{"gene":"ADD3","run_date":"2026-06-09T22:02:41","timeline":{"discoveries":[{"year":1996,"finding":"ADD3 (ADDL) encodes a 674-amino acid protein highly homologous to alpha- and beta-adducin, implicated in cell membrane skeletal organization, and maps to chromosome 10q24.2–q24.3 by FISH.","method":"cDNA cloning, sequence homology analysis, Northern blot, fluorescence in situ hybridization (FISH)","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cloning and chromosomal localization by FISH with Northern blot expression data, single lab, no functional reconstitution","pmids":["8893809"],"is_preprint":false},{"year":2009,"finding":"In red blood cells, gamma-adducin (ADD3) localizes to the spectrin-actin junction of the peripheral membrane skeleton; deletion of ADD3 in mice reduces alpha-adducin levels by ~70% in platelets and ~50% in spleen/brain, demonstrating that alpha-adducin stability depends on a heterologous binding partner (beta- or gamma-adducin) in a tissue-specific manner. Loss of gamma-adducin alone does not exacerbate the beta-adducin null hereditary spherocytosis phenotype.","method":"Targeted gene deletion (knockout mouse), peripheral blood smear, scanning electron microscopy, Western blot quantification of membrane skeleton proteins, hematological parameter measurement, double-null (gamma/beta adducin) intercross","journal":"American journal of hematology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple orthogonal readouts, double-null epistasis cross, replicated across tissues","pmids":["19425068"],"is_preprint":false},{"year":2016,"finding":"ADD3 (gamma-adducin) is required for the myogenic response of renal afferent arterioles and middle cerebral arteries; siRNA-mediated knockdown of Add3 abolished pressure-induced vasoconstriction and increased peak potassium currents approximately 3-fold in smooth muscle cells, indicating ADD3 regulates potassium channel function to maintain vascular reactivity.","method":"Dicer-substrate siRNA (DsiRNA) knockdown in ex vivo cultured arteries, pressure myography, electrophysiology (potassium current measurement) in isolated smooth muscle cells","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional knockdown with two orthogonal physiological readouts (myogenic response and electrophysiology), single lab","pmids":["27927653"],"is_preprint":false},{"year":2018,"finding":"Mutations in ADD3 cause intellectual disability, microcephaly, cataracts, and skeletal defects; in Drosophila, the ADD3 ortholog hts mutant failed to fully rescue viability of hts null flies. Simultaneous knockdown of ADD3 and KAT2B synergistically impaired kidney and heart function in flies and impaired adhesion and migration of cultured human podocytes, indicating epistatic interaction between ADD3 and KAT2B in kidney/heart pathology.","method":"Patient variant identification, Drosophila rescue assay (viability, cardiac/nephrocyte morphology and function), simultaneous RNAi knockdown in Drosophila, cell adhesion and migration assay in human podocytes","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Drosophila genetic rescue and epistasis with functional cellular readouts, single lab","pmids":["29768408"],"is_preprint":false},{"year":2020,"finding":"ADD3 depletion in glioblastoma cells promotes tumor growth and angiogenesis in vivo, associated with increased PCNA, suppressed p53 and p21 expression, and activation of VEGF-VEGFR-2 pro-angiogenic signaling in endothelial cells; ADD3 expression is functionally dependent on cell-matrix interaction.","method":"ADD3 depletion in GBM cells, in vivo tumor growth assay, Western blot for PCNA/p53/p21/VEGF/VEGFR-2, correlative in vitro and clinical microarray data","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with multiple molecular readouts, single lab","pmids":["31958485"],"is_preprint":false},{"year":2021,"finding":"QKI-5 represses inclusion of ADD3 exon 14 by binding to multiple sites in the upstream intron region of ADD3 pre-mRNA (mapped by iCLIP-seq); increased exon 14 inclusion (promoted by loss of QKI-5) enhances lung cancer cell proliferation and migration, placing ADD3 exon 14 splicing downstream of QKI-5 in a tumor-suppressive pathway.","method":"iCLIP-seq genome-wide binding mapping, alternative splicing assays, QKI-5 knockdown/overexpression, cell proliferation and migration assays, tumor QKI mutation analysis","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — nucleotide-resolution binding mapping by iCLIP-seq combined with functional splicing and phenotypic assays, multiple orthogonal methods","pmids":["33196842"],"is_preprint":false},{"year":2022,"finding":"A biallelic missense variant in ADD3 (p.Gly367Asp) causes hereditary spastic paraparesis/cerebral palsy; molecular modelling predicts loss of structural integrity. In Drosophila, pan-neuronal