{"gene":"ILDR1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2012,"finding":"ILDR1 (angulin-2) localizes to tricellular tight junctions (tTJs) at tricellular contacts in epithelial cells and recruits tricellulin to tTJs. Introduction of ILDR1 into cultured epithelial cells establishes a strong paracellular barrier. Most DFNB42-associated ILDR1 mutant proteins are defective in tricellulin recruitment.","method":"Immunofluorescence localization, epithelial barrier function assays in cultured cells (EpH4), expression of DFNB42 mutant proteins","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments with functional barrier assays, multiple orthogonal methods, replicated across multiple mutants; findings replicated by multiple independent labs","pmids":["23239027"],"is_preprint":false},{"year":2014,"finding":"In ILDR1 null mice, ILDR1 is not required for initial recruitment of tricellulin to tTJs in the cochlea in vivo; however, tricellulin becomes mislocalized in inner ear sensory epithelia after the first postnatal week. ILDR1 contributes to the ultrastructure of tTJs as revealed by freeze-fracture electron microscopy. Loss of ILDR1 causes rapid degeneration of cochlear hair cells and severe deafness, with normal endocochlear potential.","method":"Ildr1 knockout mouse analysis, immunofluorescence, freeze-fracture electron microscopy, auditory brainstem response, endocochlear potential measurement","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (EM ultrastructure, immunofluorescence, electrophysiology) in genetic knockout model, independently replicated by another lab (PMID:25822906)","pmids":["25217574"],"is_preprint":false},{"year":2015,"finding":"In Ildr1 null mice, tricellulin localization at tricellular contacts of the organ of Corti is retained but its distribution along the depth of tricellular contacts is altered. Compensatory localization of angulin-1/LSR to tricellular contacts occurs in the organ of Corti of Ildr1 null mice, where it is barely detected in wild-type. Angulin-2/ILDR1 has distinct functions beyond tricellulin recruitment that cannot be substituted by angulin-1/LSR.","method":"Ildr1 knockout mouse, immunofluorescence, auditory brainstem response testing","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple immunofluorescence analyses; findings corroborate and extend PMID:25217574 from an independent lab","pmids":["25822906"],"is_preprint":false},{"year":2015,"finding":"A novel ILDR1 variant (p.P69H) in the Ig-like domain causes partial mislocalization of ILDR1 and tricellulin at tricellular contacts, in contrast to complete failure seen with other DFNB42 mutations. Three-dimensional protein modeling predicted that ILDR1 forms a homo-trimer through its Ig-like domain and that p.P69H disturbs homo-trimer formation.","method":"Expression of mutant proteins in angulin-1/LSR knockdown epithelial cells, immunofluorescence, 3D protein modeling","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct cell-based localization assay for multiple mutants with functional inference; homo-trimer model is computational only","pmids":["25668204"],"is_preprint":false},{"year":2017,"finding":"ILDR1 binds to pre-mRNA splicing factors TRA2A, TRA2B, and SRSF1 and translocates into the nucleus when these splicing factors are present. ILDR1 affects alternative splicing of TUBD1, IQCB1, and Pcdh19. Knockdown of endogenous ILDR1 (and ILDR2) by siRNA in cultured cells alters alternative splicing of TUBD1 and IQCB1.","method":"Co-immunoprecipitation, nuclear translocation assays, siRNA knockdown, RT-PCR-based splicing assays, yeast two-hybrid (implicit from context)","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP binding plus functional splicing readout with siRNA knockdown; single lab, two orthogonal methods","pmids":["28785060"],"is_preprint":false},{"year":2017,"finding":"ILDR1 is localized to tricellular tight junctions of distal tubules in the mouse kidney. Genetic knockout of Ildr1 causes polyuria and polydipsia due to renal concentrating defects. Live microperfusion of renal distal tubules shows they are impermeable to water normally but become highly permeable to water in Ildr1 knockout animals, while paracellular ionic permeabilities are not affected. Overexpression of Ildr1 in cultured renal epithelial cells significantly reduces paracellular water permeability.","method":"Ildr1 knockout mouse, immunofluorescence localization, live renal tubule microperfusion, water permeability assays, overexpression in cultured cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional measurement by live tubule microperfusion plus knockout and overexpression experiments with specific water permeability readout; multiple orthogonal approaches in one study","pmids":["28461473"],"is_preprint":false},{"year":2020,"finding":"In the large intestine of Ildr1 knockout mice, angulin-1/LSR redistributes to tricellular tight junctions (compensating for loss of ILDR1), and paracellular transport assessed by Ussing chamber is unchanged. ILDR1 knockout mice show no detectable intestinal water transport phenotype. A similar LSR compensatory shift occurs in the kidney of Ildr1 knockout mice.","method":"Ildr1 knockout mouse, Ussing chamber measurements, immunofluorescence","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional Ussing chamber assay plus immunofluorescence in knockout; negative intestinal water phenotype contrasts with kidney phenotype from PMID:28461473, suggesting tissue-specific compensation","pmids":["32587380"],"is_preprint":false},{"year":2022,"finding":"ILDR1 promotes influenza A virus replication by binding to phospholipid scramblase 1 (PLSCR1), an antiviral protein. ILDR1 competes with viral NP protein for binding to PLSCR1, thereby inhibiting PLSCR1's antiviral activity. ILDR1 cannot directly interact with viral NP protein but competitively binds PLSCR1.","method":"Yeast two-hybrid screening, Co-immunoprecipitation, Plscr1 knockout mouse infection