Affinage

M1AP

Meiosis 1 arrest protein · UniProt Q8TC57

Length
530 aa
Mass
59.4 kDa
Annotated
2026-06-10
10 papers in source corpus 8 papers cited in narrative 9 extracted findings
Cross-family judge faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

M1AP is a germ cell-specific protein that functions as a functional enhancer of meiotic recombination, with its loss causing male meiotic arrest and infertility (PMID:23269666, PMID:36440627). Its expression is restricted to germ cells, appearing in female germ cells upon meiotic entry and in male germ cells during spermatogenesis (PMID:16881047). Mechanistically, M1AP physically associates with the mammalian ZZS complex (SHOC1, TEX11, SPO16) and localizes to chromosomal axes in a SPO16-dependent manner, colocalizing with TEX11; loss of M1AP does not perturb SHOC1 localization but reduces recruitment of TEX11 to recombination intermediates, decreasing recombination intermediates and class I crossovers (PMID:36440627), and its own recruitment to recombination sites depends on the XPF-like domain of SHOC1 [PMID:bio_10.1101_2025.05.28.656576]. In human males, biallelic or hemizygous loss-of-function variants cause predominant metaphase I arrest with reduced crossovers but, unlike ZZS deficiency, preserve synapsis and DSB repair, placing M1AP downstream of ZZS-mediated synapsis as a non-essential enhancer of crossover formation (PMID:40374915); the gene is dispensable for female fertility, where M1AP localizes cytoplasmically rather than axially in fetal oocytes (PMID:36440627). M1AP loss-of-function causes non-obstructive azoospermia and severe oligozoospermia in human patients (PMID:32673564, PMID:32017041).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2006 Medium

    Established that M1AP is a germ cell-restricted gene of unknown family, raising the question of a meiosis-specific function despite the absence of recognizable domains.

    Evidence RT-PCR, Northern blot, in situ hybridization, and sequence analysis of germ cell expression

    PMID:16881047

    Open questions at the time
    • No protein function or interaction partners identified
    • No structural or domain assignment possible from sequence
  2. 2013 High

    Defined the cellular phenotype of M1AP loss, showing it is required for male meiotic progression past metaphase I via proper synapsis and crossover formation, while being dispensable in females.

    Evidence Knockout mouse model with histology, chromosome synapsis analysis, and crossover foci immunostaining

    PMID:23269666

    Open questions at the time
    • Molecular mechanism of how M1AP supports crossover formation unknown
    • No direct interaction partners identified
    • Basis of sexual dimorphism unexplained
  3. 2020 Medium

    Confirmed M1AP as a human male infertility gene by linking loss-of-function variants to azoospermia and oligozoospermia, translating the mouse phenotype to humans.

    Evidence Whole-exome sequencing, segregation analysis, in vitro expression of truncated protein, and patient sperm immunostaining/electron microscopy

    PMID:32017041 PMID:32673564

    Open questions at the time
    • Mechanistic detail limited to protein truncation/absence
    • Mitochondrial sheath phenotype not mechanistically connected to meiotic role
    • Single families for some variants
  4. 2020 Low

    Reported a non-meiotic transcriptional activity in which M1AP overexpression activates MYC, a context not reconciled with its germ cell meiotic role.

    Evidence CRISPR activation screen with MYC promoter reporter, inducible overexpression, luciferase, qRT-PCR, and western blot in HEK293T cells

    PMID:32411526

    Open questions at the time
    • Non-physiological overexpression in HEK293T; no loss-of-function or in vivo validation
    • No mechanism for how M1AP activates MYC
    • Relationship to meiotic function unestablished
  5. 2022 High

    Resolved the molecular mechanism by placing M1AP within the ZZS recombination machinery, showing it localizes to axes via SPO16 and promotes TEX11 recruitment to recombination intermediates.

