{"gene":"LRRC23","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2021,"finding":"LRRC23 is an evolutionarily conserved testis-enriched protein that localizes to the radial spoke (RS) complex within murine sperm flagella. It is the mammalian homolog of Chlamydomonas RSP15 (a radial spoke stalk protein of RS2). LRRC23 physically interacts with RSPH3A and RSPH3B (radial spoke head proteins). Knockout of Lrrc23 in mice causes male infertility due to RS disorganization and severely impaired sperm motility, while ciliary beating in somatic cells is not significantly affected, indicating a sperm-specific requirement.","method":"Co-immunoprecipitation (interaction with RSPH3A/RSPH3B), immunofluorescence localization in sperm flagella, Lrrc23 knockout mouse model with fertility and motility phenotyping, transmission electron microscopy of sperm axoneme","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP for binding partners, clean KO with defined sperm motility and fertility phenotype, direct localization by immunofluorescence, replicated across multiple orthogonal methods in one study","pmids":["34585727"],"is_preprint":false},{"year":2023,"finding":"LRRC23 is an RS3 head component (not an RS stalk protein as previously proposed) essential for RS3 head assembly in mammalian spermatozoa. A splice-site variant causing C-terminal truncation of LRRC23 was identified in infertile males with defective sperm motility. The truncated LRRC23 fails to localize to the sperm tail. Purified recombinant LRRC23 interacts with the RS head protein RSPH9, and this interaction is abolished by C-terminal truncation. Cryo-electron tomography revealed absence of the RS3 head and the sperm-specific RS2-RS3 bridge structure in LRRC23 mutant spermatozoa. Evolutionary and structural analysis established that LRRC34 (not LRRC23) is the true RSP15 ortholog.","method":"Human genetics (splice-site variant identification in infertile males), truncation mutant mouse model, cryo-electron tomography of sperm axoneme, recombinant protein pulldown (LRRC23 vs. RSPH9), immunofluorescence of sperm flagella, evolutionary/structural comparison","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — cryo-ET structural validation, recombinant protein interaction assay with mutagenesis (truncation abolishes RSPH9 binding), human genetic variant linked to phenotype, mouse model corroboration, multiple orthogonal methods","pmids":["38091523"],"is_preprint":false},{"year":2023,"finding":"A homozygous nonsense mutation in human LRRC23 (c.376C>T; p.Arg126X) causes idiopathic asthenozoospermia and male infertility by disrupting LRRC23 protein synthesis and impairing radial spoke integrity. In vitro co-immunoprecipitation demonstrated an interaction between LRRC23 and RSPH3 in human cells, consistent with the mouse data. Intracytoplasmic sperm injection (ICSI) successfully achieved pregnancy in the affected patient.","method":"Human genetics (homozygous nonsense mutation in consanguineous family), Western blot and immunofluorescence of patient sperm, Co-immunoprecipitation (LRRC23–RSPH3), transmission electron microscopy of sperm axoneme","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — single lab, Co-IP supporting RSPH3 interaction in human cells, human mutation with loss-of-function phenotype, corroborates mouse findings","pmids":["37804054"],"is_preprint":false},{"year":2024,"finding":"Novel compound heterozygous mutations in LRRC23 (c.1018C>T: p.Q340X and c.881_897del: p.R295Gfs*32) in a non-consanguineous family cause asthenozoospermia with absence of RS3 in sperm flagella. Western blotting and immunofluorescence confirmed loss of LRRC23 protein in sperm flagella, and transmission electron microscopy showed absence of RS3 in axonemes of the affected individual, disrupting stability of the radial spoke complex and impairing motility.","method":"Human genetics (compound heterozygous variants), Western blotting and immunofluorescence of patient sperm, transmission electron microscopy of sperm axoneme, scanning electron microscopy","journal":"Asian journal of andrology","confidence":"Medium","confidence_rationale":"Tier 2-3 — human genetic variants with loss-of-function phenotype validated by protein-level and ultrastructural analysis; single lab; corroborates prior findings","pmids":["39054792"],"is_preprint":false},{"year":2005,"finding":"The leucine-rich B7 protein (LRRC23) is expressed in human ocular tissues including corneal epithelium and endothelium, lens epithelial and fiber cells, sclera, and retinal rod and cone layers. In MG-63 cells, LRRC23 localizes to