{"gene":"SPATA6","run_date":"2026-06-10T07:46:39","timeline":{"discoveries":[{"year":2015,"finding":"SPATA6 is required for formation of the segmented columns and capitulum of the sperm connecting piece (head-tail coupling apparatus). Inactivation of Spata6 in mice leads to acephalic spermatozoa and male sterility. Proteomic analyses revealed SPATA6 interacts with myosin subunits (e.g., MYL6), implicating it in myosin-based microfilament transport during late spermiogenesis.","method":"Mouse knockout (Spata6 inactivation via homologous recombination), proteomic analysis, co-immunoprecipitation/interaction studies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined cellular phenotype (acephalic sperm, sterility), proteomic identification of binding partners (MYL6), replicated across multiple subsequent studies","pmids":["25605924"],"is_preprint":false},{"year":2003,"finding":"SPATA6 encodes a 488 amino acid protein with similarity to the motor domain of kinesin-related proteins and C. elegans neural calcium sensor protein (NCS-2). The 1.8 and 1.2 kb transcripts are exclusively expressed in testis and specifically in haploid germ cells. Western blot detects a single ~53 kDa protein. The gene was localized to chromosome 1, region p32-35 in humans.","method":"cDNA cloning, RT-PCR, in situ hybridization, Western blot with antipeptide antiserum, chromosomal localization","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (cloning, expression, Western blot, ISH) in single lab establishing protein identity and expression pattern","pmids":["12771232"],"is_preprint":false},{"year":2018,"finding":"PMFBP1 cooperates with SUN5 and SPATA6 at the sperm head-tail junction. Disruption of Pmfbp1 in male mice leads to acephalic spermatozoa and disrupts PMFBP1's cooperation with SPATA6 and SUN5 in connecting the sperm head to the tail.","method":"Mouse knockout of Pmfbp1, immunofluorescence, co-immunoprecipitation demonstrating protein complex","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse phenotype plus co-IP showing SPATA6 complex membership, single lab","pmids":["30032984"],"is_preprint":false},{"year":2024,"finding":"BAG5 forms a complex with HSPA8 and promotes proper folding of SPATA6 by enhancing HSPA8's affinity for substrate proteins. BAG5-deficient male mice show misfolded SPATA6 (along with MYO5A, MYL6, DYNLT1, DCTN1, and DNAL1), abnormal HTCA assembly, acephalic spermatozoa syndrome and male infertility, phenocopying SPATA6-deficient mice.","method":"BAG5 knockout mouse, in vivo and in vitro protein folding assays, co-immunoprecipitation (BAG5-HSPA8 complex), immunofluorescence","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — KO mouse with defined phenotype phenocopying SPATA6-KO, in vitro reconstitution of BAG5-HSPA8 complex and folding assay, reciprocal Co-IP, multiple orthogonal methods","pmids":["38454159"],"is_preprint":false},{"year":2023,"finding":"CFAP52 interacts with SPATA6 and is essential for its stability. CFAP52 knockout mice show loss of connecting piece formation and acephalic spermatozoa syndrome, with SPATA6 protein levels reduced upon CFAP52 deficiency.","method":"Co-immunoprecipitation (CFAP52-SPATA6 interaction), Cfap52 knockout mouse, immunofluorescence, Western blot","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse phenotype, co-IP identifying SPATA6 as CFAP52 binding partner, single lab","pmids":["38126872"],"is_preprint":false},{"year":2022,"finding":"Loss-of-function mutation in SPATA20 leads to decreased expression of SPATA6, which plays a vital role in the assembly of the sperm head-tail conjunction in humans. The SPATA20 nonsense mutation caused degradation of SPATA20 protein with associated reduced SPATA6 levels in patient sperm.","method":"Whole-exome sequencing, Sanger sequencing, Western blot, immunofluorescence in patient samples","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — patient-based loss-of-function, Western blot confirming SPATA6 reduction, single case study","pmids":["36415156"],"is_preprint":false},{"year":2025,"finding":"CEP135 interacts with SPATA6 and AKAP3, regulating their expression and stability. CEP135 knockout mice show acephalic spermatozoa with head-to-tail connection defects, and proteomic analysis revealed significant reduction in SPATA6 protein levels upon CEP135 deletion.","method":"Conditional Cep135 knockout mouse (Stra8-Cre), co-immunoprecipitation, proteomic analysis, immunofluorescence","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined