{"gene":"TEKT2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2014,"finding":"TEKT2 localizes to the periphery of the outer dense fiber (ODF) in sperm flagella, and interacts with TEKT2BP1 (Ccdc172) as identified by yeast two-hybrid screening; TEKT2BP1 localizes to the mitochondria sheath of the flagella middle piece, suggesting the TEKT2-TEKT2BP1 complex links the ODF and mitochondria in the middle piece.","method":"Yeast two-hybrid screening, immunocytochemistry, subcellular fractionation/localization","journal":"The journal of histochemistry and cytochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus immunocytochemical localization, single lab, two complementary methods but no in vitro reconstitution or reciprocal co-IP","pmids":["24394471"],"is_preprint":false},{"year":2016,"finding":"TEKT2 is present at the acrosome cap in unactivated bull spermatozoa (distinct from TEKT3 which is in the post-acrosomal region), as determined by immunolocalization; this subcellular distribution differs from TEKT2's flagellar localization, indicating a head-specific pool.","method":"Immunofluorescence/immunocytochemistry on bull spermatozoa","journal":"Molecular reproduction and development","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single immunolocalization method, no functional consequence directly tested for TEKT2 specifically","pmids":["27883267"],"is_preprint":false},{"year":2018,"finding":"Knockdown of the oocyte-specific gene Oog1 in mice leads to increased expression of spermatogenesis-associated transcripts including Tekt2 in ovaries, establishing that Oog1 normally suppresses Tekt2 expression in female germ cells.","method":"RNAi transgenic mouse model, quantitative RT-PCR","journal":"The Journal of reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic knockdown with defined transcriptional phenotype, single lab, single method (qRT-PCR readout)","pmids":["29731491"],"is_preprint":false},{"year":2022,"finding":"In zebrafish tulp1 double-knockout retinas, tekt2 expression is downregulated and photoreceptor cilium length is reduced; dual-luciferase reporter assay showed that Tulp1a and Tulp1b transcriptionally activate the tekt2 promoter, placing TEKT2 downstream of TULP1 in a cilia-structure pathway.","method":"CRISPR knockout zebrafish model, RNA-seq, dual-luciferase reporter assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in vivo combined with reporter assay demonstrating transcriptional regulation, single lab, two orthogonal methods","pmids":["36396940"],"is_preprint":false},{"year":2022,"finding":"Knockdown of TEKT2 in cultured podocytes resisted high glucose-induced cytoskeletal remodeling and prevented downregulation of NPHS1 protein, demonstrating that TEKT2 regulates podocyte cytoskeletal dynamics downstream of high-glucose stimulation.","method":"siRNA knockdown in cultured podocytes, immunostaining/Western blot for cytoskeletal markers and NPHS1","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific cellular phenotypic readout (cytoskeletal remodeling, NPHS1 levels), single lab, two orthogonal readouts","pmids":["36251411"],"is_preprint":false},{"year":2023,"finding":"TBX5 binds to the TEKT2 promoter region (shown by chromatin immunoprecipitation) and promotes TEKT2 transcription; TBX5 knockdown in HL-1 cardiomyocytes decreased TEKT2 expression, establishing TEKT2 as a transcriptional target of TBX5.","method":"Chromatin immunoprecipitation (ChIP), quantitative PCR after TBX5 knockdown in HL-1 cells","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding plus KD confirmation, single lab, two orthogonal methods","pmids":["36936432"],"is_preprint":false},{"year":2026,"finding":"TEKT2 protein levels are significantly reduced in human non-obstructive azoospermia testicular tissues and teratozoospermia spermatozoa; Sanger sequencing of the TEKT2 regulatory region found no pathogenic variants, indicating downregulation is not caused by coding/regulatory mutations but likely by epigenetic or post-transcriptional mechanisms.","method":"Western blotting on clinical human samples (NoA and teratozoospermia), Sanger sequencing of TEKT2 regulatory region","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein-level validation in clinical cohorts plus negative sequencing result mechanistically informative; single lab, two orthogonal methods","pmids":["42133143"],"is_preprint":false}],"current_model":"TEKT2 is a filament-forming tektin protein that localizes to the outer dense fiber periphery and acrosome cap of sperm flagella, is transcriptionally regulated by TULP1 (in photoreceptor cilia), TBX5 (in cardiomyocytes), and repressed by OOG1 in oocytes; it physically interacts with TEKT2BP1/Ccdc172 at the mitochondria sheath, suggesting a structural bridging role between the ODF and mitochondria in the sperm middle piece, and in non-reproductive contexts it regulates podocyte cytoskeletal dynamics, with its downregulation in azoospermia and teratozoospermia attributed to epigenetic or post-transcriptional rather than regulatory-sequence mutations."