both the nucleus and cytoplasm, and shows partial cytoplasmic co-localization with the small leucine-rich proteoglycan mimecan by confocal microscopy. Two splice transcript variants show tissue-differential expression (variant 1 enriched in cornea; variant 2 broadly expressed).","method":"RT-PCR of human ocular tissues, immunohistochemistry with anti-LRRC23 antibody, transient co-transfection and laser scanning confocal microscopy in MG-63 cells","journal":"Molecular vision","confidence":"Low","confidence_rationale":"Tier 3 — localization by IHC and confocal microscopy, co-localization only; no functional consequence established for the mimecan interaction; single lab, single study","pmids":["16030496"],"is_preprint":false}],"current_model":"LRRC23 is a leucine-rich repeat-containing protein that functions as a radial spoke 3 (RS3) head component in mammalian sperm flagella, where it is required for RS3 head assembly and the sperm-specific RS2-RS3 bridge; it physically interacts with RS head proteins RSPH9 and RSPH3A/B through its C-terminus, and loss-of-function mutations in mice or humans cause disorganized radial spokes, severely impaired sperm motility, and male infertility without affecting somatic cilia."},"narrative":{"teleology":[{"year":2005,"claim":"Initial characterization placed LRRC23 in ocular tissues with nuclear and cytoplasmic localization and partial co-localization with mimecan, but provided no functional insight into its mechanism of action.","evidence":"RT-PCR, immunohistochemistry, and confocal co-localization in human ocular tissues and MG-63 cells","pmids":["16030496"],"confidence":"Low","gaps":["No functional assay was performed; co-localization with mimecan does not establish a direct interaction or functional role","No connection to ciliary or flagellar biology was made","Findings have not been replicated or extended by independent studies"]},{"year":2021,"claim":"A knockout mouse model resolved that LRRC23 is a testis-enriched, flagellum-localized radial spoke protein whose loss causes male infertility through RS disorganization and impaired sperm motility, without affecting somatic cilia—establishing it as a sperm-specific axonemal component.","evidence":"Lrrc23 knockout mice with fertility and motility phenotyping, Co-IP with RSPH3A/RSPH3B, immunofluorescence, and transmission EM of sperm axonemes","pmids":["34585727"],"confidence":"High","gaps":["Whether LRRC23 belongs to the RS2 stalk (as proposed by homology to Chlamydomonas RSP15) or a different RS sub-complex was unresolved","The precise binding interface and domain requirements for RSPH3A/B interaction were not defined","Human disease relevance was not yet established"]},{"year":2023,"claim":"Cryo-electron tomography and human genetic data redefined LRRC23 as an RS3 head component (not an RS2 stalk protein), showed that its C-terminus is required for RSPH9 binding and flagellar localization, and demonstrated that its loss specifically eliminates the RS3 head and the sperm-specific RS2–RS3 bridge.","evidence":"Human splice-site variant in infertile males, cryo-ET of mutant sperm axonemes, recombinant pulldown of LRRC23–RSPH9 with truncation controls, evolutionary analysis reassigning LRRC34 as the true RSP15 ortholog","pmids":["38091523"],"confidence":"High","gaps":["Full atomic-resolution structure of the RS3 head complex with LRRC23 is lacking","The complete set of RS3 head subunits that LRRC23 organizes is not fully defined","How LRRC23 is trafficked to the flagellum and its assembly timing during spermiogenesis are unknown"]},{"year":2023,"claim":"Identification of a homozygous nonsense mutation in human LRRC23 confirmed its requirement for radial spoke integrity and sperm motility in humans and validated the LRRC23–RSPH3 interaction in human cells.","evidence":"Human genetics in a consanguineous family, Co-IP of LRRC23–RSPH3 in human cells, TEM of patient sperm axoneme","pmids":["37804054"],"confidence":"Medium","gaps":["Single family; additional kindreds needed to establish LRRC23 as a recurrently mutated asthenozoospermia gene","Genotype–phenotype correlation across different mutation types is incomplete"]},{"year":2024,"claim":"Compound heterozygous LRRC23 mutations in a non-consanguineous family independently confirmed RS3 loss as the ultrastructural basis of LRRC23-associated asthenozoospermia, broadening the allelic spectrum.","evidence":"Human genetics, Western blot and immunofluorescence confirming protein loss, TEM showing RS3 absence in patient sperm","pmids":["39054792"],"confidence":"Medium","gaps":["Functional rescue experiments in patient-derived or model systems have not been performed","Whether partial LRRC23 loss produces an intermediate motility phenotype is unknown"]},{"year":null,"claim":"Key open questions include the high-resolution structure of the LRRC23-containing RS3 head complex, the mechanism by which LRRC23 is selectively required in sperm but dispensable in somatic cilia, and whether LRRC23 plays any non-flagellar role consistent with its reported ocular expression.