spermatogenesis phenotype, Co-IP demonstrating CEP135-SPATA6 interaction, proteomics, single lab","pmids":["40095067"],"is_preprint":false},{"year":2025,"finding":"NME5 loss-of-function results in near absence of SPATA6 at the head-tail coupling apparatus (HTCA) in human sperm, as confirmed by immunofluorescence analysis, indicating NME5 is required upstream of SPATA6 for HTCA integrity.","method":"Immunofluorescence of patient sperm (NME5 frameshift variant), ultrastructural electron microscopy","journal":"Clinical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — immunofluorescence in single patient, no direct protein interaction assay for NME5-SPATA6 relationship","pmids":["41499646"],"is_preprint":false},{"year":2019,"finding":"SPATA6 mRNA is a direct target of miR-23a/b-3p in human sperm. Dual luciferase assays confirmed miR-23a/b-3p binds to the 3'UTR of SPATA6 mRNA. Mutations in the miR-23a/b-3p binding site within the SPATA6 3'UTR abrogated responsiveness. SPATA6 protein levels were significantly lower in oligoasthenozoospermic men with elevated miR-23a/b-3p.","method":"Dual luciferase reporter assay, site-directed mutagenesis of 3'UTR, Western blot, RT-qPCR","journal":"Fertility and sterility","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual luciferase assay with mutagenesis confirming direct miRNA-3'UTR interaction, Western blot for protein confirmation, single lab","pmids":["31056312"],"is_preprint":false},{"year":2021,"finding":"In sheep Leydig cells, SPATA6 is localized in cytoplasm and nucleus. SPATA6 interference promotes apoptosis (increased BAX/BCL-2 ratio), blocks cell cycle at G2/M phase with downregulation of CDK1 and CCNB1. SPATA6 overexpression promotes cell cycle progression and upregulates CDK1, CDK4, CCND1, CCND2. SPATA6 overexpression also promotes testosterone secretion and StAR expression.","method":"siRNA knockdown and overexpression in primary Leydig cells, flow cytometry, Western blot, immunofluorescence localization","journal":"Theriogenology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, sheep Leydig cell model, KD/OE with phenotype but no direct pathway placement for mammalian canonical function","pmids":["33667862"],"is_preprint":false},{"year":2001,"finding":"The rat Spata6 ortholog (SRF-1) is expressed exclusively in testis beginning at 5 weeks of age, with expression in spermatocytes. The deduced amino acid sequence shows partial homology with kinesin-related proteins, suggesting a role as a molecular motor in meiosis.","method":"Differential display cloning, RT-PCR, in situ hybridization","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — initial cloning and expression paper, homology-based functional inference, no direct functional assay","pmids":["11735130"],"is_preprint":false}],"current_model":"SPATA6 is a testis-enriched protein essential for assembly of the sperm head-tail coupling apparatus (HTCA), specifically the segmented columns and capitulum of the connecting piece; it interacts with myosin subunits (MYL6, MYO5A) and is transported to the HTCA in a process that requires the co-chaperone BAG5 to activate HSPA8-mediated folding of SPATA6, and it functions in a molecular complex with SUN5 and PMFBP1 at the sperm head-tail junction, with its stability and localization further dependent on CFAP52, CEP135, NME5, and SPATA20."},"narrative":{"mechanistic_narrative":"SPATA6 is a testis-enriched, haploid germ cell-expressed protein essential for assembly of the sperm head-tail coupling apparatus (HTCA), specifically the segmented columns and capitulum of the connecting piece; loss of Spata6 in mice produces acephalic spermatozoa and male sterility [PMID:25605924, PMID:12771232]. SPATA6 functions in myosin-based microfilament transport during late spermiogenesis, interacting with myosin subunits including MYL6 [PMID:25605924]. At the sperm head-tail junction it operates within a molecular complex together with SUN5 and PMFBP1 to physically connect the head to the tail [PMID:30032984]. Proper SPATA6 function depends on a dedicated folding step: the co-chaperone BAG5 forms a complex with HSPA8 and enhances HSPA8 substrate affinity to promote SPATA6 folding, and BAG5 loss yields misfolded SPATA6, defective HTCA assembly, and acephalic sperm that phenocopy SPATA6 deficiency [PMID:38454159]. SPATA6 protein stability and HTCA localization further require CFAP52, CEP135, NME5, and SPATA20, whose loss each