experiments, ILDR1 overexpression/knockdown in cell culture","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus Co-IP for binding, in vivo knockout infection data; single lab, multiple methods","pmids":["35595813"],"is_preprint":false},{"year":2022,"finding":"ILDR1 is expressed in cholecystokinin-positive enteroendocrine cells of the gastrointestinal tract and mediates fat-stimulated CCK secretion. Ildr1 knockout mice on a high-fat diet gain less weight, have smaller adipocytes, increased metabolic activity, improved insulin sensitivity, and enhanced glucose-regulated insulin secretion compared to wild-type mice.","method":"Ildr1 knockout mouse, CLAMS metabolic chambers, ELISA hormone measurements, oral glucose tolerance test, insulin tolerance test, ex vivo islet perifusion, confocal microscopy","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal metabolic assays in genetic knockout model; single lab, establishes ILDR1 role in CCK-mediated metabolic regulation","pmids":["35749484"],"is_preprint":false},{"year":2014,"finding":"In zebrafish, ildr1b morpholino knockdown causes defective hearing, imbalanced swimming, and developmental delays in semicircular canal formation. Down-regulation of atp1b2b (Na+/K+-ATPase beta-2b subunit) was identified in ildr1b morphants, and injection of atp1b2b mRNA rescues the semicircular canal developmental delay phenotype. ildr1b knockdown also reduces lateral line neuromast numbers by disrupting posterior lateral line primordium migration, associated with attenuated FGF signaling and altered cxcr4b/cxcr7b expression.","method":"Morpholino knockdown in zebrafish, hearing/behavior assays, in situ hybridization, mRNA rescue experiments, gene expression profiling","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino knockdown with mRNA rescue epistasis; multiple phenotypic readouts; zebrafish ortholog model","pmids":["24990150"],"is_preprint":false},{"year":2023,"finding":"Combined delivery of two AAVs with different tropism (AAV2.7m8 targeting organ of Corti; AAV8BP2 targeting cochlear lateral wall) delivering Ildr1 cDNA to Ildr1w-/- mice improves cochlear structural integrity and auditory function, demonstrating that ILDR1 function is required in multiple inner ear cell types.","method":"AAV-mediated gene therapy in Ildr1 knockout mouse, auditory brainstem response, cochlear histology","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gene replacement with functional auditory rescue; single lab, direct functional rescue establishes requirement for ILDR1 in both organ of Corti and lateral wall cell types","pmids":["37481704"],"is_preprint":false},{"year":2015,"finding":"ILDR1 deficiency causes progressive degeneration of outer hair cells beginning at postnatal day 15, with disruption of the tunnel of Corti by P21 and complete loss of OHCs by P28. ILDR1 deficiency affects tricellulin expression in vivo. Differential proteomics identified 708 upregulated and 114 downregulated proteins in Ildr1-/- cochleae, including proteins involved in cell adhesion, vesicle transport, cell death, and membrane organization.","method":"Ildr1 knockout mouse, immunofluorescence, scanning electron microscopy, differential proteomics (2D-DIGE/MS)","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with direct cellular phenotype, immunofluorescence, and proteomics; single lab, corroborates independent knockout studies","pmids":["25819842"],"is_preprint":false}],"current_model":"ILDR1 (angulin-2) is a type I transmembrane protein that localizes exclusively to tricellular tight junctions in epithelia, where it recruits tricellulin, maintains tTJ ultrastructure, and regulates paracellular water permeability (but not ionic permeability) in the kidney; in the inner ear, ILDR1 is required for the structural integrity of tTJs and the postnatal survival of cochlear hair cells, with most deafness-causing mutations disrupting tricellulin recruitment; ILDR1 also binds pre-mRNA splicing factors (TRA2A, TRA2B, SRSF1) to regulate alternative splicing, promotes influenza A replication by competitively binding PLSCR1, and functions in enteroendocrine cells to mediate fat-stimulated CCK secretion and metabolic regulation."},"narrative":{"mechanistic_narrative":"ILDR1 (angulin-2) is a type I transmembrane protein that localizes to tricellular tight junctions (tTJs) at tricellular epithelial contacts, where it recruits tricellulin and establishes a strong paracellular barrier [PMID:23239027]. Through its Ig-like domain it organizes tTJ ultrastructure, and most DFNB42 deafness-causing mutations abolish tricellulin recruitment, while a domain variant predicted to disrupt homo-trimer formation causes only partial mislocalization [PMID:23239027, PMID:25668204]. In the cochlea, ILDR1 is dispensable for the initial recruitment of tricellulin but is required to maintain its correct distribution along tricellular contacts and to preserve tTJ architecture; its loss causes progressive degeneration of cochlear hair cells and severe deafness despite a normal endocochlear potential [PMID:25217574, PMID:25819842]. ILDR1 function is required in multiple inner ear cell types, as combined AAV delivery to both the organ of Corti and the cochlear lateral wall is needed to restore structure and auditory function [PMID:37481704]. In the kidney, ILDR1 at distal tubule tTJs specifically restricts paracellular water permeability without affecting ionic permeability, and its loss produces a renal concentrating defect with polyuria and polydipsia [PMID:28461473]. Loss of ILDR1 triggers tissue-specific compensatory redistribution of angulin-1/LSR to tricellular contacts, which restores barrier function in the intestine but not all ILDR1-specific functions elsewhere [PMID:25822906, PMID:32587380]. Beyond its junctional role, ILDR1 binds the pre-mRNA splicing factors TRA2A, TRA2B and SRSF1 and translocates to the nucleus to modulate alternative splicing of target transcripts [PMID:28785060], promotes