{"gene":"C14ORF39","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2016,"finding":"C14ORF39/SIX6OS1 is a component of the central element of the synaptonemal complex (SC). Yeast two-hybrid analysis revealed that SIX6OS1 directly interacts with SYCE1. Loss of SIX6OS1 in mice causes defective chromosome synapsis at meiotic prophase I, arrest at the pachytene-like stage, infertility, and impaired processing of intermediate recombination nodules before crossover formation.","method":"Yeast two-hybrid, mouse knockout, cytological analysis of meiotic chromosomes","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction assay plus clean KO mouse with defined meiotic phenotype; independently replicated in subsequent studies","pmids":["27796301"],"is_preprint":false},{"year":2020,"finding":"SYCE1 undergoes multivalent interactions with SIX6OS1 via two distinct binding interfaces: (1) the N-terminus of SIX6OS1 binds and disrupts SYCE1's core dimeric structure to form a 1:1 complex, and (2) downstream sequences of both proteins provide a second distinct interface. Both interfaces are separately disrupted by SYCE1 mutations associated with nonobstructive azoospermia and premature ovarian failure, respectively. Mice harboring SYCE1's POF mutation combined with a targeted deletion within SIX6OS1's N-terminus are infertile with failure of chromosome synapsis.","method":"Biochemical interaction studies, mouse genetics (targeted deletions/mutations), cellular analysis of synapsis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal biochemical and genetic methods in a single study, with functional mouse validation of each interface","pmids":["32917591"],"is_preprint":false},{"year":2021,"finding":"Homozygous loss-of-function mutations in C14ORF39/SIX6OS1 (frameshift, nonsense, splicing) cause complete or incomplete asynapsis of homologous chromosomes in human male germ cells, resulting in NOA with meiotic arrest, and POI in females. Truncated mutant proteins retain SYCE1 binding but show impaired polycomplex formation between C14ORF39 and SYCE1. The human phenotypes are recapitulated by Six6os1 mutant mice carrying an analogous mutation.","method":"Whole-exome sequencing, Sanger sequencing, co-immunoprecipitation (SYCE1 binding assay), cytological meiosis analysis, mouse modeling","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple human mutations with functional biochemical studies and mouse model validation across independent families","pmids":["33508233"],"is_preprint":false},{"year":2022,"finding":"Novel homozygous variants of C14ORF39 found in sporadic POI and NOA patients significantly accelerate C14ORF39 protein degradation, thereby disrupting SC assembly and meiosis.","method":"Whole-exome sequencing, functional protein stability assays, SC assembly analysis","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional protein degradation assay plus SC assembly readout in patient-derived material; single lab","pmids":["34718620"],"is_preprint":false},{"year":2023,"finding":"SYCE3 interacts with the CE complexes SYCE1-SIX6OS1 and SYCE2-TEX12, providing a mechanism for their recruitment into the SC central element after SYCE3 remodels the SYCP1 lattice.","method":"Biochemical interaction studies, separation-of-function mutagenesis in mice, structural analysis","journal":"Nature structural & molecular biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — biochemical reconstitution plus mouse mutagenesis, but SIX6OS1 interaction is one of several findings in a study primarily focused on SYCE3","pmids":["36635604"],"is_preprint":false},{"year":2023,"finding":"SRSF1 directly binds and regulates the expression of Six6os1 via alternative splicing to implement the meiotic prophase I program in mouse oocytes; conditional knockout of Srsf1 in oocytes impairs synapsis and recombination.","method":"Conditional knockout mouse, immunofluorescence, direct binding assay (SRSF1 to Six6os1 mRNA via alternative splicing analysis)","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — cKO with phenotypic readout plus evidence of direct splicing regulation, but Six6os1 is one of multiple targets; single lab","pmids":["36882745"],"is_preprint":false},{"year":2024,"finding":"BCAS2 directly binds Six6os1 pre-mRNA and regulates its expression through alternative splicing in male germ cells; conditional knockout of Bcas2 impairs synapsis during