},"narrative":{"mechanistic_narrative":"TEKT2 is a tektin family structural protein of the sperm flagellum that organizes the cytoarchitecture of the middle piece by bridging the outer dense fiber to the surrounding mitochondrial sheath. It localizes to the periphery of the outer dense fiber and physically interacts with TEKT2BP1/Ccdc172, which resides at the mitochondrial sheath, positioning the TEKT2-TEKT2BP1 complex as a structural link between these two compartments [PMID:24394471]. A distinct head-associated pool of TEKT2 is present at the acrosome cap of spermatozoa [PMID:27883267]. Its expression is controlled by tissue-specific transcriptional inputs: TULP1 activates the tekt2 promoter to support photoreceptor cilium length [PMID:36396940], TBX5 binds the TEKT2 promoter and drives its transcription in cardiomyocytes [PMID:36936432], and Oog1 suppresses Tekt2 in female germ cells [PMID:29731491]. Beyond ciliary and flagellar contexts, TEKT2 regulates podocyte cytoskeletal dynamics downstream of high-glucose stimulation, where its loss preserves NPHS1 levels and prevents cytoskeletal remodeling [PMID:36251411]. TEKT2 protein is reduced in human non-obstructive azoospermia and teratozoospermia in the absence of coding or regulatory-region mutations, indicating epigenetic or post-transcriptional downregulation [PMID:42133143].","teleology":[{"year":2014,"claim":"Established the structural role of TEKT2 in the sperm middle piece by identifying its physical partner and the spatial logic of their interaction.","evidence":"Yeast two-hybrid screening with immunocytochemical localization in sperm flagella","pmids":["24394471"],"confidence":"Medium","gaps":["No reciprocal co-IP or in vitro reconstitution of the TEKT2-TEKT2BP1 complex","Functional consequence of disrupting the bridge not tested","Filament assembly mechanism not addressed"]},{"year":2016,"claim":"Revealed that TEKT2 has a head-localized pool at the acrosome cap distinct from its flagellar distribution, broadening its possible roles in sperm.","evidence":"Immunofluorescence on bull spermatozoa","pmids":["27883267"],"confidence":"Low","gaps":["Single immunolocalization method without functional test","Role of the acrosomal pool unknown","Not confirmed in other species"]},{"year":2018,"claim":"Showed that TEKT2 expression is actively repressed in female germ cells, identifying Oog1 as a negative transcriptional regulator and explaining its germline sex specificity.","evidence":"RNAi transgenic mouse with qRT-PCR readout in ovaries","pmids":["29731491"],"confidence":"Medium","gaps":["Direct versus indirect repression not distinguished","Single qRT-PCR readout","No protein-level confirmation"]},{"year":2022,"claim":"Placed TEKT2 downstream of TULP1 in a transcriptional pathway governing photoreceptor cilium structure, extending its role beyond sperm to sensory cilia.","evidence":"CRISPR knockout zebrafish, RNA-seq, and dual-luciferase reporter assay","pmids":["36396940"],"confidence":"Medium","gaps":["Whether TEKT2 acts as a structural cilium component in photoreceptors not directly shown","No rescue of cilium length by TEKT2","Mechanism linking promoter activation to ciliary phenotype unresolved"]},{"year":2022,"claim":"Demonstrated a non-ciliary function for TEKT2 in regulating podocyte cytoskeletal dynamics, linking it to glucose-induced remodeling and slit-diaphragm protein levels.","evidence":"siRNA knockdown in cultured podocytes with cytoskeletal imaging and NPHS1 Western blot","pmids":["36251411"],"confidence":"Medium","gaps":["Molecular mechanism connecting TEKT2 to NPHS1 not defined","In vitro culture only, no in vivo confirmation","Whether effect is direct cytoskeletal or transcriptional unclear"]},{"year":2023,"claim":"Identified TBX5 as a direct transcriptional activator of TEKT2 in cardiomyocytes, defining a tissue-specific regulatory input distinct from germline control.","evidence":"ChIP and qPCR after TBX5 knockdown in HL-1 cardiomyocytes","pmids":["36936432"],"confidence":"Medium","gaps":["Functional role of TEKT2 in cardiomyocytes not established","No structural or phenotypic consequence tested","Single cell line"]},{"year":2026,"claim":"Connected TEKT2 to human