influenza A virus replication by competitively binding the antiviral scramblase PLSCR1 [PMID:35595813], and acts in cholecystokinin-positive enteroendocrine cells to mediate fat-stimulated CCK secretion and systemic metabolic regulation [PMID:35749484].","teleology":[{"year":2012,"claim":"Established ILDR1's core molecular role: where it sits in the epithelium and how it builds a barrier, answering what the DFNB42 deafness gene actually does at the junction.","evidence":"Immunofluorescence localization and barrier assays in cultured epithelial cells expressing wild-type and DFNB42 mutant ILDR1","pmids":["23239027"],"confidence":"High","gaps":["Did not resolve the in vivo requirement versus dispensability for tricellulin recruitment","Structural basis of tricellulin recruitment not defined"]},{"year":2014,"claim":"Distinguished initial recruitment from maintenance in vivo, showing ILDR1 is needed to sustain tTJ ultrastructure and hair cell survival rather than to seed tricellulin.","evidence":"Ildr1 knockout mouse with immunofluorescence, freeze-fracture EM, ABR and endocochlear potential measurement","pmids":["25217574"],"confidence":"High","gaps":["Mechanism linking tTJ disruption to hair cell death not defined","Molecular partners maintaining ultrastructure unknown"]},{"year":2014,"claim":"Defined an ILDR1 ortholog function in inner ear and lateral line development, linking it to Na+/K+-ATPase and FGF/chemokine signaling during morphogenesis.","evidence":"ildr1b morpholino knockdown in zebrafish with atp1b2b mRNA rescue, in situ hybridization and behavioral assays","pmids":["24990150"],"confidence":"Medium","gaps":["Morpholino knockdown not confirmed by genetic mutant","Direct biochemical link between ILDR1 and atp1b2b/FGF signaling not established"]},{"year":2015,"claim":"Revealed that loss of ILDR1 triggers compensatory angulin-1/LSR redistribution yet leaves ILDR1-specific functions unfilled, showing angulins are not fully interchangeable.","evidence":"Ildr1 knockout mouse immunofluorescence and ABR testing in organ of Corti","pmids":["25822906"],"confidence":"High","gaps":["The ILDR1-specific function that LSR cannot substitute is not molecularly identified"]},{"year":2015,"claim":"Connected ILDR1 deficiency to a defined temporal course of outer hair cell degeneration and a broad proteomic signature, framing the downstream cellular consequences of tTJ failure.","evidence":"Ildr1 knockout mouse with immunofluorescence, SEM and 2D-DIGE/MS differential proteomics","pmids":["25819842"],"confidence":"Medium","gaps":["Causal drivers among the dysregulated proteins not identified","Proteomic changes are correlative"]},{"year":2015,"claim":"Linked the ILDR1 Ig-like domain to homo-trimer formation as the structural basis for tricellulin recruitment, explaining a partial-phenotype variant.","evidence":"Cell-based localization of mutant proteins in LSR-knockdown cells plus 3D protein modeling","pmids":["25668204"],"confidence":"Medium","gaps":["Homo-trimer model is computational only, not structurally confirmed","Oligomerization state in vivo unmeasured"]},{"year":2017,"claim":"Defined a specific physiological output of ILDR1 barriers: selective restriction of paracellular water but not ions in the renal distal tubule, explaining a urinary concentrating function.","evidence":"Ildr1 knockout mouse, live renal tubule microperfusion water permeability assays and overexpression in cultured renal cells","pmids":["28461473"],"confidence":"High","gaps":["Molecular mechanism by which ILDR1 selectively blocks water flux unknown","Whether this is a direct property of the tTJ or indirect not resolved"]},{"year":2017,"claim":"Uncovered an unexpected nuclear role: ILDR1 binds splicing factors and modulates alternative splicing, expanding its function beyond junctions.","evidence":"Co-immunoprecipitation, nuclear translocation assays, siRNA knockdown and RT-PCR splicing readouts in cultured cells","pmids":["28785060"],"confidence":"Medium","gaps":["Single lab; reciprocal validation and structural basis of splicing-factor binding absent","How a transmembrane protein accesses the nucleus mechanistically unclear","Physiological relevance of splicing changes untested in vivo"]},{"year":2020,"claim":"Demonstrated tissue-specific compensation, with LSR redistribution fully restoring intestinal barrier function while the kidney phenotype persists.","evidence":"Ildr1 knockout mouse Ussing chamber measurements and immunofluorescence in large intestine and kidney","pmids":["32587380"],"confidence":"Medium","gaps":["Why compensation succeeds in intestine but not kidney not mechanistically explained"]},{"year":2022,"claim":"Identified ILDR1 as a proviral host factor that competitively binds PLSCR1 to disable its antiviral activity during influenza A infection.","evidence":"Yeast two-hybrid, Co-IP, Plscr1 knockout mouse infection and ILDR1 overexpression/knockdown in cells","pmids":["35595813"],"confidence":"Medium","gaps":["Single lab; binding interface and stoichiometry of competition not defined","Relationship to ILDR1's junctional role unknown"]},{"year":2022,"claim":"Placed ILDR1 in enteroendocrine signaling, showing it mediates fat-stimulated CCK secretion and influences systemic metabolism.","evidence":"Ildr1 knockout mouse with metabolic chambers, hormone ELISA, glucose/insulin tolerance tests and ex vivo islet perifusion","pmids":["35749484"],"confidence":"Medium","gaps":["Molecular mechanism by which ILDR1 couples fat sensing to CCK release not defined","Single lab"]},{"year":2023,"claim":"Established that ILDR1 is required in multiple cochlear cell types by achieving functional rescue only when both organ of Corti and lateral wall are targeted.","evidence":"Dual-tropism AAV delivery of Ildr1 cDNA in Ildr1 knockout mice with ABR and cochlear histology","pmids":["37481704"],"confidence":"Medium","gaps":["Cell-type-specific molecular requirements not dissected","Durability and translational scope of rescue not