meiotic prophase I, resulting in NOA.","method":"CLIP-seq (crosslinking immunoprecipitation and sequencing), conditional knockout mouse, cytological analysis of synapsis","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CLIP-seq directly maps BCAS2 binding to Six6os1; cKO phenotype corroborates; single lab","pmids":["39520542"],"is_preprint":false},{"year":2025,"finding":"In C. elegans, SYP-4 (a likely ortholog of vertebrate SIX6OS1) has a C-terminal domain whose mutation disrupts crossover interference without disrupting SC assembly, and alters the molecular organization/architecture of the SC as detected by 3D-STORM super-resolution microscopy.","method":"C. elegans genetics (mutation), 3D-STORM super-resolution microscopy","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structural imaging plus genetic separation-of-function in a well-established model organism ortholog; C. elegans ortholog assignment is inferred","pmids":["39841849"],"is_preprint":false}],"current_model":"C14ORF39/SIX6OS1 is a central element component of the synaptonemal complex that directly interacts with SYCE1 through two distinct binding interfaces (an N-terminal interface that disrupts SYCE1 dimerization to form a 1:1 complex, and a secondary downstream interface), is recruited to the SC via SYCE3, and is essential for full homologous chromosome synapsis and appropriate processing of recombination intermediates into crossovers during meiotic prophase I; its expression is post-transcriptionally regulated by splicing factors SRSF1 and BCAS2, and loss-of-function mutations cause meiotic arrest, nonobstructive azoospermia, and premature ovarian insufficiency in both humans and mice."},"narrative":{"mechanistic_narrative":"C14ORF39/SIX6OS1 is a central element component of the synaptonemal complex (SC) that is essential for homologous chromosome synapsis and the processing of recombination intermediates into crossovers during meiotic prophase I [PMID:27796301]. It functions through a direct, multivalent interaction with SYCE1: the SIX6OS1 N-terminus binds and disrupts the SYCE1 core dimer to form a 1:1 complex, while downstream sequences of both proteins form a second distinct interface, and disruption of either interface causes synapsis failure and infertility in mice [PMID:32917591]. The SYCE1–SIX6OS1 complex is recruited into the SC central element by SYCE3 [PMID:36635604]. Its expression is post-transcriptionally controlled by the splicing factors SRSF1 and BCAS2, which directly bind Six6os1 transcripts and regulate its expression through alternative splicing during meiotic prophase I [PMID:36882745, PMID:39520542]. Loss-of-function and protein-destabilizing mutations in C14ORF39 cause meiotic arrest with nonobstructive azoospermia in men and premature ovarian insufficiency in women, phenotypes recapitulated in mutant mice [PMID:33508233, PMID:34718620].","teleology":[{"year":2016,"claim":"Established SIX6OS1 as a bona fide central element SC protein and defined its requirement for synapsis and recombination, answering whether this uncharacterized ORF had a meiotic function.","evidence":"Yeast two-hybrid interaction with SYCE1 plus mouse knockout with cytological meiotic analysis","pmids":["27796301"],"confidence":"High","gaps":["Molecular basis of the SYCE1 interaction not resolved","Mechanism linking synapsis defect to failed crossover formation undefined"]},{"year":2020,"claim":"Resolved how SIX6OS1 engages SYCE1, showing a two-interface architecture in which the N-terminus disrupts SYCE1 dimerization, and validated each interface genetically.","evidence":"Biochemical interaction studies with targeted mouse deletions/mutations and synapsis analysis","pmids":["32917591"],"confidence":"High","gaps":["High-resolution structure of the assembled complex not reported","How the two interfaces cooperate during SC assembly unclear"]},{"year":2021,"claim":"Demonstrated that human loss-of-function mutations cause meiotic arrest, showing C14ORF39 is causative for NOA and POI and that truncated proteins fail polycomplex formation despite retaining SYCE1 binding.","evidence":"Whole-exome sequencing across families, co-immunoprecipitation binding assays, cytology, and mouse modeling","pmids":["33508233"],"confidence":"High","gaps":["Genotype–phenotype correlation for partial vs complete asynapsis not fully mapped"]},{"year":2022,"claim":"Extended the mutational