{"gene":"TEX11","run_date":"2026-04-28T21:42:58","timeline":{"discoveries":[{"year":2008,"finding":"TEX11 (ZIP4H) was identified as a mammalian ortholog of yeast/Arabidopsis Zip4, shown to interact with NBS1 (meiosis-specific) via yeast two-hybrid screening. Tex11-deficient male mice show delayed meiotic double-strand break repair (assessed by DMC1 staining) and decreased crossover formation (assessed by MLH1 focus counts), with achiasmate chromosomes at meiosis I, establishing TEX11's role in meiotic DSB repair and crossover regulation.","method":"Yeast two-hybrid screening, mouse knockout model (Zip4h−/Y), immunostaining for DMC1 and MLH1, cytological analysis of spermatocytes","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype (DSB repair delay, reduced MLH1 foci, achiasmate chromosomes), multiple orthogonal methods","pmids":["18369460"],"is_preprint":false},{"year":2015,"finding":"TEX11 mutations (hemizygous deletions, splicing mutations, missense mutations) in humans cause meiotic arrest and azoospermia, with loss of TEX11 protein expression in spermatocytes confirmed by immunohistochemistry. TEX11 protein is specifically expressed in late spermatocytes and round/elongated spermatids in normal human testes.","method":"Array CGH, Sanger sequencing, immunohistochemistry of human testis biopsies","journal":"The New England journal of medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple mutation types identified, IHC localization directly linked to meiotic arrest phenotype, large cohort","pmids":["25970010"],"is_preprint":false},{"year":2015,"finding":"TEX11 protein levels modulate genome-wide recombination rates in both sexes in mice. An intronless autosomal Tex11 transgene functionally substitutes for the X-linked Tex11 gene, providing genetic evidence for X-to-autosomal retrotransposition. A human missense mutation V748A was identified as a potential infertility allele by functional evaluation in transgenic mouse models.","method":"Transgenic mouse models, genetic rescue experiment with autosomal Tex11 transgene, recombination rate measurement","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple transgenic lines, direct functional substitution assay, genome-wide recombination measurement","pmids":["26136358"],"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 spermatogonia. TEX11 promotes nuclear translocation of ERβ and enhances its transcriptional activity, while suppressing non-genomic ERβ signaling (AKT and ERK phosphorylation). Overexpression of TEX11 suppresses germ cell proliferation and upregulates pro-apoptotic Bax.","method":"Yeast two-hybrid screening, co-immunoprecipitation, cell-based overexpression assays, reporter assays, Western blot for AKT/ERK phosphorylation","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 — yeast two-hybrid plus co-IP plus functional cell assays, single lab","pmids":["22383461"],"is_preprint":false},{"year":2021,"finding":"The mammalian ortholog of yeast Zip4, TEX11, interacts with the synaptonemal complex central element TEX12, paralleling the yeast Zip4–Ecm11 interaction. This suggests a conserved mechanism by which TEX11 directly couples crossover formation to synaptonemal complex assembly.","method":"Co-immunoprecipitation, interaction assays demonstrating TEX11-TEX12 binding","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP demonstrating TEX11-TEX12 interaction, supported by mechanistic framework from yeast ortholog study","pmids":["34969823"],"is_preprint":false},{"year":2022,"finding":"TEX11 promotes transcription of COP1 by upregulating FOXO3a expression in colorectal cancer cells. Enhanced COP1 accelerates degradation of the transcriptional repressor c-Jun, which in turn enhances p21 transcription, inhibiting cell cycle progression (S-phase entry) and proliferation.","method":"Knockdown/overexpression in CRC cell lines and xenograft models, Western blot, luciferase reporter assays, flow cytometry","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple cell lines, in vivo xenograft, mechanistic pathway dissection with reporters, single lab","pmids":["36258021"],"is_preprint":false},{"year":2011,"finding":"TEX11 is exclusively expressed in germ cells in the adult pig testis, is X-linked, and its expression is correlated with the onset of meiosis, establishing conservation of TEX11's meiotic function and expression pattern across species (pig and mouse).","method":"RT-PCR, Western blot, tissue expression profiling in porcine testis","journal":"Spermatogenesis","confidence":"Low","confidence_rationale":"Tier 3 — expression profiling with no direct functional experiment, single lab","pmids":["22319663"],"is_preprint":false},{"year":2021,"finding":"TEX11 frameshift mutation (p.D51fs) in a patient with azoospermia results in no detectable TEX11 protein expression (confirmed by Western blot of transfected