{"gene":"TEX11","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2008,"finding":"ZIP4H (TEX11) was identified as an NBS1-interacting protein via yeast two-hybrid screening. Loss of ZIP4H in male mice delays meiotic double-strand break repair (as shown by DMC1 staining) and reduces crossover formation (as shown by decreased MLH1 focus formation), leading to achiasmate chromosomes at meiosis I. These findings establish ZIP4H as a functional collaborator of the Mre11 complex in mammalian meiotic DSB repair and crossover regulation.","method":"Yeast two-hybrid screening, mouse knockout (Zip4h−/Y), immunostaining for DMC1 (DSB repair marker) and MLH1 (crossover marker), cytological analysis of spermatocytes","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic interaction established by knockout mouse with multiple orthogonal cytological assays (DMC1, MLH1 staining), yeast two-hybrid binding confirmation; single lab but multiple orthogonal methods","pmids":["18369460"],"is_preprint":false},{"year":2005,"finding":"Bioinformatic analysis (ABRA method) predicts Spo22/Zip4 (the yeast ortholog of TEX11) is a 22-unit tetratricopeptide repeat (TPR) protein. Together with Zip2 and Zip3, it is proposed to act at crossover-designated recombination sites; Zip3 contains a RING finger homologous to known ubiquitin E3s, suggesting the Zip2/Zip3/Spo22 complex mediates ubiquitin labeling during crossover formation.","method":"Bioinformatic sequence analysis (ABRA repeat annotation), structural domain prediction","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/bioinformatic prediction only, no experimental validation of TEX11/Spo22 ubiquitin activity","pmids":["16314568"],"is_preprint":false},{"year":2015,"finding":"TEX11 mutations (frameshift, splicing, missense) cause meiotic arrest and azoospermia in men. Functional transgenic mouse models showed that an intronless autosomal Tex11 transgene can substitute for X-linked Tex11, providing genetic evidence for X-to-autosomal retrotransposition. TEX11 protein levels modulate genome-wide recombination rates in both sexes in the mouse.","method":"Genetic screening (Sanger/next-generation sequencing), transgenic mouse complementation assay, recombination rate analysis in transgenic mice","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic mouse rescue (intronless autosomal transgene complementing X-linked knockout) plus genome-wide recombination rate quantification; multiple orthogonal approaches in one study","pmids":["26136358"],"is_preprint":false},{"year":2015,"finding":"Loss-of-function TEX11 mutations (including a 79-aa deletion in the SPO22 domain, splicing mutations, missense mutations) cause meiotic arrest in human testes. Immunohistochemical analysis of human testes showed TEX11 protein expression specifically in late spermatocytes, round spermatids, and elongated spermatids, and patients with TEX11 mutations lacked TEX11 expression with meiotic arrest.","method":"Array CGH, Sanger sequencing, immunohistochemistry of human testis biopsies","journal":"The New England journal of medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in human patients with defined meiotic arrest phenotype and localization by IHC; no in vitro reconstitution but multiple patients and genetic confirmation","pmids":["25970010"],"is_preprint":false},{"year":2012,"finding":"TEX11 competes with estrogen receptor β (ERβ) for binding to HPIP (hematopoietic pre-B cell leukemia transcription factor-interacting protein) in cultured cells. TEX11 promotes nuclear translocation of ERβ and enhances its transcriptional activity, while suppressing ERβ nongenomic cytoplasmic signaling (reduced AKT and ERK phosphorylation). Overexpression of TEX11 in mouse germ cell-derived lines suppresses cell proliferation and estradiol-stimulated expression of cFos, Ccnd1, and Ccnb1, and elevates pro-apoptotic Bax expression.","method":"Yeast two-hybrid screening (identification of HPIP), co-immunoprecipitation/binding competition assays in cultured cells, ERβ nuclear translocation assay, AKT/ERK phosphorylation assay, cell proliferation assay with TEX11 overexpression in GC-1/GC-2 cells, RT-PCR for target genes","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus functional competition assays in cultured cells; single lab with multiple readouts but no structural or in vitro reconstitution validation","pmids":["22383461"],"is_preprint":false},{"year":2022,"finding":"In colorectal cancer cells, TEX11 promotes COP1 transcription by upregulating FOXO3a expression; enhanced COP1 then accelerates degradation of the negative transcriptional regulator c-Jun, which in turn enhances p21 transcription, inhibiting cell cycle S-phase progression and proliferation. TEX11 overexpression inhibits CRC cell proliferation in vitro and in vivo.","method":"Overexpression and knockdown of TEX11 in CRC cell lines, in vivo tumor xenograft, Western blotting, reporter/transcription assays for FOXO3a, COP1, c-Jun, and p21","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined pathway placement by loss/gain of function with multiple molecular readouts and in vivo validation; single