spectrum by showing certain patient variants act by accelerating C14ORF39 protein degradation, identifying protein stability as a disease mechanism.","evidence":"Whole-exome sequencing with protein stability and SC assembly assays","pmids":["34718620"],"confidence":"Medium","gaps":["Degradation pathway/E3 ligase not identified","Single-lab functional assays"]},{"year":2023,"claim":"Identified SYCE3 as the recruiter of the SYCE1–SIX6OS1 complex into the central element, clarifying how the complex is incorporated into the SC after SYCP1 lattice remodeling.","evidence":"Biochemical reconstitution, separation-of-function mouse mutagenesis, and structural analysis","pmids":["36635604"],"confidence":"Medium","gaps":["SIX6OS1 interaction was secondary to a SYCE3-focused study","Order and stoichiometry of central element assembly incompletely defined"]},{"year":2023,"claim":"Showed that Six6os1 expression is post-transcriptionally controlled, with SRSF1 directly regulating it via alternative splicing to execute the oocyte prophase I program.","evidence":"Oocyte conditional Srsf1 knockout with immunofluorescence and splicing analysis","pmids":["36882745"],"confidence":"Medium","gaps":["Six6os1 is one of multiple SRSF1 targets; its specific contribution to the phenotype not isolated"]},{"year":2024,"claim":"Identified a second splicing regulator, BCAS2, that directly binds Six6os1 pre-mRNA in male germ cells, reinforcing splicing-dependent control of synapsis.","evidence":"CLIP-seq mapping of BCAS2 binding plus conditional knockout with synapsis cytology","pmids":["39520542"],"confidence":"Medium","gaps":["Whether SRSF1 and BCAS2 act on the same splice events not resolved","Single-lab study"]},{"year":2025,"claim":"Used a C. elegans ortholog to separate SC architecture from crossover regulation, showing a C-terminal domain controls crossover interference and SC molecular organization independent of assembly.","evidence":"C. elegans genetic mutation with 3D-STORM super-resolution microscopy","pmids":["39841849"],"confidence":"Medium","gaps":["Ortholog assignment to SIX6OS1 is inferred, not established","Whether the vertebrate protein has an analogous crossover-interference function untested"]},{"year":null,"claim":"How SIX6OS1 mechanistically couples central element assembly to crossover designation and interference in vertebrates remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of the assembled vertebrate central element","Link between SC architecture and crossover interference in mammals undefined","Degradation/turnover regulation of C14ORF39 not mapped to a pathway"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0]}],"complexes":["synaptonemal complex central element","SYCE1-SIX6OS1 complex"],"partners":["SYCE1","SYCE3","SRSF1","BCAS2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N1H7","full_name":"Protein SIX6OS1","aliases":["Six6 opposite strand transcript 1"],"length_aa":587,"mass_kda":68.2,"function":"Meiotic protein that localizes to the central element of the synaptonemal complex and is required for chromosome synapsis during meiotic recombination. Required for the appropriate processing of intermediate recombination nodules before crossover formation","subcellular_location":"Chromosome","url":"https://www.uniprot.org/uniprotkb/Q8N1H7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C14ORF39"},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/C14ORF39","total_profiled":1310},"omim":[{"mim_id":"619203","title":"PREMATURE OVARIAN FAILURE 18; POF18","url":"https://www.omim.org/entry/619203"},{"mim_id":"619202","title":"SPERMATOGENIC FAILURE 52; SPGF52","url":"https://www.omim.org/entry/619202"},{"mim_id":"617307","title":"CHROMOSOME 14 OPEN READING FRAME 39; C14ORF39","url":"https://www.omim.org/entry/617307"},{"mim_id":"616950","title":"SPERMATOGENIC FAILURE 15; SPGF15","url":"https://www.omim.org/entry/616950"},{"mim_id":"616947","title":"PREMATURE OVARIAN FAILURE 12; POF12","url":"https://www.omim.org/entry/616947"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"pituitary gland","ntpm":4.5},{"tissue":"salivary gland","ntpm":4.4},{"tissue":"testis","ntpm":10.1}],"url":"https://www.proteinatlas.org/search/C14ORF39"},"hgnc":{"alias_symbol":["SIX6OS1"],"prev_symbol":[]},"alphafold":{"accession":"Q8N1H7","domains":[{"cath_id":"1.20.5","chopping":"9-101","consensus_level":"high","plddt":96.1771,"start":9,"end":101},{"cath_id":"1.20.5","chopping":"190-231","consensus_level":"medium","plddt":90.0931,"start":190,"end":231}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N1H7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N1H7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N1H7-F1-predicted_aligned_error_v6.png","plddt_mean":58.