HEK293 cells), and testicular histology shows meiotic arrest at the pachytene stage with TEX11 expression in late-pachytene spermatocytes and round spermatids in fertile testes.","method":"Whole-exome sequencing, Sanger sequencing, immunohistochemistry, Western blot of transfected cells","journal":"Asian journal of andrology","confidence":"Medium","confidence_rationale":"Tier 2 — functional validation of specific mutation by transfection/Western blot plus patient histology","pmids":["33762476"],"is_preprint":false},{"year":2025,"finding":"In vitro and in silico analysis of the TEX11 c.652del237bp in-frame deletion showed that the deletion produces a truncated mRNA and protein in transfected HEK293 cells, and in silico modeling suggests the deletion does not significantly impact the ZZS complex structure, raising questions about its pathogenicity. TEX11 is described as a component of the ZZS complex (with Zip2, Zip4, and Spo16 from S. cerevisiae) required for DSB repair promotion during meiosis.","method":"Plasmid transfection into HEK293 cells, qPCR, Western blot, in silico structural modeling","journal":"Genes","confidence":"Low","confidence_rationale":"Tier 3 — single lab, in vitro only, no direct meiotic assay","pmids":["41300722"],"is_preprint":false}],"current_model":"TEX11 is a meiosis-specific, X-linked protein (mammalian ortholog of yeast/Arabidopsis Zip4) that localizes to late spermatocytes and promotes meiotic double-strand break repair and crossover formation by functioning within the ZMM complex; it directly interacts with the synaptonemal complex central element TEX12 to couple crossover designation to SC assembly, and in spermatogonia it competes with ERβ for binding to HPIP to modulate germ cell proliferation — loss-of-function causes meiotic arrest and azoospermia in both mice and men."},"narrative":{"teleology":[{"year":2008,"claim":"The identification of TEX11 as a mammalian Zip4 ortholog that interacts with NBS1 and whose deletion causes delayed DSB repair and reduced crossovers established it as a central meiotic recombination factor, resolving what mammalian gene fulfills the Zip4/ZMM crossover-promoting function.","evidence":"Yeast two-hybrid screen plus Tex11-knockout mouse with DMC1 and MLH1 immunostaining in spermatocytes","pmids":["18369460"],"confidence":"High","gaps":["Mechanism by which TEX11 promotes DSB repair (enzymatic vs. scaffolding role) was not defined","Relationship between TEX11 and synaptonemal complex assembly was not addressed","Whether TEX11 functions similarly in female meiosis was untested"]},{"year":2012,"claim":"Discovery that TEX11 competes with ERβ for HPIP binding in spermatogonia and modulates ERβ nuclear translocation revealed a second, non-crossover function in regulating germ cell proliferation signaling.","evidence":"Yeast two-hybrid, co-IP, cell-based overexpression with reporter assays and Western blot for AKT/ERK phosphorylation","pmids":["22383461"],"confidence":"Medium","gaps":["Physiological relevance in vivo during spermatogonial proliferation was not tested","Whether this HPIP-ERβ axis contributes to the meiotic arrest phenotype of TEX11 loss is unknown","Findings from a single lab without independent replication"]},{"year":2015,"claim":"Identification of TEX11 loss-of-function mutations in azoospermic men and demonstration that TEX11 dosage modulates genome-wide recombination rates via transgenic rescue translated the mouse findings into human disease and established TEX11 as a dosage-sensitive crossover regulator.","evidence":"Array CGH and sequencing of infertile men; autosomal Tex11 transgene rescue in knockout mice with MLH1 focus quantification","pmids":["25970010","26136358"],"confidence":"High","gaps":["The structural basis for TEX11 dosage sensitivity on crossover number was not determined","Genotype–phenotype correlation for specific human TEX11 variants remained incomplete","Whether heterozygous females show recombination phenotypes was not fully resolved"]},{"year":2021,"claim":"Demonstration that TEX11 directly binds the SC central element TEX12 — paralleling yeast Zip4–Ecm11 — provided a molecular mechanism by which crossover designation is coupled to synaptonemal complex assembly.","evidence":"Co-immunoprecipitation showing TEX11–TEX12 interaction, interpreted through yeast ortholog framework","pmids":["34969823"],"confidence":"Medium","gaps":["Structural details of the TEX11–TEX12 interface are lacking","Whether disruption of TEX11–TEX12 interaction specifically uncouples crossover formation from SC assembly in vivo has not been tested","Full reconstitution of the mammalian ZMM/ZZS complex has not been achieved"]},{"year":2021,"claim":"A TEX11 frameshift mutation (p.D51fs) confirmed to abolish protein expression was linked to pachytene-arrest azoospermia, reinforcing the strict requirement for TEX11 