male infertility phenotypes and showed that downregulation is not driven by sequence variants, pointing toward epigenetic/post-transcriptional control.","evidence":"Western blotting on human NoA and teratozoospermia samples plus Sanger sequencing of the regulatory region","pmids":["42133143"],"confidence":"Medium","gaps":["Specific epigenetic or post-transcriptional mechanism not identified","Causality versus correlation with infertility not established","Small clinical cohort"]},{"year":null,"claim":"How TEKT2 assembles into tektin filaments and mechanically couples the outer dense fiber to the mitochondrial sheath, and what unifies its roles across flagella, sensory cilia, and podocytes, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of TEKT2 filament assembly","No knockout fertility phenotype in the corpus","Mechanistic basis of non-ciliary podocyte function undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[3]}],"pathway":[],"complexes":[],"partners":["TEKT2BP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UIF3","full_name":"Tektin-2","aliases":["Tektin-t","Testicular tektin","Testicular tektin B1-like protein","TEKTB1","Tektin-B1"],"length_aa":430,"mass_kda":49.7,"function":"Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia and flagellar axoneme (PubMed:36191189). Plays a key role in the assembly or attachment of the inner dynein arm to microtubules in sperm flagella and tracheal cilia. Forms filamentous polymers in the walls of ciliary and flagellar microtubules","subcellular_location":"Cytoplasm, cytoskeleton, cilium axoneme; Cytoplasm, cytoskeleton, flagellum axoneme; Cytoplasm, cytoskeleton, microtubule organizing center","url":"https://www.uniprot.org/uniprotkb/Q9UIF3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TEKT2","classification":"Not Classified","n_dependent_lines":106,"n_total_lines":1208,"dependency_fraction":0.08774834437086093},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TEKT2","total_profiled":1310},"omim":[{"mim_id":"612683","title":"TEKTIN 3; TEKT3","url":"https://www.omim.org/entry/612683"},{"mim_id":"608953","title":"TEKTIN 2; TEKT2","url":"https://www.omim.org/entry/608953"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Connecting piece","reliability":"Supported"},{"location":"Flagellar centriole","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":27.0},{"tissue":"fallopian tube","ntpm":59.0},{"tissue":"testis","ntpm":68.7}],"url":"https://www.proteinatlas.org/search/TEKT2"},"hgnc":{"alias_symbol":["TEKTB1"],"prev_symbol":[]},"alphafold":{"accession":"Q9UIF3","domains":[{"cath_id":"-","chopping":"35-61_90-192_221-325_332-397","consensus_level":"medium","plddt":96.8179,"start":35,"end":397}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIF3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIF3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIF3-F1-predicted_aligned_error_v6.png","plddt_mean":91.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TEKT2","jax_strain_url":"https://www.jax.org/strain/search?query=TEKT2"},"sequence":{"accession":"Q9UIF3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UIF3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UIF3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIF3"}},"corpus_meta":[{"pmid":"21519551","id":"PMC_21519551","title":"Identification of genes concordantly expressed with Atoh1 during inner ear development.","date":"2011","source":"Anatomy & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21519551","citation_count":34,"is_preprint":false},{"pmid":"36396940","id":"PMC_36396940","title":"Tulp1 deficiency causes early-onset retinal degeneration through affecting ciliogenesis and activating ferroptosis in zebrafish.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36396940","citation_count":24,"is_preprint":false},{"pmid":"24394471","id":"PMC_24394471","title":"Molecular cloning and subcellular localization of Tektin2-binding protein 1 (Ccdc 172) in rat spermatozoa.","date":"2014","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/24394471","citation_count":21,"is_preprint":false},{"pmid":"34591790","id":"PMC_34591790","title":"Downregulation of KIF2C and TEKT2 is associated with male infertility and testicular carcinoma.","date":"2021","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/34591790","citation_count":17,"is_preprint":false},{"pmid":"29642674","id":"PMC_29642674","title":"Expression pattern of prohibitin, capping actin protein of muscle Z-line beta subunit and tektin-2 gene in Murrah buffalo sperm and its relationship with sperm motility.","date":"2018","source":"Asian-Australasian journal of animal sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29642674","citation_count":15,"is_preprint":false},{"pmid":"36251411","id":"PMC_36251411","title":"Integrative transcriptome analysis reveals TEKT2 and PIAS2 involvement in diabetic nephropathy.","date":"2022","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/36251411","citation_count":11,"is_preprint":false},{"pmid":"35886074","id":"PMC_35886074","title":"Further Insights on RNA Expression and Sperm Motility.