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C14ORF39","jax_strain_url":"https://www.jax.org/strain/search?query=C14ORF39"},"sequence":{"accession":"Q8N1H7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N1H7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N1H7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N1H7"}},"corpus_meta":[{"pmid":"35172124","id":"PMC_35172124","title":"Whole-exome sequencing improves the diagnosis and care of men with non-obstructive azoospermia.","date":"2022","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35172124","citation_count":99,"is_preprint":false},{"pmid":"34794894","id":"PMC_34794894","title":"Genetics of ovarian insufficiency and defects of folliculogenesis.","date":"2021","source":"Best practice & research. 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Yeast two-hybrid analysis revealed that SIX6OS1 directly interacts with SYCE1. Loss of SIX6OS1 in mice causes defective chromosome synapsis at meiotic prophase I, arrest at the pachytene-like stage, infertility, and impaired processing of intermediate recombination nodules before crossover formation.\",\n      \"method\": \"Yeast two-hybrid, mouse knockout, cytological analysis of meiotic chromosomes\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction assay plus clean KO mouse with defined meiotic phenotype; independently replicated in subsequent studies\",\n      \"pmids\": [\"27796301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SYCE1 undergoes multivalent interactions with SIX6OS1 via two distinct binding interfaces: (1) the N-terminus of SIX6OS1 binds and disrupts SYCE1's core dimeric structure to form a 1:1 complex, and (2) downstream sequences of both proteins provide a second distinct interface. Both interfaces are separately disrupted by SYCE1 mutations associated with nonobstructive azoospermia and premature ovarian failure, respectively. Mice harboring SYCE1's POF mutation combined with a targeted deletion within SIX6OS1's N-terminus are infertile with failure of chromosome synapsis.\",\n      \"method\": \"Biochemical interaction studies, mouse genetics (targeted deletions/mutations), cellular analysis of synapsis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal biochemical and genetic methods in a single study, with functional mouse validation of each interface\",\n      \"pmids\": [\"32917591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Homozygous loss-of-function mutations in C14ORF39/SIX6OS1 (frameshift, nonsense, splicing) cause complete or incomplete asynapsis of homologous chromosomes in human male germ cells, resulting in NOA with meiotic arrest, and POI in females. Truncated mutant proteins retain SYCE1 binding but show impaired polycomplex formation between C14ORF39 and SYCE1. The human phenotypes are recapitulated by Six6os1 mutant mice carrying an analogous mutation.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, co-immunoprecipitation (SYCE1 binding assay), cytological meiosis analysis, mouse modeling\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple human mutations with functional biochemical studies and mouse model validation across independent families\",\n      \"pmids\": [\"33508233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Novel homozygous variants of C14ORF39 found in sporadic POI and NOA patients significantly accelerate C14ORF39 protein degradation, thereby disrupting SC assembly and meiosis.\",\n      \"method\": \"Whole-exome sequencing, functional protein stability assays, SC assembly analysis\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional protein degradation assay plus SC assembly readout in patient-derived material; single lab\",\n      \"pmids\": [\"34718620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SYCE3 interacts with the CE complexes SYCE1-SIX6OS1 and SYCE2-TEX12, providing a mechanism for their recruitment into the SC central element after SYCE3 remodels the SYCP1 lattice.