lab","pmids":["36258021"],"is_preprint":false},{"year":2025,"finding":"TEX11 is a component of the trimeric ZZS complex (with SHOC1/Zip2-like and SPO16/Spo16-like proteins) that binds recombination intermediates after strand invasion to stabilize them and promote crossover formation during meiosis. Disruption of SHOC1's XPF-like domain impairs recruitment of TEX11 and other ZMM factors to recombination intermediates, abolishing crossover formation.","method":"Mouse genetic models (CRISPR/Cas9), co-immunoprecipitation/complex assembly, chromatin immunoprecipitation, cytological analysis of meiotic spreads","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — preprint, complex membership established by co-IP and localization at recombination intermediates, single study; TEX11 role in complex inferred from SHOC1 variant disrupting TEX11 recruitment","pmids":["bio_10.1101_2025.05.28.656576"],"is_preprint":true},{"year":2025,"finding":"In vitro expression of the TEX11-c.652del237bp in-frame deletion variant in HEK293 cells produces a truncated mRNA and truncated protein (confirmed by qPCR and Western blot). In silico structural modeling suggests this deletion does not significantly impact the ZZS complex structure, raising doubt about its pathogenicity. The corresponding mouse model is fertile, suggesting species-specific differences in TEX11 function.","method":"Transfection of plasmid constructs into HEK293 cells, qPCR, Western blot, in silico structural modeling, CRISPR/Cas9 mouse model","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro expression analysis with Western blot confirms truncated protein production; mouse model shows negative phenotypic result; two orthogonal methods in one study","pmids":["41300722"],"is_preprint":false},{"year":2026,"finding":"In mouse knock-in models, a frameshift TEX11 variant (Tex11D) causes complete NOA with maturation arrest and no epididymal sperm, while a missense variant (Tex11A) causes no spermatogenesis or fertility defects. A third variant (Tex11L) causes reduced testis weight and epididymal sperm counts with incompletely penetrant infertility and a distinct epididymal phenotype (reduced sperm density in caput, amorphous material in cauda).","method":"CRISPR/Cas9 knock-in mouse models, testis weight measurement, epididymal sperm count, fertility breeding assays, histology","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — preprint; clean CRISPR knock-in mouse models with variant-specific phenotypic readouts; single study","pmids":["41756962"],"is_preprint":true},{"year":2024,"finding":"A partial deletion of TEX11 exons 9–11 (mimicking a human variant in the SPO22 domain) introduced by CRISPR/Cas9 into mice (Tex11Ex9-11del/Y) does not impair spermatogenesis or fertility; sperm concentration, motility, morphology, and testis transcriptome were all normal. This negative result indicates that this specific SPO22 deletion does not functionally disrupt TEX11 in mice, highlighting species-specific differences.","method":"CRISPR/Cas9 mouse model, sperm analysis, RNA-seq of testis transcriptome, fertility assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — negative finding from clean CRISPR knock-in mouse with multiple phenotypic assays (sperm parameters, fertility, transcriptome); single lab but multiple orthogonal readouts","pmids":["39231187"],"is_preprint":false}],"current_model":"TEX11 is a meiosis-specific, X-linked protein that forms part of the conserved ZZS trimeric complex (with SHOC1 and SPO16) to bind and stabilize strand-invasion recombination intermediates, promote meiotic double-strand break repair through interaction with NBS1, and regulate genome-wide crossover formation and chromosomal synapsis; loss-of-function mutations or deletions in its TPR-containing or SPO22 domain cause meiotic arrest and azoospermia in men and male mice, while in somatic contexts TEX11 can modulate cell proliferation by competing with ERβ for HPIP binding and by activating a FOXO3a/COP1/c-Jun/p21 axis."},"narrative":{"mechanistic_narrative":"TEX11 is a meiosis-specific protein that regulates genome-wide crossover formation and meiotic double-strand break (DSB) repair during spermatogenesis [PMID:18369460, PMID:26136358]. It was first identified as an NBS1-interacting partner whose loss in male mice delays DSB repair (reduced DMC1 resolution) and reduces crossovers (decreased MLH1 foci), producing achiasmate chromosomes at meiosis I and establishing TEX11 as a functional collaborator of the Mre11/NBS1 complex [PMID:18369460]. TEX11 acts as a component of the trimeric ZZS complex together with SHOC1 and SPO16, binding recombination intermediates after strand invasion to stabilize them and promote crossover formation; recruitment of TEX11 to these intermediates depends on the SHOC1 XPF-like domain [PMID:bio_10.1101_2025.05.28.656576]. TEX11 protein levels set genome-wide recombination rates, and an intronless autosomal Tex11 transgene rescues the X-linked knockout, providing evidence for retrotransposition [PMID:26136358]. In men, loss-of-function TEX11 mutations cause meiotic arrest and azoospermia, with TEX11 normally expressed in late spermatocytes