{"gene":"SIPA1L3","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2015,"finding":"SIPA1L3 loss-of-function (balanced translocation reducing expression, knockdown in 3D cell culture, and knockout in mouse) disrupts epithelial cell polarity, actin cytoskeleton organization, and adherens junction formation. A patient missense variant p.Asp148Tyr caused abnormal clustering of actin stress fibres and decreased adherens junction formation in an epithelial cell line, establishing a role for SIPA1L3 in epithelial morphogenesis and adhesion.","method":"Germline translocation mapping, siRNA knockdown in 3D cell culture, Sipa1l3−/− mouse model, zebrafish knockdown, missense variant functional analysis in epithelial cell line (actin/junction staining)","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal loss-of-function models (human translocation, mouse KO, zebrafish KD, cell line variant) with consistent cellular phenotypes across species and labs","pmids":["26231217"],"is_preprint":false},{"year":2015,"finding":"SIPA1L3 encodes a Rap GTPase-activating protein (RapGAP) whose Rap-GAP domain is required for function; a homozygous nonsense variant p.R1497* truncating the protein causes autosomal recessive congenital cataract, confirming SIPA1L3 as a functional RapGAP that interacts with small GTPases of the Rap family.","method":"Linkage analysis, whole-exome sequencing, identification of homozygous truncating variant in consanguineous family; domain architecture analysis placing Rap-GAP domain","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic/domain evidence from two independent families; enzymatic RapGAP activity inferred from domain homology rather than direct in vitro assay","pmids":["25804400"],"is_preprint":false},{"year":2015,"finding":"SIPA1L3/SPAR3 localizes to excitatory postsynapses in rat brain; its C-terminus is required for postsynaptic targeting and serves as an interaction module for the Fezzin protein ProSAPiP1/Lzts3, a binding partner of the postsynaptic scaffold Shank3, identifying SIPA1L3 as a synaptic RapGAP.","method":"Immunofluorescence localization in rat brain neurons, C-terminal deletion constructs for targeting analysis, co-immunoprecipitation/interaction assay with ProSAPiP1/Lzts3","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional domain mapping and binding partner identification; single lab, two orthogonal methods","pmids":["26364583"],"is_preprint":false},{"year":2016,"finding":"In Xenopus, Sipa1l3 directly interacts with EphA4 (Epha4), forming a functional complex for ocular development. Epha4 acts upstream of Sipa1l3 (EphA4 loss-of-function phenocopies Sipa1l3 loss; rescue experiments establish epistatic order). Downstream, both Epha4 and Sipa1l3 inhibit canonical Wnt/β-catenin signaling (depletion of either upregulates the Wnt target axin2), and the phenotype is rescued by blocking Wnt/β-catenin or activating non-canonical Wnt signaling.","method":"Xenopus loss-of-function (morpholino knockdown), co-interaction assay (direct Epha4–Sipa1l3 interaction), genetic rescue/epistasis experiments, axin2 expression assay, Wnt pathway inhibitor/activator rescue","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal epistasis, direct binding interaction, and pathway rescue with multiple orthogonal methods in one rigorous study","pmids":["27993984"],"is_preprint":false},{"year":2021,"finding":"A missense variant p.Lys624Arg within the predicted RapGAP domain of SIPA1L3 is associated with cataracts. Homology modelling based on the Rap1–Rap1GAP crystal structure suggests Lys624 is structurally equivalent to Lys194 of Rap1GAP, a residue critical for Rap·GTP binding affinity at the Rap1–RapGAP interface, implying the variant impairs SIPA1L3's regulatory interaction with Rap·GTP.","method":"Whole-exome sequencing + Sanger validation; homology modelling based on Rap1–Rap1GAP complex structure","journal":"Frontiers in genetics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — mechanism is computational/structural modelling only; no direct in vitro GAP activity assay performed","pmids":["34603379"],"is_preprint":false},{"year":2025,"finding":"SIPA1L3 interacts with AMOT (angiomotin) through its PDZ domain, which inhibits binding of AMOT to PATJ (Pals1-associated tight junction protein) and decreases AMOT anchoring to tight junctions, thereby promoting cancer cell proliferation and invasion in NSCLC.","method":"Western blotting, co-immunoprecipitation, SIPA1L3 PDZ-domain mutant analysis, siRNA knockdown with proliferation/invasion assays in vitro and in vivo","journal":"Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, domain-mutant evidence, and functional KD phenotype; single lab","pmids":["41088697"],"is_preprint":false},{"year":2025,"finding":"SIPA1L3 localizes to electrical synapses (gap junctions) in retinal neurons and interacts with the gap junction