addressed"]},{"year":null,"claim":"It remains unknown how a single tricellular junctional protein mechanistically integrates its barrier, nuclear splicing, antiviral, and enteroendocrine roles, and what structural features govern its selective control of water permeability.","evidence":"No single study reconciles the junctional and non-junctional functions","pmids":[],"confidence":"Low","gaps":["No experimental structure of ILDR1 or its complexes","Mechanistic link between transmembrane localization and nuclear splicing function unresolved","Selective water-versus-ion barrier mechanism undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[5]}],"complexes":["tricellular tight junction"],"partners":["TRA2A","TRA2B","SRSF1","PLSCR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86SU0","full_name":"Immunoglobulin-like domain-containing receptor 1","aliases":["Angulin-2"],"length_aa":546,"mass_kda":62.8,"function":"Maintains epithelial barrier function by recruiting MARVELD2/tricellulin to tricellular tight junctions (tTJs) (PubMed:23239027). Crucial for normal hearing by maintaining the structural and functional integrity of tTJs, which are critical for the survival of auditory neurosensory HCs. Mediates fatty acids and lipoproteins-stimulated CCK/cholecystokinin secretion in the small intestine. In the inner ear, may regulate alternative pre-mRNA splicing via binding to TRA2A, TRA2B and SRSF1 (By similarity) (Microbial infection) Promotes influenza virus infection by inhibiting viral nucleoprotein NP binding to PLSCR1 and thereby PLSCR1-mediated antiviral activity","subcellular_location":"Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q86SU0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ILDR1","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/ILDR1","total_profiled":1310},"omim":[{"mim_id":"618081","title":"IMMUNOGLOBULIN-LIKE DOMAIN-CONTAINING RECEPTOR 2; ILDR2","url":"https://www.omim.org/entry/618081"},{"mim_id":"609739","title":"IMMUNOGLOBULIN-LIKE DOMAIN-CONTAINING RECEPTOR 1; ILDR1","url":"https://www.omim.org/entry/609739"},{"mim_id":"609646","title":"DEAFNESS, AUTOSOMAL RECESSIVE 42; DFNB42","url":"https://www.omim.org/entry/609646"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"parathyroid gland","ntpm":14.7}],"url":"https://www.proteinatlas.org/search/ILDR1"},"hgnc":{"alias_symbol":["MGC50831"],"prev_symbol":["DFNB42"]},"alphafold":{"accession":"Q86SU0","domains":[{"cath_id":"2.60.40.10","chopping":"21-166","consensus_level":"high","plddt":91.1263,"start":21,"end":166},{"cath_id":"-","chopping":"175-226","consensus_level":"high","plddt":69.0327,"start":175,"end":226}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86SU0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86SU0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86SU0-F1-predicted_aligned_error_v6.png","plddt_mean":58.97},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ILDR1","jax_strain_url":"https://www.jax.org/strain/search?query=ILDR1"},"sequence":{"accession":"Q86SU0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86SU0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86SU0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86SU0"}},"corpus_meta":[{"pmid":"23239027","id":"PMC_23239027","title":"Analysis of the 'angulin' proteins LSR, ILDR1 and ILDR2--tricellulin recruitment, epithelial barrier function and implication in deafness pathogenesis.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/23239027","citation_count":175,"is_preprint":false},{"pmid":"21255762","id":"PMC_21255762","title":"Loss-of-function mutations of ILDR1 cause autosomal-recessive hearing impairment DFNB42.","date":"2011","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21255762","citation_count":89,"is_preprint":false},{"pmid":"30804975","id":"PMC_30804975","title":"Targeted Next Generation Sequencing Revealed a Novel Homozygous Loss-of-Function Mutation in ILDR1 Gene Causes Autosomal Recessive Nonsyndromic Sensorineural Hearing Loss in a Chinese Family.","date":"2019","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30804975","citation_count":76,"is_preprint":false},{"pmid":"25217574","id":"PMC_25217574","title":"ILDR1 null mice, a model of human deafness DFNB42, show structural aberrations of tricellular tight junctions and degeneration of auditory hair cells.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25217574","citation_count":50,"is_preprint":false},{"pmid":"25822906","id":"PMC_25822906","title":"Deficiency of angulin-2/ILDR1, a tricellular tight junction-associated membrane protein, causes deafness with cochlear hair cell degeneration in mice.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25822906","citation_count":31,"is_preprint":false},{"pmid":"28461473","id":"PMC_28461473","title":"ILDR1 is important for paracellular water transport and urine concentration mechanism.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28461473","citation_count":27,"is_preprint":false},{"pmid":"25819842","id":"PMC_25819842","title":"ILDR1 deficiency causes degeneration of cochlear outer hair cells and disrupts the structure of the organ of Corti: a mouse model for human DFNB42.","date":"2015","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/25819842","citation_count":20,"is_preprint":false},{"pmid":"24768815","id":"PMC_24768815","title":"ILDR1: Novel mutation and a rare cause of congenital deafness in the Saudi Arabian population.","date":"2014","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24768815","citation_count":18,"is_preprint":false},{"pmid":"28785060","id":"PMC_28785060","title":"Angulin proteins ILDR1 and ILDR2 regulate alternative pre-mRNA splicing through binding to splicing factors TRA2A, TRA2B, or SRSF1.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28785060","citation_count":17,"is_preprint":false},{"pmid":"25668204","id":"PMC_25668204","title":"Downsloping high-frequency hearing loss due to inner ear tricellular tight junction disruption by a novel ILDR1 mutation in the Ig-like domain.