and spermatids and absent in affected patients [PMID:25970010]. Beyond its meiotic role, TEX11 modulates cell proliferation in somatic/cultured-cell contexts: it competes with estrogen receptor β (ERβ) for HPIP binding, enhancing ERβ nuclear transcriptional activity while suppressing its cytoplasmic AKT/ERK signaling [PMID:22383461], and in colorectal cancer cells it inhibits proliferation through a FOXO3a→COP1→c-Jun→p21 axis [PMID:36258021]. Multiple knock-in mouse studies show that the meiotic requirement is variant- and species-specific, as several human-mimicking SPO22-domain and missense alleles do not disrupt mouse spermatogenesis [PMID:41300722, PMID:41756962, PMID:39231187].","teleology":[{"year":2005,"claim":"Before functional data, the question was what type of protein TEX11/Spo22 is and where it acts; bioinformatics predicted a 22-unit TPR architecture functioning at crossover-designated recombination sites alongside Zip2 and Zip3.","evidence":"Bioinformatic repeat annotation (ABRA) and structural domain prediction of the yeast Spo22/Zip4 ortholog","pmids":["16314568"],"confidence":"Low","gaps":["Purely computational; no experimental validation of TPR structure or of any ubiquitin-labeling activity","Inferred only from yeast ortholog, not mammalian TEX11"]},{"year":2008,"claim":"It was unknown how TEX11 connects to the DSB repair machinery; identifying it as an NBS1 interactor whose knockout delays DSB repair and reduces crossovers placed it functionally within meiotic recombination and crossover control.","evidence":"Yeast two-hybrid screen, Zip4h−/Y mouse knockout with DMC1 and MLH1 cytology in spermatocytes","pmids":["18369460"],"confidence":"High","gaps":["Did not define how TEX11 acts biochemically on recombination intermediates","Did not establish the larger complex in which TEX11 operates"]},{"year":2012,"claim":"Whether TEX11 has functions outside meiosis was unaddressed; competition with ERβ for HPIP and modulation of ERβ signaling and proliferation revealed a somatic, hormone-signaling-linked activity.","evidence":"Yeast two-hybrid, co-IP/binding competition, ERβ translocation and AKT/ERK phosphorylation assays, proliferation assays in GC-1/GC-2 cells","pmids":["22383461"],"confidence":"Medium","gaps":["No structural basis for HPIP/ERβ competition","Physiological relevance of this somatic pathway in vivo not established"]},{"year":2015,"claim":"Whether TEX11 disruption causes human infertility and whether its dosage controls recombination were open; human mutation analyses and transgenic mouse rescue showed loss-of-function causes azoospermia/meiotic arrest and that TEX11 levels set genome-wide recombination rates.","evidence":"Human genetic screening and testis IHC; transgenic mouse complementation and recombination rate quantification","pmids":["26136358","25970010"],"confidence":"Medium","gaps":["Molecular mechanism by which TEX11 dosage tunes recombination not resolved","Did not define the protein complex mediating crossover stabilization"]},{"year":2025,"claim":"The biochemical mechanism by which TEX11 promotes crossovers was clarified by placing it in the trimeric ZZS complex with SHOC1 and SPO16 that binds and stabilizes post-strand-invasion recombination intermediates.","evidence":"Mouse CRISPR/Cas9 models, co-IP/complex assembly, ChIP, and meiotic spread cytology (preprint)","pmids":["bio_10.1101_2025.05.28.656576"],"confidence":"Medium","gaps":["TEX11 role inferred from a SHOC1 XPF-domain variant disrupting recruitment rather than direct TEX11 perturbation","Preprint, single study","Structure of the ZZS complex bound to intermediates not resolved"]},{"year":2025,"claim":"Whether specific human TEX11 variants are truly pathogenic was tested; an in-frame deletion variant produced truncated protein but did not perturb modeled ZZS structure and the corresponding mouse was fertile, indicating species-specific functional differences.","evidence":"HEK293 expression with qPCR/Western blot, in silico structural modeling, CRISPR/Cas9 mouse model","pmids":["41300722"],"confidence":"Medium","gaps":["Pathogenicity of the variant in humans remains unresolved by the negative mouse result","Structural modeling not experimentally validated"]},{"year":2024,"claim":"Whether a SPO22-domain exon 9-11 deletion mimicking a human variant disrupts function was tested; the mouse showed normal spermatogenesis, fertility, and transcriptome, reinforcing species-specific differences in TEX11 requirements.","evidence":"CRISPR/Cas9 Tex11Ex9-11del/Y mouse with sperm analysis, fertility assays, and testis RNA-seq","pmids":["39231187"],"confidence":"Medium","gaps":["Does not exclude pathogenicity of the orthologous human variant","Mechanistic basis of species difference unknown"]},{"year":2026,"claim":"How distinct human-derived TEX11 alleles map to phenotypic severity was examined; knock-in mice showed allele-specific outcomes ranging from complete maturation arrest to normal fertility to partial, incompletely penetrant defects.","evidence":"CRISPR/Cas9 knock-in mouse models (Tex11D, Tex11A, Tex11L) with testis weight, sperm counts, histology, and breeding assays (preprint)","pmids":["41756962"],"confidence":"Medium","gaps":["Molecular reason for allele-specific severity not defined","Preprint, single study","Direct translation of mouse allele phenotypes to human patients uncertain"]},{"year":null,"claim":"How TEX11 biochemically recognizes and stabilizes recombination intermediates within the ZZS complex, and how its dosage quantitatively controls genome-wide crossover designation, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experimentally determined structure of the TEX11-containing ZZS complex on DNA","Mechanism linking TEX11 abundance to recombination rate undefined","Reconciliation of human pathogenicity with species-specific mouse phenotypes incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,6]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,6]}],"complexes":["ZZS complex (TEX11-SHOC1-SPO16)"],"partners":["NBS1","SHOC1","SPO16","HPIP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IYF3","full_name":"Testis-expressed protein 11","aliases":["Protein ZIP4 homolog","ZIP4H"],"length_aa":940,"mass_kda":107.9,"function":"Regulator of crossing-over during meiosis. Involved in initiation and/or maintenance of chromosome synapsis and formation of crossovers","subcellular_location":"Chromosome","url":"https://www.uniprot.org/uniprotkb/Q8IYF3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TEX11","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TEX11","total_profiled":1310},"omim":[{"mim_id":"618968","title":"CHROMOSOME 1 OPEN READING FRAME 146; C1ORF146","url":"https://www.omim.org/entry/618968"},{"mim_id":"618038","title":"SHORTAGE IN CHIASMATA 1; SHOC1","url":"https://www.omim.org/entry/618038"},{"mim_id":"612041","title":"RING FINGER PROTEIN 212; RNF212","url":"https://www.omim.org/entry/612041"},{"mim_id":"309120","title":"SPERMATOGENIC FAILURE, X-LINKED, 2; SPGFX2","url":"https://www.omim.org/entry/309120"},{"mim_id":"300311","title":"TESTIS-EXPRESSED GENE 11; TEX11","url":"https://www.omim.org/entry/300311"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"pancreas","ntpm":55.5}],"url":"https://www.proteinatlas.org/search/TEX11"},"hgnc":{"alias_symbol":["TSGA3","TGC1","ZIP4","ZIP4H","MZIP4","Spo22"],"prev_symbol":[]},"alphafold":{"accession":"Q8IYF3","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYF3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYF3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYF3-F1-predicted_aligned_error_v6.png","plddt_mean":86.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TEX11","jax_strain_url":"https://www.jax.org/strain/search?query=TEX11"},"sequence":{"accession":"Q8IYF3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IYF3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IYF3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYF3"}},"corpus_meta":[{"pmid":"25970010","id":"PMC_25970010","title":"X-linked TEX11 mutations, meiotic arrest, and azoospermia in infertile men.","date":"2015","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25970010","citation_count":248,"is_preprint":false},{"pmid":"26136358","id":"PMC_26136358","title":"TEX11 is mutated in infertile men with azoospermia and regulates genome-wide recombination rates in mouse.","date":"2015","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26136358","citation_count":137,"is_preprint":false},{"pmid":"14612438","id":"PMC_14612438","title":"Zn2+-stimulated endocytosis of the mZIP4 zinc transporter regulates its location at the plasma membrane.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14612438","citation_count":121,"is_preprint":false},{"pmid":"18369460","id":"PMC_18369460","title":"ZIP4H (TEX11) deficiency in the mouse impairs meiotic double strand break repair and the regulation of crossing over.","date":"2008","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18369460","citation_count":108,"is_preprint":false},{"pmid":"16314568","id":"PMC_16314568","title":"Bioinformatic analyses implicate the collaborating meiotic crossover/chiasma proteins Zip2, Zip3, and Spo22/Zip4 in ubiquitin labeling.","date":"2005","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16314568","citation_count":69,"is_preprint":false},{"pmid":"29661171","id":"PMC_29661171","title":"A novel TEX11 mutation induces azoospermia: a case report of infertile brothers and literature review.","date":"2018","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29661171","citation_count":46,"is_preprint":false},{"pmid":"29932616","id":"PMC_29932616","title":"Expression analysis of genes encoding TEX11, TEX12, TEX14 and TEX15 in testis tissues of men with non-obstructive azoospermia.","date":"2018","source":"JBRA assisted reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/29932616","citation_count":27,"is_preprint":false},{"pmid":"22383461","id":"PMC_22383461","title":"TEX11 modulates germ cell proliferation by competing with estrogen receptor β for the binding to HPIP.","date":"2012","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/22383461","citation_count":26,"is_preprint":false},{"pmid":"33762476","id":"PMC_33762476","title":"A new TEX11 mutation causes azoospermia and testicular meiotic arrest.","date":"2021","source":"Asian journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/33762476","citation_count":19,"is_preprint":false},{"pmid":"34621296","id":"PMC_34621296","title":"Novel Hemizygous Mutations of TEX11 Cause Meiotic Arrest and Non-obstructive Azoospermia in Chinese Han Population.