reduces SPATA6 levels or its presence at the HTCA [PMID:38126872, PMID:36415156, PMID:40095067, PMID:41499646]. SPATA6 expression is post-transcriptionally controlled by miR-23a/b-3p, which directly targets its 3'UTR and is elevated in oligoasthenozoospermic men with reduced SPATA6 [PMID:31056312].","teleology":[{"year":2001,"claim":"Established SPATA6 (rat ortholog SRF-1) as a testis-restricted gene expressed during spermatogenesis, raising the hypothesis it acts as a molecular motor in male germ cells.","evidence":"Differential display cloning, RT-PCR and in situ hybridization in rat testis","pmids":["11735130"],"confidence":"Low","gaps":["Function inferred only from sequence homology to kinesin-related proteins","No direct functional assay","Cellular role undefined"]},{"year":2003,"claim":"Defined the human SPATA6 protein as a 488-aa, ~53 kDa product expressed exclusively in haploid germ cells, fixing protein identity and expression pattern.","evidence":"cDNA cloning, RT-PCR, in situ hybridization, Western blot and chromosomal mapping","pmids":["12771232"],"confidence":"Medium","gaps":["Homology-based motor assignment not functionally tested","No interacting partners or subcellular role established"]},{"year":2015,"claim":"Pinned SPATA6 to a specific structure and process — formation of the segmented columns and capitulum of the connecting piece — and linked it to myosin-based transport, explaining how its loss causes acephalic spermatozoa.","evidence":"Spata6 knockout mouse with acephalic sperm/sterility phenotype plus proteomic and Co-IP identification of myosin subunit (MYL6) interactions","pmids":["25605924"],"confidence":"High","gaps":["Mechanism of myosin-based transport not reconstituted","Direct vs indirect MYL6 interaction not resolved","Structural basis of HTCA assembly unknown"]},{"year":2018,"claim":"Placed SPATA6 in a defined junctional complex with SUN5 and PMFBP1, establishing the molecular partners that physically couple sperm head to tail.","evidence":"Pmfbp1 knockout mouse, immunofluorescence and Co-IP showing SPATA6/SUN5/PMFBP1 cooperation","pmids":["30032984"],"confidence":"Medium","gaps":["Stoichiometry and direct binding interfaces of the complex not defined","Single lab","Order of complex assembly unclear"]},{"year":2019,"claim":"Identified a post-transcriptional control mechanism, showing SPATA6 mRNA is a direct miR-23a/b-3p target whose dysregulation lowers SPATA6 in subfertile men.","evidence":"Dual luciferase reporter with 3'UTR mutagenesis, Western blot and RT-qPCR in human sperm","pmids":["31056312"],"confidence":"Medium","gaps":["In vivo contribution of this miRNA axis to fertility not tested","Single lab","Other regulators of SPATA6 expression unexplored"]},{"year":2023,"claim":"Showed SPATA6 protein stability depends on CFAP52, identifying an upstream factor whose loss reduces SPATA6 and abolishes connecting piece formation.","evidence":"Cfap52 knockout mouse, Co-IP, immunofluorescence and Western blot","pmids":["38126872"],"confidence":"Medium","gaps":["Whether CFAP52 directly stabilizes SPATA6 or acts indirectly unresolved","Single lab"]},{"year":2024,"claim":"Revealed a chaperone requirement for SPATA6 folding, with BAG5 activating HSPA8-mediated folding of SPATA6, explaining why folding failure phenocopies SPATA6 loss.","evidence":"Bag5 knockout mouse, in vivo/in vitro folding assays, reciprocal Co-IP of BAG5-HSPA8 complex and immunofluorescence","pmids":["38454159"],"confidence":"High","gaps":["Direct chaperone-substrate contact between HSPA8 and SPATA6 not mapped","Folding of SPATA6 vs other HTCA clients not distinguished"]},{"year":2022,"claim":"Extended SPATA6 dependency to human disease, linking SPATA20 loss-of-function to reduced SPATA6 and defective head-tail conjunction.","evidence":"Whole-exome and Sanger sequencing, Western blot and immunofluorescence in patient sperm","pmids":["36415156"],"confidence":"Medium","gaps":["Single case study","Direct SPATA20-SPATA6 interaction not tested","Mechanism of SPATA6 reduction unclear"]},{"year":2025,"claim":"Identified CEP135 and NME5 as additional upstream factors required for SPATA6 abundance/localization at the HTCA, broadening the network controlling SPATA6 deposition.","evidence":"Conditional Cep135 knockout mouse with Co-IP and proteomics; immunofluorescence/EM of NME5-variant patient sperm","pmids":["40095067","41499646"],"confidence":"Medium","gaps":["NME5-SPATA6 relationship rests on single-patient