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25668204","citation_count":16,"is_preprint":false},{"pmid":"15641023","id":"PMC_15641023","title":"A novel autosomal recessive nonsyndromic hearing impairment locus (DFNB42) maps to chromosome 3q13.31-q22.3.","date":"2005","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/15641023","citation_count":15,"is_preprint":false},{"pmid":"29224747","id":"PMC_29224747","title":"Next-generation sequencing identifies three novel missense variants in ILDR1 and MYO6 genes in an Iranian family with hearing loss with review of the literature.","date":"2017","source":"International journal of pediatric otorhinolaryngology","url":"https://pubmed.ncbi.nlm.nih.gov/29224747","citation_count":11,"is_preprint":false},{"pmid":"37481704","id":"PMC_37481704","title":"Combined AAV-mediated gene replacement therapy improves auditory function in a mouse model of human DFNB42 deafness.","date":"2023","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37481704","citation_count":11,"is_preprint":false},{"pmid":"24990150","id":"PMC_24990150","title":"Ildr1b is essential for semicircular canal development, migration of the posterior lateral line primordium and hearing ability in zebrafish: implications for a role in the recessive hearing impairment DFNB42.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24990150","citation_count":11,"is_preprint":false},{"pmid":"35595813","id":"PMC_35595813","title":"ILDR1 promotes influenza A virus replication through binding to PLSCR1.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35595813","citation_count":10,"is_preprint":false},{"pmid":"28900455","id":"PMC_28900455","title":"Diverse pattern of gap junction beta-2 and gap junction beta-4 genes mutations and lack of contribution of DFNB21, DFNB24, DFNB29, and DFNB42 loci in autosomal recessive nonsyndromic hearing loss patients in Hormozgan, Iran.","date":"2017","source":"Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28900455","citation_count":10,"is_preprint":false},{"pmid":"32587380","id":"PMC_32587380","title":"Angulin-2/ILDR1, a tricellular tight junction protein, does not affect water transport in the mouse large intestine.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32587380","citation_count":7,"is_preprint":false},{"pmid":"28945813","id":"PMC_28945813","title":"Identification of a novel frameshift mutation in the ILDR1 gene in a UAE family, mutations review and phenotype genotype correlation.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28945813","citation_count":7,"is_preprint":false},{"pmid":"22365942","id":"PMC_22365942","title":"A new recurrent chromosomal translocation t(3;11)(q13;q14) in myelodysplastic syndromes associated with overexpression of the ILDR1 gene.","date":"2012","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/22365942","citation_count":5,"is_preprint":false},{"pmid":"29849566","id":"PMC_29849566","title":"A Novel p.G141R Mutation in ILDR1 Leads to Recessive Nonsyndromic Deafness DFNB42 in Two Chinese Han Families.","date":"2018","source":"Neural plasticity","url":"https://pubmed.ncbi.nlm.nih.gov/29849566","citation_count":4,"is_preprint":false},{"pmid":"35749484","id":"PMC_35749484","title":"Ildr1 gene deletion protects against diet-induced obesity and hyperglycemia.","date":"2022","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/35749484","citation_count":3,"is_preprint":false},{"pmid":"28713423","id":"PMC_28713423","title":"Discovering the Unexpected with the Utilization of NGS in Diagnostics of Non-syndromic Hearing Loss Disorders: The Family Case of ILDR1-Dependent Hearing Loss Disorder.","date":"2017","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28713423","citation_count":3,"is_preprint":false},{"pmid":"36814109","id":"PMC_36814109","title":"Imputation of SNPs associated with presbycusis through linkage disequilibrium analysis in the ILDR1 gene.","date":"2023","source":"Journal of genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36814109","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13423,"output_tokens":3362,"usd":0.04535,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10943,"output_tokens":3786,"usd":0.074682,"stage2_stop_reason":"end_turn"},"total_usd":0.120032,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"ILDR1 (angulin-2) localizes to tricellular tight junctions (tTJs) at tricellular contacts in epithelial cells and recruits tricellulin to tTJs. Introduction of ILDR1 into cultured epithelial cells establishes a strong paracellular barrier. Most DFNB42-associated ILDR1 mutant proteins are defective in tricellulin recruitment.\",\n      \"method\": \"Immunofluorescence localization, epithelial barrier function assays in cultured cells (EpH4), expression of DFNB42 mutant proteins\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments with functional barrier assays, multiple orthogonal methods, replicated across multiple mutants; findings replicated by multiple independent labs\",\n      \"pmids\": [\"23239027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In ILDR1 null mice, ILDR1 is not required for initial recruitment of tricellulin to tTJs in the cochlea in vivo; however, tricellulin becomes mislocalized in inner ear sensory epithelia after the first postnatal week. ILDR1 contributes to the ultrastructure of tTJs as revealed by freeze-fracture electron microscopy. Loss of ILDR1 causes rapid degeneration of cochlear hair cells and severe deafness, with normal endocochlear potential.