\",\n      \"method\": \"Biochemical interaction studies, separation-of-function mutagenesis in mice, structural analysis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical reconstitution plus mouse mutagenesis, but SIX6OS1 interaction is one of several findings in a study primarily focused on SYCE3\",\n      \"pmids\": [\"36635604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SRSF1 directly binds and regulates the expression of Six6os1 via alternative splicing to implement the meiotic prophase I program in mouse oocytes; conditional knockout of Srsf1 in oocytes impairs synapsis and recombination.\",\n      \"method\": \"Conditional knockout mouse, immunofluorescence, direct binding assay (SRSF1 to Six6os1 mRNA via alternative splicing analysis)\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — cKO with phenotypic readout plus evidence of direct splicing regulation, but Six6os1 is one of multiple targets; single lab\",\n      \"pmids\": [\"36882745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BCAS2 directly binds Six6os1 pre-mRNA and regulates its expression through alternative splicing in male germ cells; conditional knockout of Bcas2 impairs synapsis during meiotic prophase I, resulting in NOA.\",\n      \"method\": \"CLIP-seq (crosslinking immunoprecipitation and sequencing), conditional knockout mouse, cytological analysis of synapsis\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CLIP-seq directly maps BCAS2 binding to Six6os1; cKO phenotype corroborates; single lab\",\n      \"pmids\": [\"39520542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In C. elegans, SYP-4 (a likely ortholog of vertebrate SIX6OS1) has a C-terminal domain whose mutation disrupts crossover interference without disrupting SC assembly, and alters the molecular organization/architecture of the SC as detected by 3D-STORM super-resolution microscopy.\",\n      \"method\": \"C. elegans genetics (mutation), 3D-STORM super-resolution microscopy\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structural imaging plus genetic separation-of-function in a well-established model organism ortholog; C. elegans ortholog assignment is inferred\",\n      \"pmids\": [\"39841849\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C14ORF39/SIX6OS1 is a central element component of the synaptonemal complex that directly interacts with SYCE1 through two distinct binding interfaces (an N-terminal interface that disrupts SYCE1 dimerization to form a 1:1 complex, and a secondary downstream interface), is recruited to the SC via SYCE3, and is essential for full homologous chromosome synapsis and appropriate processing of recombination intermediates into crossovers during meiotic prophase I; its expression is post-transcriptionally regulated by splicing factors SRSF1 and BCAS2, and loss-of-function mutations cause meiotic arrest, nonobstructive azoospermia, and premature ovarian insufficiency in both humans and mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"C14ORF39/SIX6OS1 is a central element component of the synaptonemal complex (SC) that is essential for homologous chromosome synapsis and the processing of recombination intermediates into crossovers during meiotic prophase I [#0]. It functions through a direct, multivalent interaction with SYCE1: the SIX6OS1 N-terminus binds and disrupts the SYCE1 core dimer to form a 1:1 complex, while downstream sequences of both proteins form a second distinct interface, and disruption of either interface causes synapsis failure and infertility in mice [#1]. The SYCE1\\u2013SIX6OS1 complex is recruited into the SC central element by SYCE3 [#4]. Its expression is post-transcriptionally controlled by the splicing factors SRSF1 and BCAS2, which directly bind Six6os1 transcripts and regulate its expression through alternative splicing during meiotic prophase I [#5, #6]. Loss-of-function and protein-destabilizing mutations in C14ORF39 cause meiotic arrest with nonobstructive azoospermia in men and premature ovarian insufficiency in women, phenotypes recapitulated in mutant mice [#2, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established SIX6OS1 as a bona fide central element SC protein and defined its requirement for synapsis and recombination, answering whether this uncharacterized ORF had a meiotic function.