubules; females normal RECAPITULATES metaphase I arrest (HIGH). Shows a milder output (oligozoospermia) than most men (NOA), and SCO degeneration not reported in men PMID:23269666
M1ap c.1074+2T>C knock-in / knockout mice (Li 2023) M1AP axis foci lost; fewer recombination intermediates and crossovers; reduced TEX11 recruitment; female fertility normal RECAPITULATES the recombination defect (HIGH) PMID:36440627
M1ap⁻/⁻ mouse with Western diet (Houston 2026) subfertility, made worse by diet PARTIALLY_RECAPITULATES. The mouse is "subfertile" rather than sterile; human relevance unproven PMID:42671480
M1ap G317R knock-in (Ding 2023) fertile, normal histology negative control showing that variant is benign PMID:37459509
HEK293T co-IP; minigene splice assays human M1AP binds SHOC1, TEX11 and SPO16; splice defects confirmed IN_VITRO PMID:40374915

"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.

Outcome Count
References checked 14
Resolved 14
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 14
On topic 14
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 30
Resolved 27
Unresolved (possible confabulation) 1
Obsolete 0
Unverifiable 2

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.