\",\n      \"method\": \"Ildr1 knockout mouse analysis, immunofluorescence, freeze-fracture electron microscopy, auditory brainstem response, endocochlear potential measurement\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (EM ultrastructure, immunofluorescence, electrophysiology) in genetic knockout model, independently replicated by another lab (PMID:25822906)\",\n      \"pmids\": [\"25217574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In Ildr1 null mice, tricellulin localization at tricellular contacts of the organ of Corti is retained but its distribution along the depth of tricellular contacts is altered. Compensatory localization of angulin-1/LSR to tricellular contacts occurs in the organ of Corti of Ildr1 null mice, where it is barely detected in wild-type. Angulin-2/ILDR1 has distinct functions beyond tricellulin recruitment that cannot be substituted by angulin-1/LSR.\",\n      \"method\": \"Ildr1 knockout mouse, immunofluorescence, auditory brainstem response testing\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple immunofluorescence analyses; findings corroborate and extend PMID:25217574 from an independent lab\",\n      \"pmids\": [\"25822906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A novel ILDR1 variant (p.P69H) in the Ig-like domain causes partial mislocalization of ILDR1 and tricellulin at tricellular contacts, in contrast to complete failure seen with other DFNB42 mutations. Three-dimensional protein modeling predicted that ILDR1 forms a homo-trimer through its Ig-like domain and that p.P69H disturbs homo-trimer formation.\",\n      \"method\": \"Expression of mutant proteins in angulin-1/LSR knockdown epithelial cells, immunofluorescence, 3D protein modeling\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct cell-based localization assay for multiple mutants with functional inference; homo-trimer model is computational only\",\n      \"pmids\": [\"25668204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ILDR1 binds to pre-mRNA splicing factors TRA2A, TRA2B, and SRSF1 and translocates into the nucleus when these splicing factors are present. ILDR1 affects alternative splicing of TUBD1, IQCB1, and Pcdh19. Knockdown of endogenous ILDR1 (and ILDR2) by siRNA in cultured cells alters alternative splicing of TUBD1 and IQCB1.\",\n      \"method\": \"Co-immunoprecipitation, nuclear translocation assays, siRNA knockdown, RT-PCR-based splicing assays, yeast two-hybrid (implicit from context)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP binding plus functional splicing readout with siRNA knockdown; single lab, two orthogonal methods\",\n      \"pmids\": [\"28785060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ILDR1 is localized to tricellular tight junctions of distal tubules in the mouse kidney. Genetic knockout of Ildr1 causes polyuria and polydipsia due to renal concentrating defects. Live microperfusion of renal distal tubules shows they are impermeable to water normally but become highly permeable to water in Ildr1 knockout animals, while paracellular ionic permeabilities are not affected. Overexpression of Ildr1 in cultured renal epithelial cells significantly reduces paracellular water permeability.\",\n      \"method\": \"Ildr1 knockout mouse, immunofluorescence localization, live renal tubule microperfusion, water permeability assays, overexpression in cultured cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional measurement by live tubule microperfusion plus knockout and overexpression experiments with specific water permeability readout; multiple orthogonal approaches in one study\",\n      \"pmids\": [\"28461473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In the large intestine of Ildr1 knockout mice, angulin-1/LSR redistributes to tricellular tight junctions (compensating for loss of ILDR1), and paracellular transport assessed by Ussing chamber is unchanged. ILDR1 knockout mice show no detectable intestinal water transport phenotype. A similar LSR compensatory shift occurs in the kidney of Ildr1 knockout mice.\",\n      \"method\": \"Ildr1 knockout mouse, Ussing chamber measurements, immunofluorescence\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional Ussing chamber assay plus immunofluorescence in knockout; negative intestinal water phenotype contrasts with kidney phenotype from PMID:28461473, suggesting tissue-specific compensation\",\n      \"pmids\": [\"32587380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ILDR1 promotes influenza A virus replication by binding to phospholipid scramblase 1 (PLSCR1), an antiviral protein. ILDR1 competes with viral NP protein for binding to PLSCR1, thereby inhibiting PLSCR1's antiviral activity. ILDR1 cannot directly interact with viral NP protein but competitively binds PLSCR1.\",\n      \"method\": \"Yeast two-hybrid screening, Co-immunoprecipitation, Plscr1 knockout mouse infection experiments, ILDR1 overexpression/knockdown in cell culture\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus Co-IP for binding, in vivo knockout infection data; single lab, multiple methods\",\n      \"pmids\": [\"35595813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ILDR1 is expressed in cholecystokinin-positive enteroendocrine cells of the gastrointestinal tract and mediates fat-stimulated CCK secretion. Ildr1 knockout mice on a high-fat diet gain less weight, have smaller adipocytes, increased metabolic activity, improved insulin sensitivity, and enhanced glucose-regulated insulin secretion compared to wild-type mice.\",\n      \"method\": \"Ildr1 knockout mouse, CLAMS metabolic chambers, ELISA hormone measurements, oral glucose tolerance test, insulin tolerance test, ex vivo islet perifusion, confocal microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal metabolic assays in genetic knockout model; single lab, establishes ILDR1 role in CCK-mediated metabolic regulation\",\n      \"pmids\": [\"35749484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In zebrafish, ildr1b morpholino knockdown causes defective hearing, imbalanced swimming, and developmental delays in semicircular canal formation. Down-regulation of atp1b2b (Na+/K+-ATPase beta-2b subunit) was identified in ildr1b morphants, and injection of atp1b2b mRNA rescues the semicircular canal developmental delay phenotype. ildr1b knockdown also reduces lateral line neuromast numbers by disrupting posterior lateral line primordium migration, associated with attenuated FGF signaling and altered cxcr4b/cxcr7b expression.