{"gene":"TEX44","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":2025,"finding":"TEX44 physically interacts with carnitine palmitoyltransferase 1B (CPT1B) to form a mitochondrial glue that anchors adjacent mitochondria and facilitates assembly of the sperm-specific mitochondrial sheath.","method":"Co-immunoprecipitation, Tex44 knockout mice, in vitro reconstitution with purified TEX44 protein","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal interaction demonstrated, in vitro assay with purified protein, KO mouse with defined phenotype, multiple orthogonal methods in single study","pmids":["40849303"],"is_preprint":false},{"year":2025,"finding":"Purified TEX44 protein modulates CPT1B enzymatic activity by limiting the conversion of long-chain fatty acids (palmitic acid, myristic acid) into acyl-carnitines, thereby reducing reactive oxygen species (ROS) production; loss of TEX44 leads to unregulated fatty acid β-oxidation and excessive ROS generation causing oxidative damage to sperm DNA and flagellar structure.","method":"In vitro enzymatic assay with purified TEX44 protein, Tex44 knockout mice with ROS and oxidative damage readouts","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of enzymatic modulation plus KO mouse phenotype with mechanistic readouts","pmids":["40849303"],"is_preprint":false},{"year":2024,"finding":"Loss of TEX44 in mice causes disorganized junction between the midpiece and principal piece of the sperm flagellum, loss of axonemal microtubule doublets and outer dense fibers in the principal piece, and severely impaired sperm motility, establishing TEX44 as required for correct sperm flagellum assembly during spermiogenesis.","method":"CRISPR/Cas9 complete gene deletion in mice, electron microscopy of flagellar ultrastructure, motility assays","journal":"Cellular & Molecular Biology Letters","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined ultrastructural and functional phenotype","pmids":["38750428"],"is_preprint":false},{"year":2025,"finding":"Germ cell-specific Cpt1b knockout mice phenocopy TEX44 deficiency (mitochondrial sheath defects, reduced sperm motility), providing genetic epistasis evidence that TEX44 functions upstream of or in concert with CPT1B in the same pathway.","method":"Conditional Cpt1b knockout mice with phenotypic comparison to Tex44 KO","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis via parallel KO models with identical phenotypic readouts","pmids":["40849303"],"is_preprint":false}],"current_model":"TEX44 is a testis-expressed protein that localizes to the mitochondrial sheath of sperm, where it physically interacts with CPT1B to anchor adjacent mitochondria and directly modulates CPT1B enzymatic activity, limiting long-chain fatty acid β-oxidation and thereby restraining ROS production; loss of TEX44 disrupts mitochondrial sheath assembly, causes flagellar structural defects, and leads to oxidative damage and severe male subfertility."},"narrative":{"teleology":[{"year":2024,"claim":"Whether TEX44 is required for sperm flagellum formation was unknown; gene deletion revealed that TEX44 is essential for correct assembly of the midpiece–principal piece junction, maintenance of axonemal doublets and outer dense fibers, and sperm motility.","evidence":"CRISPR/Cas9 complete Tex44 gene deletion in mice with transmission electron microscopy and motility assays","pmids":["38750428"],"confidence":"High","gaps":["Molecular binding partners mediating TEX44's structural role were unidentified","Whether flagellar defects reflect a primary mitochondrial sheath defect or an independent cytoskeletal role was unresolved","No enzymatic or metabolic function had been attributed to TEX44"]},{"year":2025,"claim":"How TEX44 organizes the mitochondrial sheath was resolved: TEX44 binds CPT1B to glue adjacent mitochondria together, and simultaneously limits CPT1B-mediated long-chain fatty acid β-oxidation to prevent excessive ROS; germ cell-specific Cpt1b knockout phenocopies Tex44 loss, confirming they operate in the same pathway.","evidence":"Co-immunoprecipitation, in vitro enzymatic reconstitution with purified TEX44, Tex44 KO and conditional Cpt1b KO mice with ROS and oxidative damage readouts","pmids":["40849303"],"confidence":"High","gaps":["Structural basis of the TEX44–CPT1B interaction (binding interface, stoichiometry) is undefined","Whether TEX44 has additional mitochondrial partners beyond CPT1B is unknown","Whether human TEX44 mutations cause male infertility has not been demonstrated"]},{"year":null,"claim":"Key open questions include the atomic-level mechanism by which TEX44 inhibits CPT1B catalysis, whether TEX44 has roles outside spermiogenesis, and whether TEX44 variants are causative in human asthenozoospermia or multiple morphological abnormalities of the sperm flagella (MMAF).","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the