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic-resolution structure of LRRC23 within the RS3 head complex","Molecular basis of sperm-specific versus somatic cilia dispensability is unexplained","Any functional significance of LRRC23 expression outside the testis remains uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1,2,3]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1]}],"complexes":["Radial spoke 3 (RS3) head complex"],"partners":["RSPH9","RSPH3A","RSPH3B","RSPH3"],"other_free_text":[]},"mechanistic_narrative":"LRRC23 is a leucine-rich repeat-containing protein that functions as a structural component of the radial spoke 3 (RS3) head in mammalian sperm flagella, where it is essential for RS3 head assembly and formation of the sperm-specific RS2–RS3 bridge [PMID:38091523]. LRRC23 physically interacts with radial spoke head proteins RSPH9 and RSPH3A/B through its C-terminus, and loss of this interaction—by truncation or nonsense mutation—abolishes its flagellar localization and disrupts radial spoke integrity [PMID:34585727, PMID:38091523, PMID:37804054]. Loss-of-function mutations in LRRC23 cause asthenozoospermia and male infertility in both mice and humans without affecting somatic cilia motility, establishing a sperm-specific requirement [PMID:34585727, PMID:37804054, PMID:39054792]."},"prefetch_data":{"uniprot":{"accession":"Q53EV4","full_name":"Leucine-rich repeat-containing protein 23","aliases":["Leucine-rich protein B7"],"length_aa":343,"mass_kda":39.8,"function":"Essential for sperm motility and male fertility. Plays an important role in the proper assembly of the third radial spoke (RS3) head and the bridge structure between RS2 and RS3 in the sperm flagella","subcellular_location":"Cell projection, cilium, flagellum; Cytoplasm, cytoskeleton, flagellum axoneme; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q53EV4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRRC23","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LRRC23","total_profiled":1310},"omim":[{"mim_id":"620848","title":"SPERMATOGENIC FAILURE 92; SPGF92","url":"https://www.omim.org/entry/620848"},{"mim_id":"620708","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 23; LRRC23","url":"https://www.omim.org/entry/620708"},{"mim_id":"608247","title":"KERATIN 73, TYPE II; KRT73","url":"https://www.omim.org/entry/608247"},{"mim_id":"258150","title":"SPERMATOGENIC FAILURE 1; SPGF1","url":"https://www.omim.org/entry/258150"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Nucleoli rim","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"fallopian tube","ntpm":95.7}],"url":"https://www.proteinatlas.org/search/LRRC23"},"hgnc":{"alias_symbol":["B7","LRPB7"],"prev_symbol":[]},"alphafold":{"accession":"Q53EV4","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53EV4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q53EV4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q53EV4-F1-predicted_aligned_error_v6.png","plddt_mean":88.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LRRC23","jax_strain_url":"https://www.jax.org/strain/search?query=LRRC23"},"sequence":{"accession":"Q53EV4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q53EV4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q53EV4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53EV4"}},"corpus_meta":[{"pmid":"8717514","id":"PMC_8717514","title":"CD28/B7 system of T cell costimulation.","date":"1996","source":"Annual review of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8717514","citation_count":2082,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10581077","id":"PMC_10581077","title":"B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion.","date":"1999","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10581077","citation_count":2049,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7534215","id":"PMC_7534215","title":"B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy.","date":"1995","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/7534215","citation_count":1499,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11910893","id":"PMC_11910893","title":"The B7-CD28 superfamily.","date":"2002","source":"Nature reviews. 