scaffold proteins ZO-1, ZO-2, and Connexin 36 (Cx36), establishing SIPA1L3 as a novel scaffold component of electrical synapses.","method":"In vivo BioID proximity labeling (TurboID) in mouse (AII amacrine cells) and zebrafish retina; subcellular localization by immunofluorescence; binding interaction assays with ZO-1, ZO-2, and Cx36","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo proximity labeling plus direct binding interaction tests; replicated across two species (mouse and zebrafish)","pmids":["42159345","39651118"],"is_preprint":false},{"year":2017,"finding":"A spontaneous 16.7 kb genomic deletion encompassing the first 14 exons of mouse Sipa1l3 produces a truncated protein lacking part of the Rap-GAP domain and two other domains, and causes juvenile cataracts in homozygous mice, confirming that Rap-GAP domain integrity is required for normal lens development.","method":"Homozygosity mapping, haplotype analysis, mRNA-level deletion characterization (4 coding exons deleted), genotyping of affected vs. unaffected mice","journal":"Mammalian genome","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic model with defined truncating deletion and consistent phenotype; domain consequence inferred from sequence, no in vitro enzymatic validation","pmids":["28951961"],"is_preprint":false}],"current_model":"SIPA1L3/SPAR3 is a Rap GTPase-activating protein (RapGAP) that acts downstream of EphA4 to suppress canonical Wnt/β-catenin signaling during eye/lens development; it regulates epithelial cell polarity, actin cytoskeletal organization, and adherens junction formation via its RapGAP domain, localizes to excitatory postsynapses in neurons via its C-terminus where it binds the Fezzin ProSAPiP1/Lzts3, scaffolds electrical synapses by interacting with ZO-1, ZO-2, and Connexin 36, and in non-neural epithelial/cancer contexts uses its PDZ domain to inhibit AMOT–PATJ tight junction interactions."},"narrative":{"mechanistic_narrative":"SIPA1L3 (SPAR3) is a Rap GTPase-activating protein (RapGAP) that governs epithelial cell polarity, actin cytoskeletal organization, and adherens junction formation during morphogenesis, with its RapGAP domain required for function [PMID:26231217, PMID:25804400]. Loss-of-function across human translocation, mouse knockout, zebrafish knockdown, and an epithelial cell-line missense variant consistently disrupts actin stress-fibre organization and junction assembly [PMID:26231217], and truncating variants that compromise the Rap-GAP domain cause autosomal recessive congenital cataract in humans and juvenile cataract in mice, establishing a requirement for SIPA1L3 in lens development [PMID:25804400, PMID:28951961]. In the developing eye, SIPA1L3 acts in a complex with EphA4 downstream of EphA4 to suppress canonical Wnt/β-catenin signaling, as depletion of either upregulates the Wnt target axin2 and the phenotype is rescued by blocking Wnt/β-catenin signaling [PMID:27993984]. Beyond epithelial development, SIPA1L3 functions as a synaptic scaffold: it localizes to excitatory postsynapses where its C-terminus binds the Fezzin protein ProSAPiP1/Lzts3 [PMID:26364583], and to electrical synapses in retinal neurons where it interacts with the gap junction scaffolds ZO-1, ZO-2, and Connexin 36 [PMID:42159345, PMID:39651118]. In NSCLC, SIPA1L3 uses its PDZ domain to bind AMOT and block the AMOT–PATJ tight-junction interaction, promoting proliferation and invasion [PMID:41088697].","teleology":[{"year":2015,"claim":"Established SIPA1L3 as a determinant of epithelial morphogenesis by linking its loss to disrupted polarity, actin organization, and adherens junctions.","evidence":"Germline translocation mapping, siRNA knockdown in 3D culture, Sipa1l3-/- mouse, zebrafish knockdown, and missense variant analysis in epithelial cells","pmids":["26231217"],"confidence":"High","gaps":["Does not define the direct molecular substrate or GAP target driving the junction phenotype","Mechanism connecting actin disorganization to junction loss not resolved"]},{"year":2015,"claim":"Identified the protein as a RapGAP whose domain integrity is required, tying truncating variants to recessive congenital cataract.","evidence":"Linkage analysis, whole-exome sequencing of a consanguineous family, and domain architecture analysis","pmids":["25804400"],"confidence":"Medium","gaps":["RapGAP enzymatic activity inferred from domain homology, not measured in vitro","Specific Rap substrate(s) not identified"]},{"year":2015,"claim":"Showed SIPA1L3 is also a synaptic RapGAP by localizing it to excitatory postsynapses and mapping its C-terminus as a ProSAPiP1/Lzts3 interaction module.","evidence":"Immunofluorescence in rat brain neurons, C-terminal deletion constructs, and co-IP with ProSAPiP1/Lzts3","pmids":["26364583"],"confidence":"Medium","gaps":["Functional consequence of the postsynaptic interaction