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34621296","citation_count":16,"is_preprint":false},{"pmid":"37124723","id":"PMC_37124723","title":"Novel mutations of TEX11 are associated with non-obstructive azoospermia.","date":"2023","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/37124723","citation_count":11,"is_preprint":false},{"pmid":"22319663","id":"PMC_22319663","title":"Characterization of the porcine testis-expressed gene 11 (Tex11).","date":"2011","source":"Spermatogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/22319663","citation_count":11,"is_preprint":false},{"pmid":"35248021","id":"PMC_35248021","title":"Association of CATSPER1, SPATA16 and TEX11 genes polymorphism with idiopathic azoospermia and oligospermia risk in Iranian population.","date":"2022","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/35248021","citation_count":7,"is_preprint":false},{"pmid":"36258021","id":"PMC_36258021","title":"Downregulation of TEX11 promotes S-Phase progression and proliferation in colorectal cancer cells through the FOXO3a/COP1/c-Jun/p21 axis.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/36258021","citation_count":6,"is_preprint":false},{"pmid":"39231187","id":"PMC_39231187","title":"A partial deletion within the meiosis-specific sporulation domain SPO22 of Tex11 is not associated with infertility in mice.","date":"2024","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/39231187","citation_count":3,"is_preprint":false},{"pmid":"36091389","id":"PMC_36091389","title":"Identification and functional analysis of Tex11 and Meig1 in spermatogenesis of Hyriopsis cumingii.","date":"2022","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/36091389","citation_count":2,"is_preprint":false},{"pmid":"35240466","id":"PMC_35240466","title":"Induced pluripotent stem cell line from a mouse model of human azoospermia with a frameshift mutation Tex11_1260Ins(TT).","date":"2022","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/35240466","citation_count":1,"is_preprint":false},{"pmid":"34439962","id":"PMC_34439962","title":"Expressional Profiling of TEX11, ESRα and BOLL Genes in Yak under Different Feeding Conditions.","date":"2021","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/34439962","citation_count":1,"is_preprint":false},{"pmid":"41300722","id":"PMC_41300722","title":"Is the TEX11-.652del237bp Exonic In-Frame Deletion Variant Associated with Azoospermia? The Results of an In Vitro and In Silico Study.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/41300722","citation_count":0,"is_preprint":false},{"pmid":"41756962","id":"PMC_41756962","title":"Tex11 Mutant Mouse Models of Human Azoospermia.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41756962","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.28.656576","title":"The XPF-like domain in SHOC1 required for homologous recombination and safeguarding autosome from meiotic silencing of unsynapsed chromatin","date":"2025-06-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.28.656576","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12385,"output_tokens":3002,"usd":0.041092,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10393,"output_tokens":3359,"usd":0.06797,"stage2_stop_reason":"end_turn"},"total_usd":0.109062,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"ZIP4H (TEX11) was identified as an NBS1-interacting protein via yeast two-hybrid screening. Loss of ZIP4H in male mice delays meiotic double-strand break repair (as shown by DMC1 staining) and reduces crossover formation (as shown by decreased MLH1 focus formation), leading to achiasmate chromosomes at meiosis I. These findings establish ZIP4H as a functional collaborator of the Mre11 complex in mammalian meiotic DSB repair and crossover regulation.\",\n      \"method\": \"Yeast two-hybrid screening, mouse knockout (Zip4h−/Y), immunostaining for DMC1 (DSB repair marker) and MLH1 (crossover marker), cytological analysis of spermatocytes\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic interaction established by knockout mouse with multiple orthogonal cytological assays (DMC1, MLH1 staining), yeast two-hybrid binding confirmation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"18369460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Bioinformatic analysis (ABRA method) predicts Spo22/Zip4 (the yeast ortholog of TEX11) is a 22-unit tetratricopeptide repeat (TPR) protein. Together with Zip2 and Zip3, it is proposed to act at crossover-designated recombination sites; Zip3 contains a RING finger homologous to known ubiquitin E3s, suggesting the Zip2/Zip3/Spo22 complex mediates ubiquitin labeling during crossover formation.