\",\n      \"method\": \"Morpholino knockdown in zebrafish, hearing/behavior assays, in situ hybridization, mRNA rescue experiments, gene expression profiling\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino knockdown with mRNA rescue epistasis; multiple phenotypic readouts; zebrafish ortholog model\",\n      \"pmids\": [\"24990150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Combined delivery of two AAVs with different tropism (AAV2.7m8 targeting organ of Corti; AAV8BP2 targeting cochlear lateral wall) delivering Ildr1 cDNA to Ildr1w-/- mice improves cochlear structural integrity and auditory function, demonstrating that ILDR1 function is required in multiple inner ear cell types.\",\n      \"method\": \"AAV-mediated gene therapy in Ildr1 knockout mouse, auditory brainstem response, cochlear histology\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gene replacement with functional auditory rescue; single lab, direct functional rescue establishes requirement for ILDR1 in both organ of Corti and lateral wall cell types\",\n      \"pmids\": [\"37481704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ILDR1 deficiency causes progressive degeneration of outer hair cells beginning at postnatal day 15, with disruption of the tunnel of Corti by P21 and complete loss of OHCs by P28. ILDR1 deficiency affects tricellulin expression in vivo. Differential proteomics identified 708 upregulated and 114 downregulated proteins in Ildr1-/- cochleae, including proteins involved in cell adhesion, vesicle transport, cell death, and membrane organization.\",\n      \"method\": \"Ildr1 knockout mouse, immunofluorescence, scanning electron microscopy, differential proteomics (2D-DIGE/MS)\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with direct cellular phenotype, immunofluorescence, and proteomics; single lab, corroborates independent knockout studies\",\n      \"pmids\": [\"25819842\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ILDR1 (angulin-2) is a type I transmembrane protein that localizes exclusively to tricellular tight junctions in epithelia, where it recruits tricellulin, maintains tTJ ultrastructure, and regulates paracellular water permeability (but not ionic permeability) in the kidney; in the inner ear, ILDR1 is required for the structural integrity of tTJs and the postnatal survival of cochlear hair cells, with most deafness-causing mutations disrupting tricellulin recruitment; ILDR1 also binds pre-mRNA splicing factors (TRA2A, TRA2B, SRSF1) to regulate alternative splicing, promotes influenza A replication by competitively binding PLSCR1, and functions in enteroendocrine cells to mediate fat-stimulated CCK secretion and metabolic regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ILDR1 (angulin-2) is a type I transmembrane protein that localizes to tricellular tight junctions (tTJs) at tricellular epithelial contacts, where it recruits tricellulin and establishes a strong paracellular barrier [#0]. Through its Ig-like domain it organizes tTJ ultrastructure, and most DFNB42 deafness-causing mutations abolish tricellulin recruitment, while a domain variant predicted to disrupt homo-trimer formation causes only partial mislocalization [#0, #3]. In the cochlea, ILDR1 is dispensable for the initial recruitment of tricellulin but is required to maintain its correct distribution along tricellular contacts and to preserve tTJ architecture; its loss causes progressive degeneration of cochlear hair cells and severe deafness despite a normal endocochlear potential [#1, #11]. ILDR1 function is required in multiple inner ear cell types, as combined AAV delivery to both the organ of Corti and the cochlear lateral wall is needed to restore structure and auditory function [#10]. In the kidney, ILDR1 at distal tubule tTJs specifically restricts paracellular water permeability without affecting ionic permeability, and its loss produces a renal concentrating defect with polyuria and polydipsia [#5]. Loss of ILDR1 triggers tissue-specific compensatory redistribution of angulin-1/LSR to tricellular contacts, which restores barrier function in the intestine but not all ILDR1-specific functions elsewhere [#2, #6]. Beyond its junctional role, ILDR1 binds the pre-mRNA splicing factors TRA2A, TRA2B and SRSF1 and translocates to the nucleus to modulate alternative splicing of target transcripts [#4], promotes influenza A virus replication by competitively binding the antiviral scramblase PLSCR1 [#7], and acts in cholecystokinin-positive enteroendocrine cells to mediate fat-stimulated CCK secretion and systemic metabolic regulation [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established ILDR1's core molecular role: where it sits in the epithelium and how it builds a barrier, answering what the DFNB42 deafness gene actually does at the junction.\",\n      \"evidence\": \"Immunofluorescence localization and barrier assays in cultured epithelial cells expressing wild-type and DFNB42 mutant ILDR1\",\n      \"pmids\": [\"23239027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the in vivo requirement versus dispensability for tricellulin recruitment\", \"Structural basis of tricellulin recruitment not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Distinguished initial recruitment from maintenance in vivo, showing ILDR1 is needed to sustain tTJ ultrastructure and hair cell survival rather than to seed tricellulin.\",\n      \"evidence\": \"Ildr1 knockout mouse with immunofluorescence, freeze-fracture EM, ABR and endocochlear potential measurement\",\n      \"pmids\": [\"25217574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking tTJ disruption to hair cell death not defined\", \"Molecular partners maintaining ultrastructure unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined an ILDR1 ortholog function in inner ear and lateral line development, linking it to Na+/K+-ATPase and FGF/chemokine signaling during morphogenesis.