not tested","Single-lab interaction without reciprocal validation across systems"]},{"year":2016,"claim":"Placed SIPA1L3 in a defined signaling axis by showing it acts downstream of EphA4 to inhibit canonical Wnt/β-catenin signaling during ocular development.","evidence":"Xenopus morpholino knockdown, direct Epha4-Sipa1l3 interaction assay, epistasis/rescue, axin2 expression, and Wnt inhibitor/activator rescue","pmids":["27993984"],"confidence":"High","gaps":["Biochemical link between RapGAP activity and Wnt pathway suppression not defined","Whether this axis operates in mammalian lens not directly tested"]},{"year":2017,"claim":"Confirmed Rap-GAP domain integrity is required for lens development via an independent truncating mouse allele.","evidence":"Homozygosity mapping and characterization of a spontaneous 16.7 kb deletion removing the first 14 exons, causing juvenile cataract","pmids":["28951961"],"confidence":"Medium","gaps":["Domain consequence inferred from sequence, not enzymatic assay","Does not isolate the RapGAP function from loss of other deleted domains"]},{"year":2021,"claim":"Used structural modelling to argue a cataract-associated variant impairs the Rap·GTP regulatory interface.","evidence":"Whole-exome sequencing with Sanger validation and homology modelling on the Rap1-Rap1GAP complex structure","pmids":["34603379"],"confidence":"Low","gaps":["Mechanism is computational only; no in vitro GAP activity assay performed","Effect of p.Lys624Arg on Rap binding not experimentally measured"]},{"year":2025,"claim":"Defined a PDZ-domain-dependent function in cancer, blocking AMOT-PATJ tight junction interactions to promote proliferation and invasion.","evidence":"Western blotting, reciprocal co-IP, PDZ-domain mutant analysis, and siRNA knockdown with proliferation/invasion assays in vitro and in vivo","pmids":["41088697"],"confidence":"Medium","gaps":["Single-lab study","Relationship between PDZ/AMOT function and RapGAP activity not integrated"]},{"year":2025,"claim":"Identified SIPA1L3 as a scaffold component of electrical synapses by demonstrating interactions with gap junction proteins in retina.","evidence":"In vivo BioID (TurboID) in mouse AII amacrine cells and zebrafish retina, immunofluorescence, and binding assays with ZO-1, ZO-2, and Cx36","pmids":["42159345","39651118"],"confidence":"Medium","gaps":["Functional impact on electrical synapse transmission not established","How RapGAP activity relates to the scaffolding role unknown"]},{"year":null,"claim":"Direct biochemical RapGAP activity and the specific Rap substrate(s) unifying SIPA1L3's roles across epithelia, synapses, and cancer remain undefined.","evidence":"No direct in vitro GAP activity assay or substrate identification appears in the corpus","pmids":[],"confidence":"Low","gaps":["No in vitro GAP activity assay reported","Substrate Rap GTPase(s) not identified","Mechanistic link between RapGAP activity and the PDZ/scaffold functions not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,5,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,3,7]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,6]}],"complexes":[],"partners":["EPHA4","AMOT","LZTS3","TJP1","TJP2","GJD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60292","full_name":"Signal-induced proliferation-associated 1-like protein 3","aliases":["SPA-1-like protein 3"],"length_aa":1781,"mass_kda":194.6,"function":"Plays a critical role in epithelial cell morphogenesis, polarity, adhesion and cytoskeletal organization in the lens (PubMed:26231217)","subcellular_location":"Apical cell membrane","url":"https://www.uniprot.org/uniprotkb/O60292/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SIPA1L3","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":[{"gene":"CALD1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SIPA1L3","total_profiled":1310},"omim":[{"mim_id":"616851","title":"CATARACT 45; CTRCT45","url":"https://www.omim.org/entry/616851"},{"mim_id":"616655","title":"SIPA1-LIKE PROTEIN 3; SIPA1L3","url":"https://www.omim.org/entry/616655"},{"mim_id":"613195","title":"WEILL-MARCHESANI SYNDROME 4; WMS4","url":"https://www.omim.org/entry/613195"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SIPA1L3"},"hgnc":{"alias_symbol":["KIAA0545","SPAR3"],"prev_symbol":[]},"alphafold":{"accession":"O60292","domains":[{"cath_id":"3.30.1120.160","chopping":"334-360_495-620","consensus_level":"medium","plddt":86.8024,"start":334,"end":620},{"cath_id":"3.40.50.11210","chopping":"623-816","consensus_level":"high","plddt":93.3813,"start":623,"end":816},{"cath_id":"1.20.5","chopping":"1751-1781","consensus_level":"medium","plddt":78.579,"start":1751,"end":1781}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60292","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60292-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60292-F1-predicted_aligned_error_v6.png","plddt_mean":55.53},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SIPA1L3","jax_strain_url":"https://www.jax.org/strain/search?query=SIPA1L3"},"sequence":{"accession":"O60292","fasta_url":"https://rest.uniprot.org/uniprotkb/O60292.