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Containing 23). The entire corpus is about the **B7/CD28 immune checkpoint family** (CD80, CD86, PD-L1, B7-H3, B7-H4, etc.) — a completely different set of genes. This is a symbol/query mismatch: the retrieved papers describe B7-family immunology, not LRRC23 biology. No discoveries about LRRC23 can be extracted from this corpus.\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to classify each paper:\n\n**Main corpus (papers 1-100):** These are overwhelmingly about the B7/CD28 immunology family (B7-1, B7-2, B7-H1, B7-H3, B7-H4, etc.) — these are ALIAS COLLISION papers. \"Leucine-rich B7\" (LRRC23) shares \"B7\" in its name but is completely unrelated to the immunological B7 family. Paper [18] describes \"leucine-rich B7 protein\" which appears to be LRRC23 (also called LRR-B7 or leucine-rich B7). → KEEP paper [18] from main corpus.\n\n**Gene2pubmed papers (1-19):**\n- Papers 1-9: General genomics/cDNA resources, not specific to LRRC23 → EXCLUDE\n- Paper 10: Chromosome 12p13 genomic sequencing — identifies region containing LRRC23 precursor → borderline, but no mechanistic findings about LRRC23 protein\n- Paper 11, 15: Transcriptome studies mentioning LRRC23 tangentially → EXCLUDE\n- Paper 12: Chromosome 12p13 gene structure → EXCLUDE (no mechanistic data on LRRC23)\n- Papers 2, 3, 4: Interactome maps with LRRC23 listed → could include if specific interaction data found\n- Paper 13: Testis proteomics with LRRC23 → expression data only → EXCLUDE\n- **Paper 14**: LRRC23 as radial spoke component in sperm → KEEP\n- **Paper 16**: LRRC23 as RS3 head component → KEEP\n- **Paper 17**: LRRC23 deficiency causes asthenozoospermia → KEEP\n- **Paper 18 (gene2pubmed)**: LRRC23 truncation and RS3 → same as paper 16 above\n- **Paper 19**: Novel LRRC23 mutations causing AZS → KEEP\n\nPapers 2, 3, 4 (BioPlex interactome): These large-scale AP-MS studies may have detected LRRC23 interactions, but the abstracts don't specify LRRC23-specific findings → EXCLUDE from detailed extraction (no specific mechanistic claim about LRRC23).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"LRRC23 is an evolutionarily conserved testis-enriched protein that localizes to the radial spoke (RS) complex within murine sperm flagella. It is the mammalian homolog of Chlamydomonas RSP15 (a radial spoke stalk protein of RS2). LRRC23 physically interacts with RSPH3A and RSPH3B (radial spoke head proteins). Knockout of Lrrc23 in mice causes male infertility due to RS disorganization and severely impaired sperm motility, while ciliary beating in somatic cells is not significantly affected, indicating a sperm-specific requirement.\",\n      \"method\": \"Co-immunoprecipitation (interaction with RSPH3A/RSPH3B), immunofluorescence localization in sperm flagella, Lrrc23 knockout mouse model with fertility and motility phenotyping, transmission electron microscopy of sperm axoneme\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP for binding partners, clean KO with defined sperm motility and fertility phenotype, direct localization by immunofluorescence, replicated across multiple orthogonal methods in one study\",\n      \"pmids\": [\"34585727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LRRC23 is an RS3 head component (not an RS stalk protein as previously proposed) essential for RS3 head assembly in mammalian spermatozoa. A splice-site variant causing C-terminal truncation of LRRC23 was identified in infertile males with defective sperm motility. The truncated LRRC23 fails to localize to the sperm tail. Purified recombinant LRRC23 interacts with the RS head protein RSPH9, and this interaction is abolished by C-terminal truncation. Cryo-electron tomography revealed absence of the RS3 head and the sperm-specific RS2-RS3 bridge structure in LRRC23 mutant spermatozoa. Evolutionary and structural analysis established that LRRC34 (not LRRC23) is the true RSP15 ortholog.\",\n      \"method\": \"Human genetics (splice-site variant identification in infertile males), truncation mutant mouse model, cryo-electron tomography of sperm axoneme, recombinant protein pulldown (LRRC23 vs. RSPH9), immunofluorescence of sperm flagella, evolutionary/structural comparison\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — cryo-ET structural validation, recombinant protein interaction assay with mutagenesis (truncation abolishes RSPH9 binding), human genetic variant linked to phenotype, mouse model corroboration, multiple orthogonal methods\",\n      \"pmids\": [\"38091523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A homozygous nonsense mutation in human LRRC23 (c.376C>T; p.Arg126X) causes idiopathic asthenozoospermia and male infertility by disrupting LRRC23 protein synthesis and impairing radial spoke integrity. In vitro co-immunoprecipitation demonstrated an interaction between LRRC23 and RSPH3 in human cells, consistent with the mouse data. Intracytoplasmic sperm injection (ICSI) successfully achieved pregnancy in the affected patient.