\",\n      \"evidence\": \"ildr1b morpholino knockdown in zebrafish with atp1b2b mRNA rescue, in situ hybridization and behavioral assays\",\n      \"pmids\": [\"24990150\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino knockdown not confirmed by genetic mutant\", \"Direct biochemical link between ILDR1 and atp1b2b/FGF signaling not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed that loss of ILDR1 triggers compensatory angulin-1/LSR redistribution yet leaves ILDR1-specific functions unfilled, showing angulins are not fully interchangeable.\",\n      \"evidence\": \"Ildr1 knockout mouse immunofluorescence and ABR testing in organ of Corti\",\n      \"pmids\": [\"25822906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The ILDR1-specific function that LSR cannot substitute is not molecularly identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected ILDR1 deficiency to a defined temporal course of outer hair cell degeneration and a broad proteomic signature, framing the downstream cellular consequences of tTJ failure.\",\n      \"evidence\": \"Ildr1 knockout mouse with immunofluorescence, SEM and 2D-DIGE/MS differential proteomics\",\n      \"pmids\": [\"25819842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal drivers among the dysregulated proteins not identified\", \"Proteomic changes are correlative\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked the ILDR1 Ig-like domain to homo-trimer formation as the structural basis for tricellulin recruitment, explaining a partial-phenotype variant.\",\n      \"evidence\": \"Cell-based localization of mutant proteins in LSR-knockdown cells plus 3D protein modeling\",\n      \"pmids\": [\"25668204\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Homo-trimer model is computational only, not structurally confirmed\", \"Oligomerization state in vivo unmeasured\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a specific physiological output of ILDR1 barriers: selective restriction of paracellular water but not ions in the renal distal tubule, explaining a urinary concentrating function.\",\n      \"evidence\": \"Ildr1 knockout mouse, live renal tubule microperfusion water permeability assays and overexpression in cultured renal cells\",\n      \"pmids\": [\"28461473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which ILDR1 selectively blocks water flux unknown\", \"Whether this is a direct property of the tTJ or indirect not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Uncovered an unexpected nuclear role: ILDR1 binds splicing factors and modulates alternative splicing, expanding its function beyond junctions.\",\n      \"evidence\": \"Co-immunoprecipitation, nuclear translocation assays, siRNA knockdown and RT-PCR splicing readouts in cultured cells\",\n      \"pmids\": [\"28785060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; reciprocal validation and structural basis of splicing-factor binding absent\", \"How a transmembrane protein accesses the nucleus mechanistically unclear\", \"Physiological relevance of splicing changes untested in vivo\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated tissue-specific compensation, with LSR redistribution fully restoring intestinal barrier function while the kidney phenotype persists.\",\n      \"evidence\": \"Ildr1 knockout mouse Ussing chamber measurements and immunofluorescence in large intestine and kidney\",\n      \"pmids\": [\"32587380\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why compensation succeeds in intestine but not kidney not mechanistically explained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified ILDR1 as a proviral host factor that competitively binds PLSCR1 to disable its antiviral activity during influenza A infection.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, Plscr1 knockout mouse infection and ILDR1 overexpression/knockdown in cells\",\n      \"pmids\": [\"35595813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; binding interface and stoichiometry of competition not defined\", \"Relationship to ILDR1's junctional role unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed ILDR1 in enteroendocrine signaling, showing it mediates fat-stimulated CCK secretion and influences systemic metabolism.\",\n      \"evidence\": \"Ildr1 knockout mouse with metabolic chambers, hormone ELISA, glucose/insulin tolerance tests and ex vivo islet perifusion\",\n      \"pmids\": [\"35749484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which ILDR1 couples fat sensing to CCK release not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that ILDR1 is required in multiple cochlear cell types by achieving functional rescue only when both organ of Corti and lateral wall are targeted.\",\n      \"evidence\": \"Dual-tropism AAV delivery of Ildr1 cDNA in Ildr1 knockout mice with ABR and cochlear histology\",\n      \"pmids\": [\"37481704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type-specific molecular requirements not dissected\", \"Durability and translational scope of rescue not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how a single tricellular junctional protein mechanistically integrates its barrier, nuclear splicing, antiviral, and enteroendocrine roles, and what structural features govern its selective control of water permeability.\",\n      \"evidence\": \"No single study reconciles the junctional and non-junctional functions\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental structure of ILDR1 or its complexes\", \"Mechanistic link between transmembrane localization and nuclear splicing function unresolved\", \"Selective water-versus-ion barrier mechanism undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"tricellular tight junction\"],\n    \"partners\": [\"TRA2A\", \"TRA2B\", \"SRSF1\", \"PLSCR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}