immunofluorescence with no interaction assay","Direct vs indirect regulation by CEP135 not resolved","Hierarchy among CFAP52/CEP135/NME5/SPATA20 unmapped"]},{"year":null,"claim":"The biochemical activity of SPATA6 itself — whether it acts as a motor, adaptor, or structural scaffold within the connecting piece — and the structural architecture of the SPATA6-containing HTCA complex remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No enzymatic or motor activity directly demonstrated","No structure of SPATA6 or its complexes","Assembly hierarchy linking folding, stabilization and junctional partners not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,2]}],"complexes":["sperm head-tail coupling apparatus (HTCA)","SPATA6-SUN5-PMFBP1 head-tail junction complex"],"partners":["MYL6","SUN5","PMFBP1","BAG5","HSPA8","CFAP52","CEP135","SPATA20"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NWH7","full_name":"Spermatogenesis-associated protein 6","aliases":[],"length_aa":488,"mass_kda":56.0,"function":"Required for formation of the sperm connecting piece during spermiogenesis. Sperm connecting piece is essential for linking the developing flagellum to the head during late spermiogenesis. May be involved in myosin-based microfilament transport through interaction with myosin subunits","subcellular_location":"Secreted; Cell projection, cilium, flagellum","url":"https://www.uniprot.org/uniprotkb/Q9NWH7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SPATA6","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/SPATA6","total_profiled":1310},"omim":[{"mim_id":"618085","title":"POLYAMINE-MODULATED FACTOR 1-BINDING PROTEIN 1; PMFBP1","url":"https://www.omim.org/entry/618085"},{"mim_id":"613947","title":"SPERMATOGENESIS-ASSOCIATED PROTEIN 6; SPATA6","url":"https://www.omim.org/entry/613947"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":46.8}],"url":"https://www.proteinatlas.org/search/SPATA6"},"hgnc":{"alias_symbol":["SRF1","FLJ10007","SRF-1"],"prev_symbol":[]},"alphafold":{"accession":"Q9NWH7","domains":[{"cath_id":"2.60.40.150","chopping":"2-163","consensus_level":"high","plddt":87.7659,"start":2,"end":163}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NWH7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NWH7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NWH7-F1-predicted_aligned_error_v6.png","plddt_mean":65.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPATA6","jax_strain_url":"https://www.jax.org/strain/search?query=SPATA6"},"sequence":{"accession":"Q9NWH7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NWH7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NWH7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NWH7"}},"corpus_meta":[{"pmid":"25605924","id":"PMC_25605924","title":"Spata6 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\"year\": 2015,\n      \"finding\": \"SPATA6 is required for formation of the segmented columns and capitulum of the sperm connecting piece (head-tail coupling apparatus). Inactivation of Spata6 in mice leads to acephalic spermatozoa and male sterility. Proteomic analyses revealed SPATA6 interacts with myosin subunits (e.g., MYL6), implicating it in myosin-based microfilament transport during late spermiogenesis.\",\n      \"method\": \"Mouse knockout (Spata6 inactivation via homologous recombination), proteomic analysis, co-immunoprecipitation/interaction studies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined cellular phenotype (acephalic sperm, sterility), proteomic identification of binding partners (MYL6), replicated across multiple subsequent studies\",\n      \"pmids\": [\"25605924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SPATA6 encodes a 488 amino acid protein with similarity to the motor domain of kinesin-related proteins and C. elegans neural calcium sensor protein (NCS-2). The 1.8 and 1.2 kb transcripts are exclusively expressed in testis and specifically in haploid germ cells. Western blot detects a single ~53 kDa protein. The gene was localized to chromosome 1, region p32-35 in humans.\",\n      \"method\": \"cDNA cloning, RT-PCR, in situ hybridization, Western blot with antipeptide antiserum, chromosomal localization\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (cloning, expression, Western blot, ISH) in single lab establishing protein identity and expression pattern\",\n      \"pmids\": [\"12771232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PMFBP1 cooperates with SUN5 and SPATA6 at the sperm head-tail junction. Disruption of Pmfbp1 in male mice leads to acephalic spermatozoa and disrupts PMFBP1's cooperation with SPATA6 and SUN5 in connecting the sperm head to the tail.