TEX44–CPT1B complex exists","No human genetic studies linking TEX44 mutations to infertility have been reported","Regulation of TEX44 expression and protein turnover during spermiogenesis is uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[2,3]}],"complexes":[],"partners":["CPT1B"],"other_free_text":[]},"mechanistic_narrative":"TEX44 is a testis-expressed mitochondrial sheath protein essential for sperm flagellum assembly and male fertility. It physically interacts with carnitine palmitoyltransferase 1B (CPT1B) to form an intermitochondrial glue that anchors adjacent mitochondria during mitochondrial sheath biogenesis in spermiogenesis [PMID:40849303]. TEX44 directly modulates CPT1B enzymatic activity, limiting long-chain fatty acid β-oxidation and thereby restraining reactive oxygen species production; loss of TEX44 causes unregulated β-oxidation, excessive ROS, oxidative damage to sperm DNA and flagella, disorganized midpiece–principal piece junctions, loss of axonemal microtubule doublets and outer dense fibers, and severe male subfertility [PMID:40849303, PMID:38750428]."},"prefetch_data":{"uniprot":{"accession":"Q53QW1","full_name":"Testis-expressed protein 44","aliases":[],"length_aa":395,"mass_kda":41.6,"function":"","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q53QW1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TEX44","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TEX44","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"testis","ntpm":146.5}],"url":"https://www.proteinatlas.org/search/TEX44"},"hgnc":{"alias_symbol":["MGC35154"],"prev_symbol":["C2orf57"]},"alphafold":{"accession":"Q53QW1","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53QW1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q53QW1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q53QW1-F1-predicted_aligned_error_v6.png","plddt_mean":47.41},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TEX44","jax_strain_url":"https://www.jax.org/strain/search?query=TEX44"},"sequence":{"accession":"Q53QW1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q53QW1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q53QW1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53QW1"}},"corpus_meta":[{"pmid":"26168773","id":"PMC_26168773","title":"Human Spermatozoa as a Model for Detecting Missing Proteins in the Context of the Chromosome-Centric Human Proteome Project.","date":"2015","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/26168773","citation_count":53,"is_preprint":false},{"pmid":"40849303","id":"PMC_40849303","title":"The TEX44-CPT1B axis regulates mitochondrial sheath assembly and fatty acid oxidation in sperm.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40849303","citation_count":5,"is_preprint":false},{"pmid":"38750428","id":"PMC_38750428","title":"The lack of Tex44 causes severe subfertility with flagellar abnormalities in male mice.","date":"2024","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/38750428","citation_count":3,"is_preprint":false},{"pmid":"34817046","id":"PMC_34817046","title":"RNA-binding protein with serine-rich domain 1 regulates microsatellite instability of uterine corpus endometrial adenocarcinoma.","date":"2021","source":"Clinics (Sao Paulo, Brazil)","url":"https://pubmed.ncbi.nlm.nih.gov/34817046","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3631,"output_tokens":951,"usd":0.012579},"stage2":{"model":"claude-opus-4-6","input_tokens":4157,"output_tokens":1086,"usd":0.071902},"total_usd":0.084481,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"TEX44 physically interacts with carnitine palmitoyltransferase 1B (CPT1B) to form a mitochondrial glue that anchors adjacent mitochondria and facilitates assembly of the sperm-specific mitochondrial sheath.\",\n      \"method\": \"Co-immunoprecipitation, Tex44 knockout mice, in vitro reconstitution with purified TEX44 protein\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal interaction demonstrated, in vitro assay with purified protein, KO mouse with defined phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"40849303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Purified TEX44 protein modulates CPT1B enzymatic activity by limiting the conversion of long-chain fatty acids (palmitic acid, myristic acid) into acyl-carnitines, thereby reducing reactive oxygen species (ROS) production; loss of TEX44 leads to unregulated fatty acid β-oxidation and excessive ROS generation causing oxidative damage to sperm DNA and flagellar structure.\",\n      \"method\": \"In vitro enzymatic assay with purified TEX44 protein, Tex44 knockout mice with ROS and oxidative damage readouts\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of enzymatic modulation plus KO mouse phenotype with mechanistic readouts\",\n      \"pmids\": [\"40849303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of TEX44 in mice causes disorganized junction between the midpiece and principal piece of the sperm flagellum, loss of axonemal microtubule doublets and outer dense fibers in the principal piece, and severely impaired sperm motility, establishing TEX44 as required for correct sperm flagellum assembly during spermiogenesis.