overexpression or knockdown of the ADD3 ortholog hts reduced lifespan and impaired locomotion, establishing neuronal requirement for ADD3 function.","method":"Whole exome sequencing, molecular modelling, Drosophila pan-neuronal overexpression and RNAi knockdown with lifespan and locomotion assays","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Drosophila gain- and loss-of-function with functional readouts, single lab, molecular modelling is computational","pmids":["36046955"],"is_preprint":false},{"year":2023,"finding":"The lncRNA SAN acts as a sponge for miR-143-3p, which targets ADD3; SAN knockdown reduces ADD3 expression via increased miR-143-3p activity, inhibiting ASC senescence and improving cell proliferation and migration. Dual-luciferase assays confirmed miR-143-3p binding to ADD3 3'UTR.","method":"Dual-luciferase reporter assay (miR-143-3p/ADD3 3'UTR), lentiviral overexpression/knockdown, miRNA mimic/inhibitor, EdU proliferation, transwell migration, SA-β-gal senescence assay, rescue experiments","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct luciferase validation of miR-143-3p/ADD3 interaction plus functional rescue experiments, single lab","pmids":["37605290"],"is_preprint":false},{"year":2024,"finding":"ADD3 is necessary and sufficient for maintaining glioblastoma stem cell (GSC) morphology, tumor-tumor connection (TTC) abundance, cell cycle progression, and chemoresistance; its effects on morphology and proliferation depend on actin cytoskeleton stability.","method":"ADD3 loss-of-function and gain-of-function in GSCs, live cell imaging of TTC/nanotube formation, cell cycle analysis, chemoresistance assays, actin cytoskeleton perturbation","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — necessity and sufficiency tested with multiple phenotypic readouts, actin dependency established, single lab","pmids":["39592188"],"is_preprint":false},{"year":2025,"finding":"ADD3 knockout in human pluripotent stem cell-derived cholangiocyte organoids causes defective cholangiocyte differentiation, failure to recruit βII-spectrin to the cell membrane, abnormal primary cilia development, reduced tight junction protein expression, lower transepithelial electrical resistance (TEER), and increased paracellular permeability. In Add3 knockout mice, bile ducts show reduced tight junction numbers and enlarged paracellular spaces, and knockout animals develop more severe biliary atresia upon RRV challenge.","method":"ADD3 knockout human pluripotent stem cell-derived cholangiocyte organoids, TEER measurement, immunofluorescence for βII-spectrin/tight junction proteins/primary cilia, electron microscopy of bile ducts, Add3 knockout mouse RRV-induced BA model, serum bilirubin and histological analysis","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — human organoid knockout plus in vivo mouse knockout with multiple orthogonal mechanistic readouts including βII-spectrin recruitment, barrier function, and ciliogenesis","pmids":["41297070"],"is_preprint":false},{"year":2017,"finding":"miR-145-5p directly targets the 3'UTR of ADD3 mRNA (validated by luciferase reporter assay); miR-145 overexpression in hepatic stellate cells (LX-2) decreases ADD3 protein and mRNA levels and suppresses p-Akt expression.","method":"Luciferase 3'UTR reporter assay, lentiviral miR-145 overexpression/inhibition in LX-2 cells, qPCR, Western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct luciferase validation plus protein-level functional follow-up, single lab","pmids":["28902846"],"is_preprint":false}],"current_model":"ADD3 (gamma-adducin) is a cytoskeletal scaffolding protein that localizes to the spectrin-actin junction of the cell membrane skeleton, where it stabilizes alpha-adducin in a tissue-dependent manner; it regulates vascular smooth muscle potassium channel function and myogenic responses, is required for cholangiocyte differentiation, βII-spectrin membrane recruitment, tight junction integrity, and primary cilia development in bile ducts, modulates glioblastoma stem cell morphology and tumor-tumor connections via actin cytoskeleton stability, and its alternative splicing (exon 14 inclusion controlled by QKI-5) promotes lung cancer cell proliferation and migration."