\",\n      \"method\": \"Human genetics (homozygous nonsense mutation in consanguineous family), Western blot and immunofluorescence of patient sperm, Co-immunoprecipitation (LRRC23–RSPH3), transmission electron microscopy of sperm axoneme\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — single lab, Co-IP supporting RSPH3 interaction in human cells, human mutation with loss-of-function phenotype, corroborates mouse findings\",\n      \"pmids\": [\"37804054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Novel compound heterozygous mutations in LRRC23 (c.1018C>T: p.Q340X and c.881_897del: p.R295Gfs*32) in a non-consanguineous family cause asthenozoospermia with absence of RS3 in sperm flagella. Western blotting and immunofluorescence confirmed loss of LRRC23 protein in sperm flagella, and transmission electron microscopy showed absence of RS3 in axonemes of the affected individual, disrupting stability of the radial spoke complex and impairing motility.\",\n      \"method\": \"Human genetics (compound heterozygous variants), Western blotting and immunofluorescence of patient sperm, transmission electron microscopy of sperm axoneme, scanning electron microscopy\",\n      \"journal\": \"Asian journal of andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — human genetic variants with loss-of-function phenotype validated by protein-level and ultrastructural analysis; single lab; corroborates prior findings\",\n      \"pmids\": [\"39054792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The leucine-rich B7 protein (LRRC23) is expressed in human ocular tissues including corneal epithelium and endothelium, lens epithelial and fiber cells, sclera, and retinal rod and cone layers. In MG-63 cells, LRRC23 localizes to both the nucleus and cytoplasm, and shows partial cytoplasmic co-localization with the small leucine-rich proteoglycan mimecan by confocal microscopy. Two splice transcript variants show tissue-differential expression (variant 1 enriched in cornea; variant 2 broadly expressed).\",\n      \"method\": \"RT-PCR of human ocular tissues, immunohistochemistry with anti-LRRC23 antibody, transient co-transfection and laser scanning confocal microscopy in MG-63 cells\",\n      \"journal\": \"Molecular vision\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — localization by IHC and confocal microscopy, co-localization only; no functional consequence established for the mimecan interaction; single lab, single study\",\n      \"pmids\": [\"16030496\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRRC23 is a leucine-rich repeat-containing protein that functions as a radial spoke 3 (RS3) head component in mammalian sperm flagella, where it is required for RS3 head assembly and the sperm-specific RS2-RS3 bridge; it physically interacts with RS head proteins RSPH9 and RSPH3A/B through its C-terminus, and loss-of-function mutations in mice or humans cause disorganized radial spokes, severely impaired sperm motility, and male infertility without affecting somatic cilia.\"\n}\n```","stage2_raw":"\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"LRRC23 is a leucine-rich repeat-containing protein that functions as a structural component of the radial spoke 3 (RS3) head in mammalian sperm flagella, where it is essential for RS3 head assembly and formation of the sperm-specific RS2–RS3 bridge [PMID:38091523]. LRRC23 physically interacts with radial spoke head proteins RSPH9 and RSPH3A/B through its C-terminus, and loss of this interaction—by truncation or nonsense mutation—abolishes its flagellar localization and disrupts radial spoke integrity [PMID:34585727, PMID:38091523, PMID:37804054]. Loss-of-function mutations in LRRC23 cause asthenozoospermia and male infertility in both mice and humans without affecting somatic cilia motility, establishing a sperm-specific requirement [PMID:34585727, PMID:37804054, PMID:39054792].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Initial characterization placed LRRC23 in ocular tissues with nuclear and cytoplasmic localization and partial co-localization with mimecan, but provided no functional insight into its mechanism of action.