Affinage

MEI1

Meiosis inhibitor protein 1 · UniProt Q5TIA1

Length
1274 aa
Mass
141.2 kDa
Annotated
2026-06-10
22 papers in source corpus 9 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MEI1 is a meiotic protein required for the formation of programmed DNA double-strand breaks (DSBs) that initiate meiotic recombination (PMID:14668445). Mouse loss-of-function mutants arrest at zygotene with failure of RAD51 to load onto meiotic chromosomes (PMID:11820814), and reduced γH2AX at leptonema comparable to Spo11-null mice identifies a defect in DSB induction rather than in the downstream repair machinery, since cisplatin-induced breaks restore RAD51 loading in mutant spermatocytes (PMID:14668445). Genetic epistasis places MEI1 upstream of DMC1, confirming it acts before homologous recombination-mediated DSB repair (PMID:15928951). Mechanistically, human MEI1 physically interacts with the DSB-promoting complex proteins ANKRD31, IHO1, REC114, and MEI4, and pathogenic biallelic variants disrupt these interactions (PMID:36759719, PMID:41706353). In humans, biallelic MEI1 variants cause infertility through reduced protein levels, aberrant splicing, and protein truncation (PMID:34037756, PMID:40164922), with patient embryos showing high rates of aneuploidy (PMID:40164922).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2002 High

    Established that MEI1 is required for homologous chromosome synapsis and acts upstream of RAD51 loading, framing it as an early meiotic factor rather than a repair protein.

    Evidence Forward genetic mouse screen with RAD51 immunofluorescence on meiotic chromosomes

    PMID:11820814

    Open questions at the time
    • Did not define the molecular step MEI1 controls
    • No biochemical activity or partner identified
  2. 2003 High

    Pinpointed the defect to programmed DSB formation itself, distinguishing MEI1 from the recombinational repair machinery.

    Evidence Positional cloning, γH2AX quantification, cisplatin rescue, and comparison with Spo11-null spermatocytes

    PMID:14668445

    Open questions at the time
    • Did not show how MEI1 promotes DSB formation mechanistically
    • Relationship to the Spo11 cleavage machinery left undefined
  3. 2005 High

    Ordered MEI1 upstream of DMC1 in the recombination pathway via epistasis, confirming it acts before DSB repair in both sexes.

    Evidence Mei1−/−; Dmc1−/− double-mutant phenotypic analysis of spermatogenesis and oogenesis

    PMID:15928951

    Open questions at the time
    • Genetic order does not reveal direct molecular partners
    • No physical interaction tested
  4. 2021 Medium

    Connected human MEI1 mutations to infertility by defining their molecular consequences on protein level and splicing.

    Evidence Western blotting and minigene splicing assays of patient variants in vitro

    PMID:34037756

    Open questions at the time
    • In vitro consequences not linked to meiotic phenotype in patient germ cells
    • No functional rescue
  5. 2023 Medium

    Provided the first physical-interaction basis for MEI1 function by linking it to the pre-DSB complex and showing patient variants disrupt these contacts.

    Evidence Co-immunoprecipitation of wild-type and mutant MEI1 with ANKRD31, IHO1, REC114, MEI4

    PMID:36759719 PMID:41706353

    Open questions at the time
    • Single lab, no reciprocal pulldown or structural validation
    • Stoichiometry and direct versus indirect binding undefined
  6. 2025 Medium

    Extended the phenotypic consequence to human embryos, linking a truncating MEI1 deletion to aneuploidy.

    Evidence Whole-exome/cDNA sequencing, western blot, immunofluorescence, and preimplantation genetic testing

    PMID:40164922 PMID:41315153

    Open questions at the time
    • Causal mechanism from truncated protein to aneuploidy not established
    • Localization data from overexpression in non-meiotic cell line

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical activity by which MEI1 promotes DSB formation and its precise role within the pre-DSB complex remain undefined.
  • No structural model of MEI1 or its complex
  • No defined enzymatic or scaffolding activity
  • Direct versus indirect role in Spo11-mediated cleavage unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Pathway
R-HSA-1474165 Reproduction 4 R-HSA-1640170 Cell Cycle 3
Partners
ANKRD31IHO1MEI4REC114