\",\n      \"evidence\": \"Yeast two-hybrid interaction with SYCE1 plus mouse knockout with cytological meiotic analysis\",\n      \"pmids\": [\"27796301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the SYCE1 interaction not resolved\", \"Mechanism linking synapsis defect to failed crossover formation undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved how SIX6OS1 engages SYCE1, showing a two-interface architecture in which the N-terminus disrupts SYCE1 dimerization, and validated each interface genetically.\",\n      \"evidence\": \"Biochemical interaction studies with targeted mouse deletions/mutations and synapsis analysis\",\n      \"pmids\": [\"32917591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the assembled complex not reported\", \"How the two interfaces cooperate during SC assembly unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that human loss-of-function mutations cause meiotic arrest, showing C14ORF39 is causative for NOA and POI and that truncated proteins fail polycomplex formation despite retaining SYCE1 binding.\",\n      \"evidence\": \"Whole-exome sequencing across families, co-immunoprecipitation binding assays, cytology, and mouse modeling\",\n      \"pmids\": [\"33508233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype\\u2013phenotype correlation for partial vs complete asynapsis not fully mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the mutational spectrum by showing certain patient variants act by accelerating C14ORF39 protein degradation, identifying protein stability as a disease mechanism.\",\n      \"evidence\": \"Whole-exome sequencing with protein stability and SC assembly assays\",\n      \"pmids\": [\"34718620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degradation pathway/E3 ligase not identified\", \"Single-lab functional assays\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified SYCE3 as the recruiter of the SYCE1\\u2013SIX6OS1 complex into the central element, clarifying how the complex is incorporated into the SC after SYCP1 lattice remodeling.\",\n      \"evidence\": \"Biochemical reconstitution, separation-of-function mouse mutagenesis, and structural analysis\",\n      \"pmids\": [\"36635604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SIX6OS1 interaction was secondary to a SYCE3-focused study\", \"Order and stoichiometry of central element assembly incompletely defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed that Six6os1 expression is post-transcriptionally controlled, with SRSF1 directly regulating it via alternative splicing to execute the oocyte prophase I program.\",\n      \"evidence\": \"Oocyte conditional Srsf1 knockout with immunofluorescence and splicing analysis\",\n      \"pmids\": [\"36882745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Six6os1 is one of multiple SRSF1 targets; its specific contribution to the phenotype not isolated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a second splicing regulator, BCAS2, that directly binds Six6os1 pre-mRNA in male germ cells, reinforcing splicing-dependent control of synapsis.\",\n      \"evidence\": \"CLIP-seq mapping of BCAS2 binding plus conditional knockout with synapsis cytology\",\n      \"pmids\": [\"39520542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SRSF1 and BCAS2 act on the same splice events not resolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Used a C. elegans ortholog to separate SC architecture from crossover regulation, showing a C-terminal domain controls crossover interference and SC molecular organization independent of assembly.\",\n      \"evidence\": \"C. elegans genetic mutation with 3D-STORM super-resolution microscopy\",\n      \"pmids\": [\"39841849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog assignment to SIX6OS1 is inferred, not established\", \"Whether the vertebrate protein has an analogous crossover-interference function untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SIX6OS1 mechanistically couples central element assembly to crossover designation and interference in vertebrates remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the assembled vertebrate central element\", \"Link between SC architecture and crossover interference in mammals undefined\", \"Degradation/turnover regulation of C14ORF39 not mapped to a pathway\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"synaptonemal complex central element\", \"SYCE1-SIX6OS1 complex\"],\n    \"partners\": [\"SYCE1\", \"SYCE3\", \"SRSF1\", \"BCAS2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}