\",\n      \"method\": \"Bioinformatic sequence analysis (ABRA repeat annotation), structural domain prediction\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/bioinformatic prediction only, no experimental validation of TEX11/Spo22 ubiquitin activity\",\n      \"pmids\": [\"16314568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TEX11 mutations (frameshift, splicing, missense) cause meiotic arrest and azoospermia in men. Functional transgenic mouse models showed that an intronless autosomal Tex11 transgene can substitute for X-linked Tex11, providing genetic evidence for X-to-autosomal retrotransposition. TEX11 protein levels modulate genome-wide recombination rates in both sexes in the mouse.\",\n      \"method\": \"Genetic screening (Sanger/next-generation sequencing), transgenic mouse complementation assay, recombination rate analysis in transgenic mice\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic mouse rescue (intronless autosomal transgene complementing X-linked knockout) plus genome-wide recombination rate quantification; multiple orthogonal approaches in one study\",\n      \"pmids\": [\"26136358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss-of-function TEX11 mutations (including a 79-aa deletion in the SPO22 domain, splicing mutations, missense mutations) cause meiotic arrest in human testes. Immunohistochemical analysis of human testes showed TEX11 protein expression specifically in late spermatocytes, round spermatids, and elongated spermatids, and patients with TEX11 mutations lacked TEX11 expression with meiotic arrest.\",\n      \"method\": \"Array CGH, Sanger sequencing, immunohistochemistry of human testis biopsies\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in human patients with defined meiotic arrest phenotype and localization by IHC; no in vitro reconstitution but multiple patients and genetic confirmation\",\n      \"pmids\": [\"25970010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TEX11 competes with estrogen receptor β (ERβ) for binding to HPIP (hematopoietic pre-B cell leukemia transcription factor-interacting protein) in cultured cells. TEX11 promotes nuclear translocation of ERβ and enhances its transcriptional activity, while suppressing ERβ nongenomic cytoplasmic signaling (reduced AKT and ERK phosphorylation). Overexpression of TEX11 in mouse germ cell-derived lines suppresses cell proliferation and estradiol-stimulated expression of cFos, Ccnd1, and Ccnb1, and elevates pro-apoptotic Bax expression.\",\n      \"method\": \"Yeast two-hybrid screening (identification of HPIP), co-immunoprecipitation/binding competition assays in cultured cells, ERβ nuclear translocation assay, AKT/ERK phosphorylation assay, cell proliferation assay with TEX11 overexpression in GC-1/GC-2 cells, RT-PCR for target genes\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus functional competition assays in cultured cells; single lab with multiple readouts but no structural or in vitro reconstitution validation\",\n      \"pmids\": [\"22383461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In colorectal cancer cells, TEX11 promotes COP1 transcription by upregulating FOXO3a expression; enhanced COP1 then accelerates degradation of the negative transcriptional regulator c-Jun, which in turn enhances p21 transcription, inhibiting cell cycle S-phase progression and proliferation. TEX11 overexpression inhibits CRC cell proliferation in vitro and in vivo.\",\n      \"method\": \"Overexpression and knockdown of TEX11 in CRC cell lines, in vivo tumor xenograft, Western blotting, reporter/transcription assays for FOXO3a, COP1, c-Jun, and p21\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined pathway placement by loss/gain of function with multiple molecular readouts and in vivo validation; single lab\",\n      \"pmids\": [\"36258021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TEX11 is a component of the trimeric ZZS complex (with SHOC1/Zip2-like and SPO16/Spo16-like proteins) that binds recombination intermediates after strand invasion to stabilize them and promote crossover formation during meiosis. Disruption of SHOC1's XPF-like domain impairs recruitment of TEX11 and other ZMM factors to recombination intermediates, abolishing crossover formation.\",\n      \"method\": \"Mouse genetic models (CRISPR/Cas9), co-immunoprecipitation/complex assembly, chromatin immunoprecipitation, cytological analysis of meiotic spreads\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, complex membership established by co-IP and localization at recombination intermediates, single study; TEX11 role in complex inferred from SHOC1 variant disrupting TEX11 recruitment\",\n      \"pmids\": [\"bio_10.1101_2025.05.28.656576\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In vitro expression of the TEX11-c.652del237bp in-frame deletion variant in HEK293 cells produces a truncated mRNA and truncated protein (confirmed by qPCR and Western blot). In silico structural modeling suggests this deletion does not significantly impact the ZZS complex structure, raising doubt about its pathogenicity. The corresponding mouse model is fertile, suggesting species-specific differences in TEX11 function.