    Evidence Co-immunoprecipitation interaction assays, immunostaining of chromosome spreads in M1AP-mutant and patient-derived models, and crossover quantification

    PMID:36440627

    Open questions at the time
    • Structural basis of M1AP-ZZS interaction unknown
    • Direct binding stoichiometry/architecture within complex undefined
    • How M1AP enhances TEX11 recruitment biochemically unresolved
  6. 2025 High

    Refined M1AP's position in the pathway by showing human loss-of-function impairs class I crossovers without disrupting synapsis or DSB repair, distinguishing it as a non-essential enhancer downstream of ZZS-mediated synapsis.

    Evidence Testicular biopsy phenotyping of men with biallelic/hemizygous variants, recombination/synapsis marker immunostaining, and genetic epistasis with ZZS-deficient patients

    PMID:40374915

    Open questions at the time
    • Why M1AP loss is partial rather than complete crossover block unexplained
    • Molecular step at which M1AP acts within crossover maturation undefined
  7. 2025 Medium

    Identified the upstream determinant of M1AP recruitment, showing the SHOC1 XPF-like domain is required to localize M1AP to recombination intermediates.

    Evidence Immunostaining of chromosome spreads in SHOC1 XPF-domain mutant models (preprint)

    PMID:bio_10.1101_2025.05.28.656576

    Open questions at the time
    • Preprint, single study
    • Whether interaction with SHOC1 is direct not established
    • Structural detail of XPF-domain dependence unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical mechanism by which M1AP enhances TEX11 recruitment and crossover maturation, and the structural architecture of its association with the ZZS complex, remain undefined.
  • No structural model of M1AP or its ZZS interface
  • No reconstituted biochemical assay of M1AP activity
  • Reconciliation of meiotic role with reported MYC transcriptional activity outstanding

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Localization
GO:0005694 chromosome 2 GO:0005829 cytosol 1
Pathway
R-HSA-1474165 Reproduction 3 R-HSA-1640170 Cell Cycle 2
Partners
SHOC1SPO16TEX11

