MEI1

MEI1 is a vertebrate-specific meiotic protein essential for the formation of genetically programmed double-strand breaks (DSBs) during meiotic prophase I, functioning upstream of recombinational repair in both sexes. MEI1-deficient spermatocytes arrest at zygotene with absent γH2AX foci at leptonema and failure of RAD51 loading—phenocopying Spo11 loss—yet retain intact repair machinery as demonstrated by cisplatin-induced rescue of RAD51 foci; genetic epistasis places MEI1 upstream of DMC1 (PMID:11820814, PMID:14668445, PMID:15928951). MEI1 physically interacts with the meiotic DSB-formation complex components ANKRD31, IHO1, REC114, and MEI4, and pathogenic variants that reduce MEI1 protein levels or disrupt these interactions cause meiotic arrest and embryonic aneuploidy (PMID:36759719, PMID:34037756, PMID:38416203). Biallelic loss-of-function variants in MEI1 are a recognized cause of non-obstructive azoospermia and early embryonic arrest in humans (PMID:41706353, PMID:40164922).

1. 2002 High

   Identification of MEI1 as a gene required for meiotic chromosome synapsis established that a previously unknown factor was needed for proper prophase I progression, as mei1 mutant spermatocytes arrested at zygotene with failed synapsis and absent RAD51 loading despite evidence of chromosome breaks.

   Evidence Forward genetic screen in mice; immunocytochemistry on mei1/mei1 meiotic chromosome spreads

   PMID:11820814

   Open questions at the time

   • Whether MEI1 functions in DSB formation versus DSB processing was unresolved
   • Molecular mechanism and protein interactions unknown
   • Female meiotic phenotype not yet characterized
2. 2003 High

   Demonstration that MEI1 loss abolishes meiotic DSB formation (not just repair) resolved the key mechanistic ambiguity—reduced γH2AX at leptonema comparable to Spo11-null animals and cisplatin rescue of RAD51 loading proved MEI1 acts at or upstream of DSB induction.

   Evidence γH2AX immunostaining, cisplatin rescue experiment, and comparison to Spo11-null phenotype in mei1 mutant mice

   PMID:14668445

   Open questions at the time

   • Whether MEI1 directly participates in DSB catalysis or acts as an accessory factor was unknown
   • No binding partners identified
   • No enzymatic activity established for MEI1
3. 2005 High

   Genetic epistasis analysis placed MEI1 definitively upstream of DMC1-mediated repair, ordering the meiotic recombination pathway: Mei1−/−;Dmc1−/− double mutants phenocopied Mei1−/− alone rather than the more severe Dmc1−/− oogenesis defect.

   Evidence Double-knockout mouse analysis with sex-specific meiotic phenotype comparison

   PMID:15928951

   Open questions at the time

   • Biochemical partners and the protein complex through which MEI1 promotes DSBs remained unidentified
   • Whether MEI1 is required for SPO11 recruitment to chromatin was untested
4. 2015 Medium

   Discovery that MEI1 expression is regulated by DNA methylation expanded understanding of how meiotic entry controls DSB machinery: promoter hypermethylation correlated with meiotic arrest in cattle-yak testis, and pharmacological demethylation reactivated expression.

   Evidence Bisulfite sequencing and 5-aza-CdR treatment in bovine cells and tissues

   PMID:26165450

   Open questions at the time

   • Whether epigenetic regulation of MEI1 is conserved in human germ cells was not tested
   • Downstream consequences of methylation-mediated silencing on DSB formation not directly measured
5. 2021 Medium

   Characterization of human pathogenic MEI1 variants established the molecular consequences of disease-associated mutations: protein-truncating and missense variants reduce protein levels, while splicing mutations cause aberrant mRNA processing.

   Evidence Western blotting and minigene splicing assays in vitro

   PMID:34037756

   Open questions at the time

   • Effect of these variants on DSB-complex interactions was not assessed
   • In vivo validation in germ cells was lacking
6. 2023 Medium

   Identification of MEI1's physical interaction with ANKRD31, IHO1, REC114, and MEI4 provided the first molecular explanation for how MEI1 participates in the DSB-formation complex, and pathogenic missense variants disrupted these interactions.

   Evidence Co-immunoprecipitation with wild-type and mutant MEI1 constructs

   PMID:36759719

   Open questions at the time

   • Stoichiometry and architecture of the MEI1-containing complex remain undefined
   • No structural data available
   • Whether MEI1 directly contacts SPO11 or acts exclusively through ANKRD31/IHO1/REC114/MEI4 is unknown
7. 2024 Medium

   Frameshift MEI1 variants were shown to reduce mRNA and protein expression without altering subcellular localization, and associated embryos exhibited widespread aneuploidy and aberrant DNA methylation, connecting MEI1 deficiency to post-zygotic genomic instability.

   Evidence Immunofluorescence, western blot, qPCR in HEK293T cells; whole-genome and bisulfite sequencing of patient embryos

   PMID:38416203

   Open questions at the time

   • Causal relationship between MEI1 loss and abnormal DNA methylation in embryos not mechanistically established
   • Overexpression in somatic cells may not recapitulate germ-cell biology
8. 2025 Medium

   Replication of MEI1-complex interaction disruption across a large NOA cohort and additional truncating variants confirmed that biallelic MEI1 loss-of-function is a recurring cause of human meiotic arrest and male infertility.

   Evidence Co-immunoprecipitation assays, cDNA sequencing, western blotting, and preimplantation genetic testing across multiple patient cohorts

   PMID:40164922 PMID:41706353

   Open questions at the time

   • No animal model rescue experiment has been performed with human variants
   • Genotype-phenotype correlations across different variant classes are incomplete

• The structural basis of MEI1's role within the DSB-formation complex, whether MEI1 directly contacts SPO11 or chromatin, and the mechanism by which MEI1 deficiency leads to aberrant embryonic DNA methylation remain unresolved.
• No structural or cryo-EM model of the MEI1-containing complex exists
• Whether MEI1 has intrinsic enzymatic or chromatin-binding activity is unknown
• Mechanism linking MEI1 loss to global DNA methylation changes in embryos is unexplored