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60292/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60292"}},"corpus_meta":[{"pmid":"26231217","id":"PMC_26231217","title":"Mutations in SIPA1L3 cause eye defects through disruption of cell polarity and cytoskeleton organization.","date":"2015","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26231217","citation_count":42,"is_preprint":false},{"pmid":"33130294","id":"PMC_33130294","title":"Host genetics influences the relationship between the gut microbiome and psychiatric disorders.","date":"2020","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/33130294","citation_count":34,"is_preprint":false},{"pmid":"33436510","id":"PMC_33436510","title":"Associations of Genetic Variants Contributing to Gut Microbiota Composition in Immunoglobin A Nephropathy.","date":"2021","source":"mSystems","url":"https://pubmed.ncbi.nlm.nih.gov/33436510","citation_count":33,"is_preprint":false},{"pmid":"32164487","id":"PMC_32164487","title":"Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal 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A patient missense variant p.Asp148Tyr caused abnormal clustering of actin stress fibres and decreased adherens junction formation in an epithelial cell line, establishing a role for SIPA1L3 in epithelial morphogenesis and adhesion.\",\n      \"method\": \"Germline translocation mapping, siRNA knockdown in 3D cell culture, Sipa1l3−/− mouse model, zebrafish knockdown, missense variant functional analysis in epithelial cell line (actin/junction staining)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal loss-of-function models (human translocation, mouse KO, zebrafish KD, cell line variant) with consistent cellular phenotypes across species and labs\",\n      \"pmids\": [\"26231217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SIPA1L3 encodes a Rap GTPase-activating protein (RapGAP) whose Rap-GAP domain is required for function; a homozygous nonsense variant p.R1497* truncating the protein causes autosomal recessive congenital cataract, confirming SIPA1L3 as a functional RapGAP that interacts with small GTPases of the Rap family.\",\n      \"method\": \"Linkage analysis, whole-exome sequencing, identification of homozygous truncating variant in consanguineous family; domain architecture analysis placing Rap-GAP domain\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic/domain evidence from two independent families; enzymatic RapGAP activity inferred from domain homology rather than direct in vitro assay\",\n      \"pmids\": [\"25804400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SIPA1L3/SPAR3 localizes to excitatory postsynapses in rat brain; its C-terminus is required for postsynaptic targeting and serves as an interaction module for the Fezzin protein ProSAPiP1/Lzts3, a binding partner of the postsynaptic scaffold Shank3, identifying SIPA1L3 as a synaptic RapGAP.\",\n      \"method\": \"Immunofluorescence localization in rat brain neurons, C-terminal deletion constructs for targeting analysis, co-immunoprecipitation/interaction assay with ProSAPiP1/Lzts3\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional domain mapping and binding partner identification; single lab, two orthogonal methods\",\n      \"pmids\": [\"26364583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Xenopus, Sipa1l3 directly interacts with EphA4 (Epha4), forming a functional complex for ocular development. Epha4 acts upstream of Sipa1l3 (EphA4 loss-of-function phenocopies Sipa1l3 loss; rescue experiments establish epistatic order). Downstream, both Epha4 and Sipa1l3 inhibit canonical Wnt/β-catenin signaling (depletion of either upregulates the Wnt target axin2), and the phenotype is rescued by blocking Wnt/β-catenin or activating non-canonical Wnt signaling.\",\n      \"method\": \"Xenopus loss-of-function (morpholino knockdown), co-interaction assay (direct Epha4–Sipa1l3 interaction), genetic rescue/epistasis experiments, axin2 expression assay, Wnt pathway inhibitor/activator rescue\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal epistasis, direct binding interaction, and pathway rescue with multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"27993984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A missense variant p.Lys624Arg within the predicted RapGAP domain of SIPA1L3 is associated with cataracts. Homology modelling based on the Rap1–Rap1GAP crystal structure suggests Lys624 is structurally equivalent to Lys194 of Rap1GAP, a residue critical for Rap·GTP binding affinity at the Rap1–RapGAP interface, implying the variant impairs SIPA1L3's regulatory interaction with Rap·GTP.