\",\n      \"evidence\": \"RT-PCR, immunohistochemistry, and confocal co-localization in human ocular tissues and MG-63 cells\",\n      \"pmids\": [\"16030496\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No functional assay was performed; co-localization with mimecan does not establish a direct interaction or functional role\",\n        \"No connection to ciliary or flagellar biology was made\",\n        \"Findings have not been replicated or extended by independent studies\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A knockout mouse model resolved that LRRC23 is a testis-enriched, flagellum-localized radial spoke protein whose loss causes male infertility through RS disorganization and impaired sperm motility, without affecting somatic cilia—establishing it as a sperm-specific axonemal component.\",\n      \"evidence\": \"Lrrc23 knockout mice with fertility and motility phenotyping, Co-IP with RSPH3A/RSPH3B, immunofluorescence, and transmission EM of sperm axonemes\",\n      \"pmids\": [\"34585727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether LRRC23 belongs to the RS2 stalk (as proposed by homology to Chlamydomonas RSP15) or a different RS sub-complex was unresolved\",\n        \"The precise binding interface and domain requirements for RSPH3A/B interaction were not defined\",\n        \"Human disease relevance was not yet established\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cryo-electron tomography and human genetic data redefined LRRC23 as an RS3 head component (not an RS2 stalk protein), showed that its C-terminus is required for RSPH9 binding and flagellar localization, and demonstrated that its loss specifically eliminates the RS3 head and the sperm-specific RS2–RS3 bridge.\",\n      \"evidence\": \"Human splice-site variant in infertile males, cryo-ET of mutant sperm axonemes, recombinant pulldown of LRRC23–RSPH9 with truncation controls, evolutionary analysis reassigning LRRC34 as the true RSP15 ortholog\",\n      \"pmids\": [\"38091523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full atomic-resolution structure of the RS3 head complex with LRRC23 is lacking\",\n        \"The complete set of RS3 head subunits that LRRC23 organizes is not fully defined\",\n        \"How LRRC23 is trafficked to the flagellum and its assembly timing during spermiogenesis are unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of a homozygous nonsense mutation in human LRRC23 confirmed its requirement for radial spoke integrity and sperm motility in humans and validated the LRRC23–RSPH3 interaction in human cells.\",\n      \"evidence\": \"Human genetics in a consanguineous family, Co-IP of LRRC23–RSPH3 in human cells, TEM of patient sperm axoneme\",\n      \"pmids\": [\"37804054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single family; additional kindreds needed to establish LRRC23 as a recurrently mutated asthenozoospermia gene\",\n        \"Genotype–phenotype correlation across different mutation types is incomplete\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Compound heterozygous LRRC23 mutations in a non-consanguineous family independently confirmed RS3 loss as the ultrastructural basis of LRRC23-associated asthenozoospermia, broadening the allelic spectrum.\",\n      \"evidence\": \"Human genetics, Western blot and immunofluorescence confirming protein loss, TEM showing RS3 absence in patient sperm\",\n      \"pmids\": [\"39054792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional rescue experiments in patient-derived or model systems have not been performed\",\n        \"Whether partial LRRC23 loss produces an intermediate motility phenotype is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the high-resolution structure of the LRRC23-containing RS3 head complex, the mechanism by which LRRC23 is selectively required in sperm but dispensable in somatic cilia, and whether LRRC23 plays any non-flagellar role consistent with its reported ocular expression.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No atomic-resolution structure of LRRC23 within the RS3 head complex\",\n        \"Molecular basis of sperm-specific versus somatic cilia dispensability is unexplained\",\n        \"Any functional significance of LRRC23 expression outside the testis remains uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"Radial spoke 3 (RS3) head complex\"\n    ],\n    \"partners\": [\n      \"RSPH9\",\n      \"RSPH3A\",\n      \"RSPH3B\",\n      \"RSPH3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}