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/35886074","citation_count":11,"is_preprint":false},{"pmid":"29731491","id":"PMC_29731491","title":"Oocyte-specific gene Oog1 suppresses the expression of spermatogenesis-specific genes in oocytes.","date":"2018","source":"The Journal of reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/29731491","citation_count":9,"is_preprint":false},{"pmid":"37815627","id":"PMC_37815627","title":"Transcriptome Analysis Reveals Spermatogenesis-Related CircRNAs and LncRNAs in Goat Spermatozoa.","date":"2023","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37815627","citation_count":8,"is_preprint":false},{"pmid":"27883267","id":"PMC_27883267","title":"Translocation of Tektin 3 to the equatorial segment of heads in bull spermatozoa exposed to dibutyryl cAMP and calyculin A.","date":"2016","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/27883267","citation_count":6,"is_preprint":false},{"pmid":"37079096","id":"PMC_37079096","title":"Cryostress induces fragmentation and alters the abundance of sperm transcripts associated with fertilizing competence and reproductive processes in buffalo.","date":"2023","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/37079096","citation_count":6,"is_preprint":false},{"pmid":"36936432","id":"PMC_36936432","title":"Case report: Novel TBX5-related pathogenic mechanism of Holt-Oram syndrome.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36936432","citation_count":5,"is_preprint":false},{"pmid":"39520808","id":"PMC_39520808","title":"Impact of gonadotropin on certain testis-related genes identified through testicular transcriptome analysis in the Asian and the African catfish.","date":"2024","source":"Comparative biochemistry and physiology. Part D, Genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/39520808","citation_count":3,"is_preprint":false},{"pmid":"38934270","id":"PMC_38934270","title":"Molecular anatomy of emerging Xenopus left-right organizer at successive developmental stages.","date":"2024","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/38934270","citation_count":3,"is_preprint":false},{"pmid":"42133143","id":"PMC_42133143","title":"From spermatogenesis to sperm function: bioinformatics and experimental insights into the role of TEKT genes in human sperm fate.","date":"2026","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/42133143","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9810,"output_tokens":1756,"usd":0.027885,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8608,"output_tokens":2429,"usd":0.051882,"stage2_stop_reason":"end_turn"},"total_usd":0.079767,"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\": 2014,\n      \"finding\": \"TEKT2 localizes to the periphery of the outer dense fiber (ODF) in sperm flagella, and interacts with TEKT2BP1 (Ccdc172) as identified by yeast two-hybrid screening; TEKT2BP1 localizes to the mitochondria sheath of the flagella middle piece, suggesting the TEKT2-TEKT2BP1 complex links the ODF and mitochondria in the middle piece.\",\n      \"method\": \"Yeast two-hybrid screening, immunocytochemistry, subcellular fractionation/localization\",\n      \"journal\": \"The journal of histochemistry and cytochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus immunocytochemical localization, single lab, two complementary methods but no in vitro reconstitution or reciprocal co-IP\",\n      \"pmids\": [\"24394471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TEKT2 is present at the acrosome cap in unactivated bull spermatozoa (distinct from TEKT3 which is in the post-acrosomal region), as determined by immunolocalization; this subcellular distribution differs from TEKT2's flagellar localization, indicating a head-specific pool.\",\n      \"method\": \"Immunofluorescence/immunocytochemistry on bull spermatozoa\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single immunolocalization method, no functional consequence directly tested for TEKT2 specifically\",\n      \"pmids\": [\"27883267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Knockdown of the oocyte-specific gene Oog1 in mice leads to increased expression of spermatogenesis-associated transcripts including Tekt2 in ovaries, establishing that Oog1 normally suppresses Tekt2 expression in female germ cells.