\",\n      \"method\": \"Whole-exome sequencing + Sanger validation; homology modelling based on Rap1–Rap1GAP complex structure\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — mechanism is computational/structural modelling only; no direct in vitro GAP activity assay performed\",\n      \"pmids\": [\"34603379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SIPA1L3 interacts with AMOT (angiomotin) through its PDZ domain, which inhibits binding of AMOT to PATJ (Pals1-associated tight junction protein) and decreases AMOT anchoring to tight junctions, thereby promoting cancer cell proliferation and invasion in NSCLC.\",\n      \"method\": \"Western blotting, co-immunoprecipitation, SIPA1L3 PDZ-domain mutant analysis, siRNA knockdown with proliferation/invasion assays in vitro and in vivo\",\n      \"journal\": \"Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, domain-mutant evidence, and functional KD phenotype; single lab\",\n      \"pmids\": [\"41088697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SIPA1L3 localizes to electrical synapses (gap junctions) in retinal neurons and interacts with the gap junction scaffold proteins ZO-1, ZO-2, and Connexin 36 (Cx36), establishing SIPA1L3 as a novel scaffold component of electrical synapses.\",\n      \"method\": \"In vivo BioID proximity labeling (TurboID) in mouse (AII amacrine cells) and zebrafish retina; subcellular localization by immunofluorescence; binding interaction assays with ZO-1, ZO-2, and Cx36\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo proximity labeling plus direct binding interaction tests; replicated across two species (mouse and zebrafish)\",\n      \"pmids\": [\"42159345\", \"39651118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A spontaneous 16.7 kb genomic deletion encompassing the first 14 exons of mouse Sipa1l3 produces a truncated protein lacking part of the Rap-GAP domain and two other domains, and causes juvenile cataracts in homozygous mice, confirming that Rap-GAP domain integrity is required for normal lens development.\",\n      \"method\": \"Homozygosity mapping, haplotype analysis, mRNA-level deletion characterization (4 coding exons deleted), genotyping of affected vs. unaffected mice\",\n      \"journal\": \"Mammalian genome\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic model with defined truncating deletion and consistent phenotype; domain consequence inferred from sequence, no in vitro enzymatic validation\",\n      \"pmids\": [\"28951961\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SIPA1L3/SPAR3 is a Rap GTPase-activating protein (RapGAP) that acts downstream of EphA4 to suppress canonical Wnt/β-catenin signaling during eye/lens development; it regulates epithelial cell polarity, actin cytoskeletal organization, and adherens junction formation via its RapGAP domain, localizes to excitatory postsynapses in neurons via its C-terminus where it binds the Fezzin ProSAPiP1/Lzts3, scaffolds electrical synapses by interacting with ZO-1, ZO-2, and Connexin 36, and in non-neural epithelial/cancer contexts uses its PDZ domain to inhibit AMOT–PATJ tight junction interactions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SIPA1L3 (SPAR3) is a Rap GTPase-activating protein (RapGAP) that governs epithelial cell polarity, actin cytoskeletal organization, and adherens junction formation during morphogenesis, with its RapGAP domain required for function [#0, #1]. Loss-of-function across human translocation, mouse knockout, zebrafish knockdown, and an epithelial cell-line missense variant consistently disrupts actin stress-fibre organization and junction assembly [#0], and truncating variants that compromise the Rap-GAP domain cause autosomal recessive congenital cataract in humans and juvenile cataract in mice, establishing a requirement for SIPA1L3 in lens development [#1, #7]. In the developing eye, SIPA1L3 acts in a complex with EphA4 downstream of EphA4 to suppress canonical Wnt/\\u03b2-catenin signaling, as depletion of either upregulates the Wnt target axin2 and the phenotype is rescued by blocking Wnt/\\u03b2-catenin signaling [#3]. Beyond epithelial development, SIPA1L3 functions as a synaptic scaffold: it localizes to excitatory postsynapses where its C-terminus binds the Fezzin protein ProSAPiP1/Lzts3 [#2], and to electrical synapses in retinal neurons where it interacts with the gap junction scaffolds ZO-1, ZO-2, and Connexin 36 [#6]. In NSCLC, SIPA1L3 uses its PDZ domain to bind AMOT and block the AMOT\\u2013PATJ tight-junction interaction, promoting proliferation and invasion [#5].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established SIPA1L3 as a determinant of epithelial morphogenesis by linking its loss to disrupted polarity, actin organization, and adherens junctions.