\",\n      \"method\": \"Mouse knockout of Pmfbp1, immunofluorescence, co-immunoprecipitation demonstrating protein complex\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse phenotype plus co-IP showing SPATA6 complex membership, single lab\",\n      \"pmids\": [\"30032984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BAG5 forms a complex with HSPA8 and promotes proper folding of SPATA6 by enhancing HSPA8's affinity for substrate proteins. BAG5-deficient male mice show misfolded SPATA6 (along with MYO5A, MYL6, DYNLT1, DCTN1, and DNAL1), abnormal HTCA assembly, acephalic spermatozoa syndrome and male infertility, phenocopying SPATA6-deficient mice.\",\n      \"method\": \"BAG5 knockout mouse, in vivo and in vitro protein folding assays, co-immunoprecipitation (BAG5-HSPA8 complex), immunofluorescence\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — KO mouse with defined phenotype phenocopying SPATA6-KO, in vitro reconstitution of BAG5-HSPA8 complex and folding assay, reciprocal Co-IP, multiple orthogonal methods\",\n      \"pmids\": [\"38454159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CFAP52 interacts with SPATA6 and is essential for its stability. CFAP52 knockout mice show loss of connecting piece formation and acephalic spermatozoa syndrome, with SPATA6 protein levels reduced upon CFAP52 deficiency.\",\n      \"method\": \"Co-immunoprecipitation (CFAP52-SPATA6 interaction), Cfap52 knockout mouse, immunofluorescence, Western blot\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse phenotype, co-IP identifying SPATA6 as CFAP52 binding partner, single lab\",\n      \"pmids\": [\"38126872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss-of-function mutation in SPATA20 leads to decreased expression of SPATA6, which plays a vital role in the assembly of the sperm head-tail conjunction in humans. The SPATA20 nonsense mutation caused degradation of SPATA20 protein with associated reduced SPATA6 levels in patient sperm.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, Western blot, immunofluorescence in patient samples\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — patient-based loss-of-function, Western blot confirming SPATA6 reduction, single case study\",\n      \"pmids\": [\"36415156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CEP135 interacts with SPATA6 and AKAP3, regulating their expression and stability. CEP135 knockout mice show acephalic spermatozoa with head-to-tail connection defects, and proteomic analysis revealed significant reduction in SPATA6 protein levels upon CEP135 deletion.\",\n      \"method\": \"Conditional Cep135 knockout mouse (Stra8-Cre), co-immunoprecipitation, proteomic analysis, immunofluorescence\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined spermatogenesis phenotype, Co-IP demonstrating CEP135-SPATA6 interaction, proteomics, single lab\",\n      \"pmids\": [\"40095067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NME5 loss-of-function results in near absence of SPATA6 at the head-tail coupling apparatus (HTCA) in human sperm, as confirmed by immunofluorescence analysis, indicating NME5 is required upstream of SPATA6 for HTCA integrity.\",\n      \"method\": \"Immunofluorescence of patient sperm (NME5 frameshift variant), ultrastructural electron microscopy\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — immunofluorescence in single patient, no direct protein interaction assay for NME5-SPATA6 relationship\",\n      \"pmids\": [\"41499646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SPATA6 mRNA is a direct target of miR-23a/b-3p in human sperm. Dual luciferase assays confirmed miR-23a/b-3p binds to the 3'UTR of SPATA6 mRNA. Mutations in the miR-23a/b-3p binding site within the SPATA6 3'UTR abrogated responsiveness. SPATA6 protein levels were significantly lower in oligoasthenozoospermic men with elevated miR-23a/b-3p.