protein in completing meiotic prophase I.","evidence":"Whole-exome sequencing of an azoospermic patient, Western blot in transfected HEK293 cells, testicular histology","pmids":["33762476"],"confidence":"Medium","gaps":["Only a single patient was studied","Functional consequence was assessed only in a non-meiotic cell line (HEK293)","Whether specific TEX11 domains are individually required for meiotic progression is unknown"]},{"year":null,"claim":"The structural architecture of the mammalian ZZS complex containing TEX11, the domain-level requirements for TEX11's interactions with NBS1 and TEX12, and whether TEX11's non-meiotic signaling roles (ERβ/HPIP axis, COP1/FOXO3a pathway) have physiological relevance in vivo remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of TEX11 or its complexes exists","In vivo significance of TEX11 in spermatogonial proliferation via HPIP/ERβ is untested","Functional domain mapping (which domains mediate crossover promotion vs. SC coupling) has not been performed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,3,7]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1,2]}],"complexes":["ZZS complex (mammalian ZMM)"],"partners":["NBS1","TEX12","HPIP","ESR2"],"other_free_text":[]},"mechanistic_narrative":"TEX11 is a meiosis-specific, X-linked protein that functions as the mammalian ortholog of yeast Zip4 to promote meiotic double-strand break repair and crossover formation during spermatogenesis. Tex11-deficient male mice exhibit delayed DSB repair (persistent DMC1 foci), reduced crossover numbers (decreased MLH1 foci), and achiasmate chromosomes leading to meiotic arrest, and TEX11 protein levels modulate genome-wide recombination rates in both sexes [PMID:18369460, PMID:26136358]. TEX11 directly interacts with the synaptonemal complex central element TEX12, coupling crossover designation to SC assembly through a mechanism conserved from the yeast Zip4–Ecm11 interaction [PMID:34969823]. Loss-of-function mutations in TEX11 — including deletions, frameshifts, and splice-site variants — cause meiotic arrest at the pachytene stage and non-obstructive azoospermia in men [PMID:25970010, PMID:33762476]."},"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 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Tex11-deficient male mice show delayed meiotic double-strand break repair (assessed by DMC1 staining) and decreased crossover formation (assessed by MLH1 focus counts), with achiasmate chromosomes at meiosis I, establishing TEX11's role in meiotic DSB repair and crossover regulation.\",\n      \"method\": \"Yeast two-hybrid screening, mouse knockout model (Zip4h−/Y), immunostaining for DMC1 and MLH1, cytological analysis of spermatocytes\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype (DSB repair delay, reduced MLH1 foci, achiasmate chromosomes), multiple orthogonal methods\",\n      \"pmids\": [\"18369460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TEX11 mutations (hemizygous deletions, splicing mutations, missense mutations) in humans cause meiotic arrest and azoospermia, with loss of TEX11 protein expression in spermatocytes confirmed by immunohistochemistry. TEX11 protein is specifically expressed in late spermatocytes and round/elongated spermatids in normal human testes.\",\n      \"method\": \"Array CGH, Sanger sequencing, immunohistochemistry of human testis biopsies\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple mutation types identified, IHC localization directly linked to meiotic arrest phenotype, large cohort\",\n      \"pmids\": [\"25970010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TEX11 protein levels modulate genome-wide recombination rates in both sexes in mice. An intronless autosomal Tex11 transgene functionally substitutes for the X-linked Tex11 gene, providing genetic evidence for X-to-autosomal retrotransposition. A human missense mutation V748A was identified as a potential infertility allele by functional evaluation in transgenic mouse models.\",\n      \"method\": \"Transgenic mouse models, genetic rescue experiment with autosomal Tex11 transgene, recombination rate measurement\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple transgenic lines, direct functional substitution assay, genome-wide recombination measurement\",\n      \"pmids\": [\"26136358\"],\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 spermatogonia. TEX11 promotes nuclear translocation of ERβ and enhances its transcriptional activity, while suppressing non-genomic ERβ signaling (AKT and ERK phosphorylation). Overexpression of TEX11 suppresses germ cell proliferation and upregulates pro-apoptotic Bax.