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 MEI1 (mouse) is required for homologous chromosome synapsis during meiosis I; mei1/mei1 spermatocytes arrest at zygotene with failure of RAD51 to associate with meiotic chromosomes despite evidence of chromosomal breaks, indicating a defect upstream of RAD51 loading. Forward genetic screen in mice; immunofluorescence for RAD51 on meiotic chromosomes; meiotic stage-specific gene expression analysis Developmental biology High 11820814
2003 MEI1 is required for genetically programmed DNA double-strand break (DSB) formation during meiotic leptonema; Mei1 mutant spermatocytes show greatly reduced γH2AX at leptonema (comparable to Spo11-null mice), and cisplatin treatment of mutant males restores RAD51 loading, demonstrating intact recombinational repair machinery but defective DSB induction. Positional cloning; cisplatin rescue experiment in mutant spermatocytes; immunofluorescence for γH2AX and RAD51; comparison with Spo11-null controls Proceedings of the National Academy of Sciences of the United States of America High 14668445
2005 Genetic epistasis places MEI1 upstream of DMC1 in the meiotic recombination pathway; double-mutant (Mei1−/−; Dmc1−/−) mice phenocopy Mei1−/− single mutants in both sexes, confirming MEI1 acts before DSB repair by homologous recombination. Double-mutant analysis (Mei1−/−; Dmc1−/−) with phenotypic comparison of spermatogenesis and oogenesis Chromosoma High 15928951
2023 Human MEI1 protein physically interacts with key meiotic DSB-promoting complex proteins ANKRD31, IHO1, REC114, and MEI4; pathogenic biallelic variants in patients with NOA disrupt these interactions. Co-immunoprecipitation assays with wild-type and mutant MEI1 constructs Journal of human genetics Medium 36759719 41706353
2021 Protein-truncating and missense mutations in MEI1 reduce MEI1 protein levels, while splicing mutations cause abnormal alternative splicing; demonstrated by western blotting and minigene analysis in vitro. Western blotting; minigene splicing assay in vitro Human reproduction (Oxford, England) Medium 34037756
2025 A homozygous whole-exon deletion of exon 19 in MEI1 produces a truncated MEI1 protein with premature termination at exon 20; embryos from affected individuals show high rates of aneuploidy. Whole-exome sequencing, Sanger sequencing, cDNA amplification/sequencing, western blotting, immunofluorescence, preimplantation genetic testing by whole-genome sequencing Reproductive sciences (Thousand Oaks, Calif.) Medium 40164922
2025 Biallelic MEI1 variants causing embryonic arrest do not alter the subcellular localization of MEI1 but significantly reduce its mRNA and protein expression levels. Western blotting, RT-qPCR, immunofluorescence in HEK293T cells transfected with mutant constructs Journal of assisted reproduction and genetics Low 41315153
2015 Bovine Mei1 promoter and gene body DNA methylation inversely correlates with Mei1 expression; treatment of bovine mammary epithelial cells with the DNA methyltransferase inhibitor 5-Aza-CdR activates Mei1 expression, indicating that DNA methylation represses Mei1 transcription. Bisulfite sequencing of promoter/gene body; 5-Aza-CdR treatment; real-time PCR Gene Low 26165450

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 The mouse meiotic mutation mei1 disrupts chromosome synapsis with sexually dimorphic consequences for meiotic progression. Developmental biology 121 11820814
2003 Positional cloning and characterization of Mei1, a vertebrate-specific gene required for normal meiotic chromosome synapsis in mice. Proceedings of the National Academy of Sciences of the United States of America 108 14668445
1994 mei-1, a gene required for meiotic spindle formation in Caenorhabditis elegans, is a member of a family of ATPases. Genetics 88 8150281
1994 Localization of the mei-1 gene product of Caenorhaditis elegans, a meiotic-specific spindle component. The Journal of cell biology 80 8027178
2005 Mei1 is epistatic to Dmc1 during mouse meiosis. Chromosoma 58 15928951
2018 A MEI1 homozygous missense mutation associated with meiotic arrest in a consanguineous family. Human reproduction (Oxford, England) 52 29659827
1998 Genetic and molecular characterization of the caenorhabditis elegans gene, mel-26, a postmeiotic negative regulator of mei-1, a meiotic-specific spindle component. Genetics 51 9725834
2006 Polymorphic alleles of the human MEI1 gene are associated with human azoospermia by meiotic arrest. Journal of human genetics 49 16683055
1993 Genetic studies of mei-1 gene activity during the transition from meiosis to mitosis in Caenorhabditis elegans. Genetics 39 8514128
2021 Novel biallelic mutations in MEI1: expanding the phenotypic spectrum to human embryonic arrest and recurrent implantation failure. Human reproduction (Oxford, England) 33 34037756
2006 The C. elegans anaphase promoting complex and MBK-2/DYRK kinase act redundantly with CUL-3/MEL-26 ubiquitin ligase to degrade MEI-1 microtubule-severing activity after meiosis. Developmental biology 33 17069791
2012 UNC-89 (obscurin) binds to MEL-26, a BTB-domain protein, and affects the function of MEI-1 (katanin) in striated muscle of Caenorhabditis elegans. Molecular biology of the cell 32 22621901
2015 Molecular characterization and epigenetic regulation of Mei1 in cattle and cattle-yak. Gene 20 26165450
2013 Microtubule severing by the katanin complex is activated by PPFR-1-dependent MEI-1 dephosphorylation. The Journal of cell biology 19 23918937
2023 Bi-allelic MEI1 variants cause meiosis arrest and non-obstructive azoospermia. Journal of human genetics 17 36759719
2022 Recombination rates in pigs differ between breeds, sexes and individuals, and are associated with the RNF212, SYCP2, PRDM7, MEI1 and MSH4 loci. Genetics, selection, evolution : GSE 14 35596132
2024 Novel MEI1 mutations cause chromosomal and DNA methylation abnormalities leading to embryonic arrest and implantation failure. Molecular genetics and genomics : MGG 7 38416203
2025 Identification of the novel homozygous whole exon deletion in MEI1 underlying azoospermia and embryonic arrest in one consanguineous family. Reproductive sciences (Thousand Oaks, Calif.) 1 40164922
2026 A common cause of non-obstructive azoospermia: biallelic MEI1 variants and implications for infertility diagnostics. Journal of assisted reproduction and genetics 0 41706353
2025 Novel variants in MEI1 cause female infertility characterized by early embryonic arrest and implantation failure. Journal of assisted reproduction and genetics 0 41315153
2025 The Impact of MEI1 Alternative Splicing Events on Spermatogenesis in Mongolian Horses. Animals : an open access journal from MDPI 0 41375492
2025 Novel biallelic MEI1 variants cause female infertility characterized by multiple pronuclei formation and aberrant embryonic development. Journal of ovarian research 0 41444636

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