\",\n      \"method\": \"Dual luciferase reporter assay, site-directed mutagenesis of 3'UTR, Western blot, RT-qPCR\",\n      \"journal\": \"Fertility and sterility\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual luciferase assay with mutagenesis confirming direct miRNA-3'UTR interaction, Western blot for protein confirmation, single lab\",\n      \"pmids\": [\"31056312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In sheep Leydig cells, SPATA6 is localized in cytoplasm and nucleus. SPATA6 interference promotes apoptosis (increased BAX/BCL-2 ratio), blocks cell cycle at G2/M phase with downregulation of CDK1 and CCNB1. SPATA6 overexpression promotes cell cycle progression and upregulates CDK1, CDK4, CCND1, CCND2. SPATA6 overexpression also promotes testosterone secretion and StAR expression.\",\n      \"method\": \"siRNA knockdown and overexpression in primary Leydig cells, flow cytometry, Western blot, immunofluorescence localization\",\n      \"journal\": \"Theriogenology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, sheep Leydig cell model, KD/OE with phenotype but no direct pathway placement for mammalian canonical function\",\n      \"pmids\": [\"33667862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The rat Spata6 ortholog (SRF-1) is expressed exclusively in testis beginning at 5 weeks of age, with expression in spermatocytes. The deduced amino acid sequence shows partial homology with kinesin-related proteins, suggesting a role as a molecular motor in meiosis.\",\n      \"method\": \"Differential display cloning, RT-PCR, in situ hybridization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — initial cloning and expression paper, homology-based functional inference, no direct functional assay\",\n      \"pmids\": [\"11735130\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SPATA6 is a testis-enriched protein essential for assembly of the sperm head-tail coupling apparatus (HTCA), specifically the segmented columns and capitulum of the connecting piece; it interacts with myosin subunits (MYL6, MYO5A) and is transported to the HTCA in a process that requires the co-chaperone BAG5 to activate HSPA8-mediated folding of SPATA6, and it functions in a molecular complex with SUN5 and PMFBP1 at the sperm head-tail junction, with its stability and localization further dependent on CFAP52, CEP135, NME5, and SPATA20.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SPATA6 is a testis-enriched, haploid germ cell-expressed protein essential for assembly of the sperm head-tail coupling apparatus (HTCA), specifically the segmented columns and capitulum of the connecting piece; loss of Spata6 in mice produces acephalic spermatozoa and male sterility [#0, #1]. SPATA6 functions in myosin-based microfilament transport during late spermiogenesis, interacting with myosin subunits including MYL6 [#0]. At the sperm head-tail junction it operates within a molecular complex together with SUN5 and PMFBP1 to physically connect the head to the tail [#2]. Proper SPATA6 function depends on a dedicated folding step: the co-chaperone BAG5 forms a complex with HSPA8 and enhances HSPA8 substrate affinity to promote SPATA6 folding, and BAG5 loss yields misfolded SPATA6, defective HTCA assembly, and acephalic sperm that phenocopy SPATA6 deficiency [#3]. SPATA6 protein stability and HTCA localization further require CFAP52, CEP135, NME5, and SPATA20, whose loss each reduces SPATA6 levels or its presence at the HTCA [#4, #5, #6, #7]. SPATA6 expression is post-transcriptionally controlled by miR-23a/b-3p, which directly targets its 3'UTR and is elevated in oligoasthenozoospermic men with reduced SPATA6 [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established SPATA6 (rat ortholog SRF-1) as a testis-restricted gene expressed during spermatogenesis, raising the hypothesis it acts as a molecular motor in male germ cells.\",\n      \"evidence\": \"Differential display cloning, RT-PCR and in situ hybridization in rat testis\",\n      \"pmids\": [\"11735130\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Function inferred only from sequence homology to kinesin-related proteins\", \"No direct functional assay\", \"Cellular role undefined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the human SPATA6 protein as a 488-aa, ~53 kDa product expressed exclusively in haploid germ cells, fixing protein identity and expression pattern.\",\n      \"evidence\": \"cDNA cloning, RT-PCR, in situ hybridization, Western blot and chromosomal mapping\",\n      \"pmids\": [\"12771232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Homology-based motor assignment not functionally tested\", \"No interacting partners or subcellular role established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Pinned SPATA6 to a specific structure and process — formation of the segmented columns and capitulum of the connecting piece — and linked it to myosin-based transport, explaining how its loss causes acephalic spermatozoa.