\",\n      \"method\": \"CRISPR/Cas9 complete gene deletion in mice, electron microscopy of flagellar ultrastructure, motility assays\",\n      \"journal\": \"Cellular & Molecular Biology Letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined ultrastructural and functional phenotype\",\n      \"pmids\": [\"38750428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Germ cell-specific Cpt1b knockout mice phenocopy TEX44 deficiency (mitochondrial sheath defects, reduced sperm motility), providing genetic epistasis evidence that TEX44 functions upstream of or in concert with CPT1B in the same pathway.\",\n      \"method\": \"Conditional Cpt1b knockout mice with phenotypic comparison to Tex44 KO\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via parallel KO models with identical phenotypic readouts\",\n      \"pmids\": [\"40849303\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TEX44 is a testis-expressed protein that localizes to the mitochondrial sheath of sperm, where it physically interacts with CPT1B to anchor adjacent mitochondria and directly modulates CPT1B enzymatic activity, limiting long-chain fatty acid β-oxidation and thereby restraining ROS production; loss of TEX44 disrupts mitochondrial sheath assembly, causes flagellar structural defects, and leads to oxidative damage and severe male subfertility.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TEX44 is a testis-expressed mitochondrial sheath protein essential for sperm flagellum assembly and male fertility. It physically interacts with carnitine palmitoyltransferase 1B (CPT1B) to form an intermitochondrial glue that anchors adjacent mitochondria during mitochondrial sheath biogenesis in spermiogenesis [PMID:40849303]. TEX44 directly modulates CPT1B enzymatic activity, limiting long-chain fatty acid β-oxidation and thereby restraining reactive oxygen species production; loss of TEX44 causes unregulated β-oxidation, excessive ROS, oxidative damage to sperm DNA and flagella, disorganized midpiece–principal piece junctions, loss of axonemal microtubule doublets and outer dense fibers, and severe male subfertility [PMID:40849303, PMID:38750428].\",\n  \"teleology\": [\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether TEX44 is required for sperm flagellum formation was unknown; gene deletion revealed that TEX44 is essential for correct assembly of the midpiece–principal piece junction, maintenance of axonemal doublets and outer dense fibers, and sperm motility.\",\n      \"evidence\": \"CRISPR/Cas9 complete Tex44 gene deletion in mice with transmission electron microscopy and motility assays\",\n      \"pmids\": [\"38750428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular binding partners mediating TEX44's structural role were unidentified\",\n        \"Whether flagellar defects reflect a primary mitochondrial sheath defect or an independent cytoskeletal role was unresolved\",\n        \"No enzymatic or metabolic function had been attributed to TEX44\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"How TEX44 organizes the mitochondrial sheath was resolved: TEX44 binds CPT1B to glue adjacent mitochondria together, and simultaneously limits CPT1B-mediated long-chain fatty acid β-oxidation to prevent excessive ROS; germ cell-specific Cpt1b knockout phenocopies Tex44 loss, confirming they operate in the same pathway.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro enzymatic reconstitution with purified TEX44, Tex44 KO and conditional Cpt1b KO mice with ROS and oxidative damage readouts\",\n      \"pmids\": [\"40849303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the TEX44–CPT1B interaction (binding interface, stoichiometry) is undefined\",\n        \"Whether TEX44 has additional mitochondrial partners beyond CPT1B is unknown\",\n        \"Whether human TEX44 mutations cause male infertility has not been demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the atomic-level mechanism by which TEX44 inhibits CPT1B catalysis, whether TEX44 has roles outside spermiogenesis, and whether TEX44 variants are causative in human asthenozoospermia or multiple morphological abnormalities of the sperm flagella (MMAF).\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of the TEX44–CPT1B complex exists\",\n        \"No human genetic studies linking TEX44 mutations to infertility have been reported\",\n        \"Regulation of TEX44 expression and protein turnover during spermiogenesis is uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CPT1B\"],\n    \"other_free_text\": []\n  }\n}\n```"}