\",\n      \"evidence\": \"Germline translocation mapping, siRNA knockdown in 3D culture, Sipa1l3-/- mouse, zebrafish knockdown, and missense variant analysis in epithelial cells\",\n      \"pmids\": [\"26231217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the direct molecular substrate or GAP target driving the junction phenotype\", \"Mechanism connecting actin disorganization to junction loss not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the protein as a RapGAP whose domain integrity is required, tying truncating variants to recessive congenital cataract.\",\n      \"evidence\": \"Linkage analysis, whole-exome sequencing of a consanguineous family, and domain architecture analysis\",\n      \"pmids\": [\"25804400\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RapGAP enzymatic activity inferred from domain homology, not measured in vitro\", \"Specific Rap substrate(s) not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed SIPA1L3 is also a synaptic RapGAP by localizing it to excitatory postsynapses and mapping its C-terminus as a ProSAPiP1/Lzts3 interaction module.\",\n      \"evidence\": \"Immunofluorescence in rat brain neurons, C-terminal deletion constructs, and co-IP with ProSAPiP1/Lzts3\",\n      \"pmids\": [\"26364583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the postsynaptic interaction not tested\", \"Single-lab interaction without reciprocal validation across systems\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed SIPA1L3 in a defined signaling axis by showing it acts downstream of EphA4 to inhibit canonical Wnt/\\u03b2-catenin signaling during ocular development.\",\n      \"evidence\": \"Xenopus morpholino knockdown, direct Epha4-Sipa1l3 interaction assay, epistasis/rescue, axin2 expression, and Wnt inhibitor/activator rescue\",\n      \"pmids\": [\"27993984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical link between RapGAP activity and Wnt pathway suppression not defined\", \"Whether this axis operates in mammalian lens not directly tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Confirmed Rap-GAP domain integrity is required for lens development via an independent truncating mouse allele.\",\n      \"evidence\": \"Homozygosity mapping and characterization of a spontaneous 16.7 kb deletion removing the first 14 exons, causing juvenile cataract\",\n      \"pmids\": [\"28951961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain consequence inferred from sequence, not enzymatic assay\", \"Does not isolate the RapGAP function from loss of other deleted domains\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Used structural modelling to argue a cataract-associated variant impairs the Rap\\u00b7GTP regulatory interface.\",\n      \"evidence\": \"Whole-exome sequencing with Sanger validation and homology modelling on the Rap1-Rap1GAP complex structure\",\n      \"pmids\": [\"34603379\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanism is computational only; no in vitro GAP activity assay performed\", \"Effect of p.Lys624Arg on Rap binding not experimentally measured\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a PDZ-domain-dependent function in cancer, blocking AMOT-PATJ tight junction interactions to promote proliferation and invasion.\",\n      \"evidence\": \"Western blotting, reciprocal co-IP, PDZ-domain mutant analysis, and siRNA knockdown with proliferation/invasion assays in vitro and in vivo\",\n      \"pmids\": [\"41088697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Relationship between PDZ/AMOT function and RapGAP activity not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified SIPA1L3 as a scaffold component of electrical synapses by demonstrating interactions with gap junction proteins in retina.\",\n      \"evidence\": \"In vivo BioID (TurboID) in mouse AII amacrine cells and zebrafish retina, immunofluorescence, and binding assays with ZO-1, ZO-2, and Cx36\",\n      \"pmids\": [\"42159345\", \"39651118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional impact on electrical synapse transmission not established\", \"How RapGAP activity relates to the scaffolding role unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Direct biochemical RapGAP activity and the specific Rap substrate(s) unifying SIPA1L3's roles across epithelia, synapses, and cancer remain undefined.\",\n      \"evidence\": \"No direct in vitro GAP activity assay or substrate identification appears in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vitro GAP activity assay reported\", \"Substrate Rap GTPase(s) not identified\", \"Mechanistic link between RapGAP activity and the PDZ/scaffold functions not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 3, 7]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EPHA4\", \"AMOT\", \"LZTS3\", \"TJP1\", \"TJP2\", \"GJD2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}