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, cell-based overexpression assays, reporter assays, Western blot for AKT/ERK phosphorylation\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid plus co-IP plus functional cell assays, single lab\",\n      \"pmids\": [\"22383461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The mammalian ortholog of yeast Zip4, TEX11, interacts with the synaptonemal complex central element TEX12, paralleling the yeast Zip4–Ecm11 interaction. This suggests a conserved mechanism by which TEX11 directly couples crossover formation to synaptonemal complex assembly.\",\n      \"method\": \"Co-immunoprecipitation, interaction assays demonstrating TEX11-TEX12 binding\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP demonstrating TEX11-TEX12 interaction, supported by mechanistic framework from yeast ortholog study\",\n      \"pmids\": [\"34969823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TEX11 promotes transcription of COP1 by upregulating FOXO3a expression in colorectal cancer cells. Enhanced COP1 accelerates degradation of the transcriptional repressor c-Jun, which in turn enhances p21 transcription, inhibiting cell cycle progression (S-phase entry) and proliferation.\",\n      \"method\": \"Knockdown/overexpression in CRC cell lines and xenograft models, Western blot, luciferase reporter assays, flow cytometry\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple cell lines, in vivo xenograft, mechanistic pathway dissection with reporters, single lab\",\n      \"pmids\": [\"36258021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TEX11 is exclusively expressed in germ cells in the adult pig testis, is X-linked, and its expression is correlated with the onset of meiosis, establishing conservation of TEX11's meiotic function and expression pattern across species (pig and mouse).\",\n      \"method\": \"RT-PCR, Western blot, tissue expression profiling in porcine testis\",\n      \"journal\": \"Spermatogenesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — expression profiling with no direct functional experiment, single lab\",\n      \"pmids\": [\"22319663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TEX11 frameshift mutation (p.D51fs) in a patient with azoospermia results in no detectable TEX11 protein expression (confirmed by Western blot of transfected HEK293 cells), and testicular histology shows meiotic arrest at the pachytene stage with TEX11 expression in late-pachytene spermatocytes and round spermatids in fertile testes.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, immunohistochemistry, Western blot of transfected cells\",\n      \"journal\": \"Asian journal of andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional validation of specific mutation by transfection/Western blot plus patient histology\",\n      \"pmids\": [\"33762476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In vitro and in silico analysis of the TEX11 c.652del237bp in-frame deletion showed that the deletion produces a truncated mRNA and protein in transfected HEK293 cells, and in silico modeling suggests the deletion does not significantly impact the ZZS complex structure, raising questions about its pathogenicity. TEX11 is described as a component of the ZZS complex (with Zip2, Zip4, and Spo16 from S. cerevisiae) required for DSB repair promotion during meiosis.\",\n      \"method\": \"Plasmid transfection into HEK293 cells, qPCR, Western blot, in silico structural modeling\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, in vitro only, no direct meiotic assay\",\n      \"pmids\": [\"41300722\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TEX11 is a meiosis-specific, X-linked protein (mammalian ortholog of yeast/Arabidopsis Zip4) that localizes to late spermatocytes and promotes meiotic double-strand break repair and crossover formation by functioning within the ZMM complex; it directly interacts with the synaptonemal complex central element TEX12 to couple crossover designation to SC assembly, and in spermatogonia it competes with ERβ for binding to HPIP to modulate germ cell proliferation — loss-of-function causes meiotic arrest and azoospermia in both mice and men.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TEX11 is a meiosis-specific, X-linked protein that functions as the mammalian ortholog of yeast Zip4 to promote meiotic double-strand break repair and crossover formation during spermatogenesis. Tex11-deficient male mice exhibit delayed DSB repair (persistent DMC1 foci), reduced crossover numbers (decreased MLH1 foci), and achiasmate chromosomes leading to meiotic arrest, and TEX11 protein levels modulate genome-wide recombination rates in both sexes [PMID:18369460, PMID:26136358]. TEX11 directly interacts with the synaptonemal complex central element TEX12, coupling crossover designation to SC assembly through a mechanism conserved from the yeast Zip4–Ecm11 interaction [PMID:34969823]. Loss-of-function mutations in TEX11 — including deletions, frameshifts, and splice-site variants — cause meiotic arrest at the pachytene stage and non-obstructive azoospermia in men [PMID:25970010, PMID:33762476].