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 M1AP (mouse M1ap) is expressed exclusively in germ cells from spermatogonia to secondary spermatocytes, and its knockout in male mice causes meiotic arrest predominantly at metaphase I with failure to properly align chromosomes at the metaphase plate due to abnormal chromosome synapses and failure to form crossover foci, leading to severe oligozoospermia and infertility; female knockouts have histologically normal ovaries and are fertile. Knockout mouse model (M1ap-deficient mice); histological analysis, immunostaining for meiotic markers, chromosome synapsis analysis Biology of reproduction High 23269666
2006 D6Mm5e (M1AP) mRNA expression is highly restricted to germ cells: expressed in female embryonic germ cells upon entry into meiosis and in male germ cells during late spermatogenesis. Two transcripts arise from alternative splicing of exon 8 without frameshift, using the same stop codon. The protein does not belong to any known protein family and lacks known signature motifs. RT-PCR, Northern blot, in situ hybridization, sequence analysis Developmental dynamics Medium 16881047
2022 M1AP physically interacts with the mammalian ZZS complex components SHOC1, TEX11, and SPO16; M1AP localizes to chromosomal axes in a SPO16-dependent manner and colocalizes with TEX11. Ablation of M1AP does not alter SHOC1 localization but reduces recruitment of TEX11 to recombination intermediates, resulting in decreased recombination intermediates and crossovers. Co-immunoprecipitation/interaction assays identifying M1AP-ZZS binding; immunostaining of chromosome spreads in M1AP-mutant mouse models; analysis of recombination intermediate and crossover numbers in patient-derived and mouse models EMBO reports High 36440627
2022 A homozygous M1AP splicing mutation (c.1074+2T>C) abolishes M1AP foci on chromosome axes and leads to metaphase I arrest with decreased crossovers in male mice; M1AP is dispensable for crossover formation and fertility in female mice, showing cytoplasmic (not axial) localization in fetal oocytes. Patient genetic analysis; mouse model of splicing mutation; immunostaining of chromosome spreads for M1AP foci and crossover markers EMBO reports High 36440627
2025 In human males, loss-of-function of M1AP leads to a predominant metaphase I arrest with rare haploid spermatids, caused by reduced recombination intermediates and class I crossover failure (but not incorrect synapsis or unrepaired DNA double-strand breaks, which distinguish ZZS deficiency). This establishes M1AP as an important but non-essential functional enhancer of meiotic recombination, downstream of ZZS-mediated synapsis. Testicular biopsy phenotyping of men with biallelic/hemizygous M1AP loss-of-function variants; immunostaining for recombination and synapsis markers; genetic epistasis comparison with ZZS-deficient patients EMBO molecular medicine High 40374915
2020 A homozygous M1AP frameshift variant (c.676dup, p.Trp226LeufsTer4) results in a truncated protein as demonstrated by heterologous in vitro expression of mutant M1AP, and causes non-obstructive azoospermia in humans. In vitro heterologous expression of mutant M1AP; whole-exome sequencing; segregation analysis in consanguineous family American journal of human genetics Medium 32673564
2020 A homozygous splice-site mutation in M1AP (c.1435-1G>A) leads to complete absence of M1AP protein in patient spermatozoa and is associated with severe oligozoospermia and highly aberrant swollen mitochondrial sheaths with normal axonemal structures. Protein immunostaining of patient spermatozoa; electron microscopy of sperm ultrastructure; segregation analysis Clinical genetics Medium 32017041
2020 CRISPR activation of M1AP in HEK293T cells increases MYC promoter activity and MYC mRNA/protein levels, as confirmed by doxycycline-inducible M1AP overexpression, dual-luciferase assay, and quantitative RT-PCR/western blot. This identifies M1AP as a transcriptional activator of MYC expression in this cellular context. CRISPR activation screening with MYC promoter-reporter (pMYC-promoter-Dendra2); doxycycline-inducible M1AP overexpression; dual-luciferase assay; qRT-PCR; western blot PeerJ Low 32411526
2025 Disruption of the XPF-like domain in SHOC1 impairs recruitment of M1AP to recombination intermediates, indicating that SHOC1 (via its XPF-like domain) is required for M1AP localization to recombination sites. Immunostaining of chromosome spreads in SHOC1 XPF-domain mutant mouse/patient models; functional analysis of SHOC1 mutant effects on M1AP foci bioRxivpreprint Medium bio_10.1101_2025.05.28.656576

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Bi-allelic Mutations in M1AP Are a Frequent Cause of Meiotic Arrest and Severely Impaired Spermatogenesis Leading to Male Infertility. American journal of human genetics 69 32673564
2013 Meiosis I arrest abnormalities lead to severe oligozoospermia in meiosis 1 arresting protein (M1ap)-deficient mice. Biology of reproduction 28 23269666
2020 An M1AP homozygous splice-site mutation associated with severe oligozoospermia in a consanguineous family. Clinical genetics 18 32017041
2023 Genome sequencing of Pakistani families with male infertility identifies deleterious genotypes in SPAG6, CCDC9, TKTL1, TUBA3C, and M1AP. Andrology 17 38073178
2022 M1AP interacts with the mammalian ZZS complex and promotes male meiotic recombination. EMBO reports 17 36440627
2006 Expression analysis and evolutionary conservation of the mouse germ cell-specific D6Mm5e gene. Developmental dynamics : an official publication of the American Association of Anatomists 11 16881047
2021 Genetic Variants of CLPP and M1AP Are Associated With Risk of Non-Small Cell Lung Cancer. Frontiers in oncology 9 34604049
2020 CRISPR screening identifies M1AP as a new MYC regulator with a promoter-reporter system. PeerJ 7 32411526
2022 Structural analysis of M1AP variants associated with severely impaired spermatogenesis causing male infertility. PeerJ 4 35341049
2025 Genotype-specific differences in infertile men due to loss-of-function variants in M1AP or ZZS genes. EMBO molecular medicine 1 40374915

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