\",\n      \"evidence\": \"Spata6 knockout mouse with acephalic sperm/sterility phenotype plus proteomic and Co-IP identification of myosin subunit (MYL6) interactions\",\n      \"pmids\": [\"25605924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of myosin-based transport not reconstituted\", \"Direct vs indirect MYL6 interaction not resolved\", \"Structural basis of HTCA assembly unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed SPATA6 in a defined junctional complex with SUN5 and PMFBP1, establishing the molecular partners that physically couple sperm head to tail.\",\n      \"evidence\": \"Pmfbp1 knockout mouse, immunofluorescence and Co-IP showing SPATA6/SUN5/PMFBP1 cooperation\",\n      \"pmids\": [\"30032984\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and direct binding interfaces of the complex not defined\", \"Single lab\", \"Order of complex assembly unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a post-transcriptional control mechanism, showing SPATA6 mRNA is a direct miR-23a/b-3p target whose dysregulation lowers SPATA6 in subfertile men.\",\n      \"evidence\": \"Dual luciferase reporter with 3'UTR mutagenesis, Western blot and RT-qPCR in human sperm\",\n      \"pmids\": [\"31056312\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo contribution of this miRNA axis to fertility not tested\", \"Single lab\", \"Other regulators of SPATA6 expression unexplored\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed SPATA6 protein stability depends on CFAP52, identifying an upstream factor whose loss reduces SPATA6 and abolishes connecting piece formation.\",\n      \"evidence\": \"Cfap52 knockout mouse, Co-IP, immunofluorescence and Western blot\",\n      \"pmids\": [\"38126872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CFAP52 directly stabilizes SPATA6 or acts indirectly unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a chaperone requirement for SPATA6 folding, with BAG5 activating HSPA8-mediated folding of SPATA6, explaining why folding failure phenocopies SPATA6 loss.\",\n      \"evidence\": \"Bag5 knockout mouse, in vivo/in vitro folding assays, reciprocal Co-IP of BAG5-HSPA8 complex and immunofluorescence\",\n      \"pmids\": [\"38454159\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct chaperone-substrate contact between HSPA8 and SPATA6 not mapped\", \"Folding of SPATA6 vs other HTCA clients not distinguished\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended SPATA6 dependency to human disease, linking SPATA20 loss-of-function to reduced SPATA6 and defective head-tail conjunction.\",\n      \"evidence\": \"Whole-exome and Sanger sequencing, Western blot and immunofluorescence in patient sperm\",\n      \"pmids\": [\"36415156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case study\", \"Direct SPATA20-SPATA6 interaction not tested\", \"Mechanism of SPATA6 reduction unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified CEP135 and NME5 as additional upstream factors required for SPATA6 abundance/localization at the HTCA, broadening the network controlling SPATA6 deposition.\",\n      \"evidence\": \"Conditional Cep135 knockout mouse with Co-IP and proteomics; immunofluorescence/EM of NME5-variant patient sperm\",\n      \"pmids\": [\"40095067\", \"41499646\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NME5-SPATA6 relationship rests on single-patient immunofluorescence with no interaction assay\", \"Direct vs indirect regulation by CEP135 not resolved\", \"Hierarchy among CFAP52/CEP135/NME5/SPATA20 unmapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical activity of SPATA6 itself — whether it acts as a motor, adaptor, or structural scaffold within the connecting piece — and the structural architecture of the SPATA6-containing HTCA complex remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No enzymatic or motor activity directly demonstrated\", \"No structure of SPATA6 or its complexes\", \"Assembly hierarchy linking folding, stabilization and junctional partners not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\"sperm head-tail coupling apparatus (HTCA)\", \"SPATA6-SUN5-PMFBP1 head-tail junction complex\"],\n    \"partners\": [\"MYL6\", \"SUN5\", \"PMFBP1\", \"BAG5\", \"HSPA8\", \"CFAP52\", \"CEP135\", \"SPATA20\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}