\",\n      \"method\": \"Transfection of plasmid constructs into HEK293 cells, qPCR, Western blot, in silico structural modeling, CRISPR/Cas9 mouse model\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro expression analysis with Western blot confirms truncated protein production; mouse model shows negative phenotypic result; two orthogonal methods in one study\",\n      \"pmids\": [\"41300722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In mouse knock-in models, a frameshift TEX11 variant (Tex11D) causes complete NOA with maturation arrest and no epididymal sperm, while a missense variant (Tex11A) causes no spermatogenesis or fertility defects. A third variant (Tex11L) causes reduced testis weight and epididymal sperm counts with incompletely penetrant infertility and a distinct epididymal phenotype (reduced sperm density in caput, amorphous material in cauda).\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse models, testis weight measurement, epididymal sperm count, fertility breeding assays, histology\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint; clean CRISPR knock-in mouse models with variant-specific phenotypic readouts; single study\",\n      \"pmids\": [\"41756962\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A partial deletion of TEX11 exons 9–11 (mimicking a human variant in the SPO22 domain) introduced by CRISPR/Cas9 into mice (Tex11Ex9-11del/Y) does not impair spermatogenesis or fertility; sperm concentration, motility, morphology, and testis transcriptome were all normal. This negative result indicates that this specific SPO22 deletion does not functionally disrupt TEX11 in mice, highlighting species-specific differences.\",\n      \"method\": \"CRISPR/Cas9 mouse model, sperm analysis, RNA-seq of testis transcriptome, fertility assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — negative finding from clean CRISPR knock-in mouse with multiple phenotypic assays (sperm parameters, fertility, transcriptome); single lab but multiple orthogonal readouts\",\n      \"pmids\": [\"39231187\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TEX11 is a meiosis-specific, X-linked protein that forms part of the conserved ZZS trimeric complex (with SHOC1 and SPO16) to bind and stabilize strand-invasion recombination intermediates, promote meiotic double-strand break repair through interaction with NBS1, and regulate genome-wide crossover formation and chromosomal synapsis; loss-of-function mutations or deletions in its TPR-containing or SPO22 domain cause meiotic arrest and azoospermia in men and male mice, while in somatic contexts TEX11 can modulate cell proliferation by competing with ERβ for HPIP binding and by activating a FOXO3a/COP1/c-Jun/p21 axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TEX11 is a meiosis-specific protein that regulates genome-wide crossover formation and meiotic double-strand break (DSB) repair during spermatogenesis [#0, #2]. It was first identified as an NBS1-interacting partner whose loss in male mice delays DSB repair (reduced DMC1 resolution) and reduces crossovers (decreased MLH1 foci), producing achiasmate chromosomes at meiosis I and establishing TEX11 as a functional collaborator of the Mre11/NBS1 complex [#0]. TEX11 acts as a component of the trimeric ZZS complex together with SHOC1 and SPO16, binding recombination intermediates after strand invasion to stabilize them and promote crossover formation; recruitment of TEX11 to these intermediates depends on the SHOC1 XPF-like domain [#6]. TEX11 protein levels set genome-wide recombination rates, and an intronless autosomal Tex11 transgene rescues the X-linked knockout, providing evidence for retrotransposition [#2]. In men, loss-of-function TEX11 mutations cause meiotic arrest and azoospermia, with TEX11 normally expressed in late spermatocytes and spermatids and absent in affected patients [#3]. Beyond its meiotic role, TEX11 modulates cell proliferation in somatic/cultured-cell contexts: it competes with estrogen receptor \\u03b2 (ER\\u03b2) for HPIP binding, enhancing ER\\u03b2 nuclear transcriptional activity while suppressing its cytoplasmic AKT/ERK signaling [#4], and in colorectal cancer cells it inhibits proliferation through a FOXO3a\\u2192COP1\\u2192c-Jun\\u2192p21 axis [#5]. Multiple knock-in mouse studies show that the meiotic requirement is variant- and species-specific, as several human-mimicking SPO22-domain and missense alleles do not disrupt mouse spermatogenesis [#7, #8, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Before functional data, the question was what type of protein TEX11/Spo22 is and where it acts; bioinformatics predicted a 22-unit TPR architecture functioning at crossover-designated recombination sites alongside Zip2 and Zip3.\",\n      \"evidence\": \"Bioinformatic repeat annotation (ABRA) and structural domain prediction of the yeast Spo22/Zip4 ortholog\",\n      \"pmids\": [\"16314568\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Purely computational; no experimental validation of TPR structure or of any ubiquitin-labeling activity\", \"Inferred only from yeast ortholog, not mammalian TEX11\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"It was unknown how TEX11 connects to the DSB repair machinery; identifying it as an NBS1 interactor whose knockout delays DSB repair and reduces crossovers placed it functionally within meiotic recombination and crossover control.