\",\n      \"method\": \"RNAi transgenic mouse model, quantitative RT-PCR\",\n      \"journal\": \"The Journal of reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockdown with defined transcriptional phenotype, single lab, single method (qRT-PCR readout)\",\n      \"pmids\": [\"29731491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In zebrafish tulp1 double-knockout retinas, tekt2 expression is downregulated and photoreceptor cilium length is reduced; dual-luciferase reporter assay showed that Tulp1a and Tulp1b transcriptionally activate the tekt2 promoter, placing TEKT2 downstream of TULP1 in a cilia-structure pathway.\",\n      \"method\": \"CRISPR knockout zebrafish model, RNA-seq, dual-luciferase reporter assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in vivo combined with reporter assay demonstrating transcriptional regulation, single lab, two orthogonal methods\",\n      \"pmids\": [\"36396940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of TEKT2 in cultured podocytes resisted high glucose-induced cytoskeletal remodeling and prevented downregulation of NPHS1 protein, demonstrating that TEKT2 regulates podocyte cytoskeletal dynamics downstream of high-glucose stimulation.\",\n      \"method\": \"siRNA knockdown in cultured podocytes, immunostaining/Western blot for cytoskeletal markers and NPHS1\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific cellular phenotypic readout (cytoskeletal remodeling, NPHS1 levels), single lab, two orthogonal readouts\",\n      \"pmids\": [\"36251411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TBX5 binds to the TEKT2 promoter region (shown by chromatin immunoprecipitation) and promotes TEKT2 transcription; TBX5 knockdown in HL-1 cardiomyocytes decreased TEKT2 expression, establishing TEKT2 as a transcriptional target of TBX5.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), quantitative PCR after TBX5 knockdown in HL-1 cells\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding plus KD confirmation, single lab, two orthogonal methods\",\n      \"pmids\": [\"36936432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TEKT2 protein levels are significantly reduced in human non-obstructive azoospermia testicular tissues and teratozoospermia spermatozoa; Sanger sequencing of the TEKT2 regulatory region found no pathogenic variants, indicating downregulation is not caused by coding/regulatory mutations but likely by epigenetic or post-transcriptional mechanisms.\",\n      \"method\": \"Western blotting on clinical human samples (NoA and teratozoospermia), Sanger sequencing of TEKT2 regulatory region\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein-level validation in clinical cohorts plus negative sequencing result mechanistically informative; single lab, two orthogonal methods\",\n      \"pmids\": [\"42133143\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TEKT2 is a filament-forming tektin protein that localizes to the outer dense fiber periphery and acrosome cap of sperm flagella, is transcriptionally regulated by TULP1 (in photoreceptor cilia), TBX5 (in cardiomyocytes), and repressed by OOG1 in oocytes; it physically interacts with TEKT2BP1/Ccdc172 at the mitochondria sheath, suggesting a structural bridging role between the ODF and mitochondria in the sperm middle piece, and in non-reproductive contexts it regulates podocyte cytoskeletal dynamics, with its downregulation in azoospermia and teratozoospermia attributed to epigenetic or post-transcriptional rather than regulatory-sequence mutations.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TEKT2 is a tektin family structural protein of the sperm flagellum that organizes the cytoarchitecture of the middle piece by bridging the outer dense fiber to the surrounding mitochondrial sheath. It localizes to the periphery of the outer dense fiber and physically interacts with TEKT2BP1/Ccdc172, which resides at the mitochondrial sheath, positioning the TEKT2-TEKT2BP1 complex as a structural link between these two compartments [#0]. A distinct head-associated pool of TEKT2 is present at the acrosome cap of spermatozoa [#1]. Its expression is controlled by tissue-specific transcriptional inputs: TULP1 activates the tekt2 promoter to support photoreceptor cilium length [#3], TBX5 binds the TEKT2 promoter and drives its transcription in cardiomyocytes [#5], and Oog1 suppresses Tekt2 in female germ cells [#2]. Beyond ciliary and flagellar contexts, TEKT2 regulates podocyte cytoskeletal dynamics downstream of high-glucose stimulation, where its loss preserves NPHS1 levels and prevents cytoskeletal remodeling [#4]. TEKT2 protein is reduced in human non-obstructive azoospermia and teratozoospermia in the absence of coding or regulatory-region mutations, indicating epigenetic or post-transcriptional downregulation [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established the structural role of TEKT2 in the sperm middle piece by identifying its physical partner and the spatial logic of their interaction.