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"The identification of TEX11 as a mammalian Zip4 ortholog that interacts with NBS1 and whose deletion causes delayed DSB repair and reduced crossovers established it as a central meiotic recombination factor, resolving what mammalian gene fulfills the Zip4/ZMM crossover-promoting function.\",\n      \"evidence\": \"Yeast two-hybrid screen plus Tex11-knockout mouse with DMC1 and MLH1 immunostaining in spermatocytes\",\n      \"pmids\": [\"18369460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which TEX11 promotes DSB repair (enzymatic vs. scaffolding role) was not defined\",\n        \"Relationship between TEX11 and synaptonemal complex assembly was not addressed\",\n        \"Whether TEX11 functions similarly in female meiosis was untested\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that TEX11 competes with ERβ for HPIP binding in spermatogonia and modulates ERβ nuclear translocation revealed a second, non-crossover function in regulating germ cell proliferation signaling.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, cell-based overexpression with reporter assays and Western blot for AKT/ERK phosphorylation\",\n      \"pmids\": [\"22383461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Physiological relevance in vivo during spermatogonial proliferation was not tested\",\n        \"Whether this HPIP-ERβ axis contributes to the meiotic arrest phenotype of TEX11 loss is unknown\",\n        \"Findings from a single lab without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of TEX11 loss-of-function mutations in azoospermic men and demonstration that TEX11 dosage modulates genome-wide recombination rates via transgenic rescue translated the mouse findings into human disease and established TEX11 as a dosage-sensitive crossover regulator.\",\n      \"evidence\": \"Array CGH and sequencing of infertile men; autosomal Tex11 transgene rescue in knockout mice with MLH1 focus quantification\",\n      \"pmids\": [\"25970010\", \"26136358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The structural basis for TEX11 dosage sensitivity on crossover number was not determined\",\n        \"Genotype–phenotype correlation for specific human TEX11 variants remained incomplete\",\n        \"Whether heterozygous females show recombination phenotypes was not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstration that TEX11 directly binds the SC central element TEX12 — paralleling yeast Zip4–Ecm11 — provided a molecular mechanism by which crossover designation is coupled to synaptonemal complex assembly.\",\n      \"evidence\": \"Co-immunoprecipitation showing TEX11–TEX12 interaction, interpreted through yeast ortholog framework\",\n      \"pmids\": [\"34969823\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural details of the TEX11–TEX12 interface are lacking\",\n        \"Whether disruption of TEX11–TEX12 interaction specifically uncouples crossover formation from SC assembly in vivo has not been tested\",\n        \"Full reconstitution of the mammalian ZMM/ZZS complex has not been achieved\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A TEX11 frameshift mutation (p.D51fs) confirmed to abolish protein expression was linked to pachytene-arrest azoospermia, reinforcing the strict requirement for TEX11 protein in completing meiotic prophase I.\",\n      \"evidence\": \"Whole-exome sequencing of an azoospermic patient, Western blot in transfected HEK293 cells, testicular histology\",\n      \"pmids\": [\"33762476\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Only a single patient was studied\",\n        \"Functional consequence was assessed only in a non-meiotic cell line (HEK293)\",\n        \"Whether specific TEX11 domains are individually required for meiotic progression is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural architecture of the mammalian ZZS complex containing TEX11, the domain-level requirements for TEX11's interactions with NBS1 and TEX12, and whether TEX11's non-meiotic signaling roles (ERβ/HPIP axis, COP1/FOXO3a pathway) have physiological relevance in vivo remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of TEX11 or its complexes exists\",\n        \"In vivo significance of TEX11 in spermatogonial proliferation via HPIP/ERβ is untested\",\n        \"Functional domain mapping (which domains mediate crossover promotion vs. SC coupling) has not been performed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 3, 7]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\n      \"ZZS complex (mammalian ZMM)\"\n    ],\n    \"partners\": [\n      \"NBS1\",\n      \"TEX12\",\n      \"HPIP\",\n      \"ESR2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}