\",\n      \"evidence\": \"Yeast two-hybrid screen, Zip4h\\u2212/Y mouse knockout with DMC1 and MLH1 cytology in spermatocytes\",\n      \"pmids\": [\"18369460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how TEX11 acts biochemically on recombination intermediates\", \"Did not establish the larger complex in which TEX11 operates\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Whether TEX11 has functions outside meiosis was unaddressed; competition with ER\\u03b2 for HPIP and modulation of ER\\u03b2 signaling and proliferation revealed a somatic, hormone-signaling-linked activity.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP/binding competition, ER\\u03b2 translocation and AKT/ERK phosphorylation assays, proliferation assays in GC-1/GC-2 cells\",\n      \"pmids\": [\"22383461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural basis for HPIP/ER\\u03b2 competition\", \"Physiological relevance of this somatic pathway in vivo not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Whether TEX11 disruption causes human infertility and whether its dosage controls recombination were open; human mutation analyses and transgenic mouse rescue showed loss-of-function causes azoospermia/meiotic arrest and that TEX11 levels set genome-wide recombination rates.\",\n      \"evidence\": \"Human genetic screening and testis IHC; transgenic mouse complementation and recombination rate quantification\",\n      \"pmids\": [\"26136358\", \"25970010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which TEX11 dosage tunes recombination not resolved\", \"Did not define the protein complex mediating crossover stabilization\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The biochemical mechanism by which TEX11 promotes crossovers was clarified by placing it in the trimeric ZZS complex with SHOC1 and SPO16 that binds and stabilizes post-strand-invasion recombination intermediates.\",\n      \"evidence\": \"Mouse CRISPR/Cas9 models, co-IP/complex assembly, ChIP, and meiotic spread cytology (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.05.28.656576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TEX11 role inferred from a SHOC1 XPF-domain variant disrupting recruitment rather than direct TEX11 perturbation\", \"Preprint, single study\", \"Structure of the ZZS complex bound to intermediates not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether specific human TEX11 variants are truly pathogenic was tested; an in-frame deletion variant produced truncated protein but did not perturb modeled ZZS structure and the corresponding mouse was fertile, indicating species-specific functional differences.\",\n      \"evidence\": \"HEK293 expression with qPCR/Western blot, in silico structural modeling, CRISPR/Cas9 mouse model\",\n      \"pmids\": [\"41300722\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathogenicity of the variant in humans remains unresolved by the negative mouse result\", \"Structural modeling not experimentally validated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether a SPO22-domain exon 9-11 deletion mimicking a human variant disrupts function was tested; the mouse showed normal spermatogenesis, fertility, and transcriptome, reinforcing species-specific differences in TEX11 requirements.\",\n      \"evidence\": \"CRISPR/Cas9 Tex11Ex9-11del/Y mouse with sperm analysis, fertility assays, and testis RNA-seq\",\n      \"pmids\": [\"39231187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not exclude pathogenicity of the orthologous human variant\", \"Mechanistic basis of species difference unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"How distinct human-derived TEX11 alleles map to phenotypic severity was examined; knock-in mice showed allele-specific outcomes ranging from complete maturation arrest to normal fertility to partial, incompletely penetrant defects.\",\n      \"evidence\": \"CRISPR/Cas9 knock-in mouse models (Tex11D, Tex11A, Tex11L) with testis weight, sperm counts, histology, and breeding assays (preprint)\",\n      \"pmids\": [\"41756962\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular reason for allele-specific severity not defined\", \"Preprint, single study\", \"Direct translation of mouse allele phenotypes to human patients uncertain\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TEX11 biochemically recognizes and stabilizes recombination intermediates within the ZZS complex, and how its dosage quantitatively controls genome-wide crossover designation, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimentally determined structure of the TEX11-containing ZZS complex on DNA\", \"Mechanism linking TEX11 abundance to recombination rate undefined\", \"Reconciliation of human pathogenicity with species-specific mouse phenotypes incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"complexes\": [\"ZZS complex (TEX11-SHOC1-SPO16)\"],\n    \"partners\": [\"NBS1\", \"SHOC1\", \"SPO16\", \"HPIP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}