\",\n      \"evidence\": \"Yeast two-hybrid screening with immunocytochemical localization in sperm flagella\",\n      \"pmids\": [\"24394471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reciprocal co-IP or in vitro reconstitution of the TEKT2-TEKT2BP1 complex\", \"Functional consequence of disrupting the bridge not tested\", \"Filament assembly mechanism not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed that TEKT2 has a head-localized pool at the acrosome cap distinct from its flagellar distribution, broadening its possible roles in sperm.\",\n      \"evidence\": \"Immunofluorescence on bull spermatozoa\",\n      \"pmids\": [\"27883267\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single immunolocalization method without functional test\", \"Role of the acrosomal pool unknown\", \"Not confirmed in other species\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed that TEKT2 expression is actively repressed in female germ cells, identifying Oog1 as a negative transcriptional regulator and explaining its germline sex specificity.\",\n      \"evidence\": \"RNAi transgenic mouse with qRT-PCR readout in ovaries\",\n      \"pmids\": [\"29731491\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect repression not distinguished\", \"Single qRT-PCR readout\", \"No protein-level confirmation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed TEKT2 downstream of TULP1 in a transcriptional pathway governing photoreceptor cilium structure, extending its role beyond sperm to sensory cilia.\",\n      \"evidence\": \"CRISPR knockout zebrafish, RNA-seq, and dual-luciferase reporter assay\",\n      \"pmids\": [\"36396940\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TEKT2 acts as a structural cilium component in photoreceptors not directly shown\", \"No rescue of cilium length by TEKT2\", \"Mechanism linking promoter activation to ciliary phenotype unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated a non-ciliary function for TEKT2 in regulating podocyte cytoskeletal dynamics, linking it to glucose-induced remodeling and slit-diaphragm protein levels.\",\n      \"evidence\": \"siRNA knockdown in cultured podocytes with cytoskeletal imaging and NPHS1 Western blot\",\n      \"pmids\": [\"36251411\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism connecting TEKT2 to NPHS1 not defined\", \"In vitro culture only, no in vivo confirmation\", \"Whether effect is direct cytoskeletal or transcriptional unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified TBX5 as a direct transcriptional activator of TEKT2 in cardiomyocytes, defining a tissue-specific regulatory input distinct from germline control.\",\n      \"evidence\": \"ChIP and qPCR after TBX5 knockdown in HL-1 cardiomyocytes\",\n      \"pmids\": [\"36936432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of TEKT2 in cardiomyocytes not established\", \"No structural or phenotypic consequence tested\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected TEKT2 to human male infertility phenotypes and showed that downregulation is not driven by sequence variants, pointing toward epigenetic/post-transcriptional control.\",\n      \"evidence\": \"Western blotting on human NoA and teratozoospermia samples plus Sanger sequencing of the regulatory region\",\n      \"pmids\": [\"42133143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific epigenetic or post-transcriptional mechanism not identified\", \"Causality versus correlation with infertility not established\", \"Small clinical cohort\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TEKT2 assembles into tektin filaments and mechanically couples the outer dense fiber to the mitochondrial sheath, and what unifies its roles across flagella, sensory cilia, and podocytes, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of TEKT2 filament assembly\", \"No knockout fertility phenotype in the corpus\", \"Mechanistic basis of non-ciliary podocyte function undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"TEKT2BP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}