},"narrative":{"mechanistic_narrative":"ADD3 encodes gamma-adducin, a membrane-skeletal scaffolding protein homologous to alpha- and beta-adducin that localizes to the spectrin-actin junction of the peripheral membrane skeleton [PMID:8893809, PMID:19425068]. In erythroid and other tissues it stabilizes alpha-adducin in a tissue-specific manner, with its loss reducing alpha-adducin levels without exacerbating the beta-adducin-null spherocytosis phenotype, indicating partial functional redundancy among adducin paralogs [PMID:19425068]. Through its actin-cytoskeletal scaffolding role, ADD3 supports epithelial barrier organization: in cholangiocytes it is required for recruitment of betaII-spectrin to the membrane, tight junction integrity, transepithelial barrier function, and primary cilia development, and its loss in mice predisposes to severe biliary atresia [PMID:41297070]. ADD3 also regulates the myogenic response of resistance arteries by controlling smooth-muscle potassium channel function [PMID:27927653], and modulates glioblastoma stem cell morphology, tumor-tumor connections, cell-cycle progression, and chemoresistance in an actin-dependent manner [PMID:39592188]. ADD3 expression is post-transcriptionally controlled, with QKI-5 repressing inclusion of exon 14 to limit lung cancer cell proliferation and migration [PMID:33196842] and multiple miRNAs (miR-145-5p, miR-143-3p) targeting its 3'UTR [PMID:28902846, PMID:37605290]. Biallelic ADD3 variants cause a neurodevelopmental syndrome encompassing intellectual disability, microcephaly, and spastic paraparesis/cerebral palsy [PMID:29768408, PMID:36046955].","teleology":[{"year":1996,"claim":"Establishing ADD3 as a third adducin paralog defined its candidate role in membrane-skeletal organization before any function was tested.","evidence":"cDNA cloning, sequence homology analysis, and FISH mapping to 10q24","pmids":["8893809"],"confidence":"Medium","gaps":["No functional assay or interaction partner demonstrated","Tissue distribution beyond Northern blot not characterized"]},{"year":2009,"claim":"Genetic knockout resolved whether gamma-adducin is functionally redundant, showing it stabilizes alpha-adducin in a tissue-specific way and is dispensable for the spherocytosis phenotype.","evidence":"Add3 knockout mouse with membrane skeleton protein quantification, electron microscopy, and beta/gamma double-null epistasis cross","pmids":["19425068"],"confidence":"High","gaps":["Molecular basis of tissue-specific alpha-adducin stabilization unresolved","Direct binding stoichiometry at the spectrin-actin junction not mapped"]},{"year":2016,"claim":"Knockdown in resistance arteries linked ADD3 to vascular reactivity through potassium channel control, extending its role beyond a passive scaffold.","evidence":"DsiRNA knockdown in ex vivo arteries with pressure myography and potassium current electrophysiology","pmids":["27927653"],"confidence":"High","gaps":["Which potassium channel ADD3 acts on is not identified","Whether regulation is direct or via cytoskeletal coupling is unknown"]},{"year":2018,"claim":"Patient variants plus Drosophila genetics established ADD3 as a disease gene and uncovered an epistatic interaction with KAT2B in kidney/heart pathology.","evidence":"Patient variant identification, Drosophila hts rescue and double-RNAi assays, podocyte adhesion/migration assays","pmids":["29768408"],"confidence":"Medium","gaps":["Mechanism linking ADD3 to KAT2B not defined","Causality of individual variants relies partly on fly orthology"]},{"year":2017,"claim":"Identification of miR-145-5p targeting established post-transcriptional control of ADD3 abundance in hepatic stellate cells.","evidence":"Luciferase 3'UTR reporter, miR-145 overexpression/inhibition in LX-2 cells with qPCR and Western blot","pmids":["28902846"],"confidence":"Medium","gaps":["Functional consequence of ADD3 loss for stellate cell biology not directly tested","Single cell-line context"]},{"year":2020,"claim":"Loss-of-function in glioblastoma showed ADD3 restrains tumor growth and angiogenesis, tying its expression to cell-matrix interaction.","evidence":"ADD3 depletion in GBM cells with in vivo tumor assays, Western blot for PCNA/p53/p21/VEGF/VEGFR-2","pmids":["31958485"],"confidence":"Medium","gaps":["Mechanism connecting ADD3 to p53/p21 and VEGF signaling unresolved","Direct molecular partners in this context unknown"]},{"year":2021,"claim":"Mapping QKI-5 binding to ADD3 pre-mRNA placed exon 14 alternative splicing in a defined tumor-suppressive regulatory pathway.","evidence":"iCLIP-seq binding mapping, splicing assays, QKI-5 perturbation, proliferation/migration assays","pmids":["33196842"],"confidence":"High","gaps":["Functional difference between exon 14-included and -skipped isoforms at the protein level not defined","Whether splice isoforms differ in spectrin/actin binding unknown"]},{"year":2022,"claim":"A biallelic missense variant and neuronal Drosophila assays extended ADD3 disease association to spastic paraparesis/cerebral palsy and established a neuronal requirement.","evidence":"Whole exome sequencing, molecular modelling, Drosophila pan-neuronal overexpression and RNAi with lifespan/locomotion readouts","pmids":["36046955"],"confidence":"Medium","gaps":["Structural prediction is computational","Neuronal molecular role of ADD3 not mechanistically defined"]},{"year":2023,"claim":"A lncRNA-miRNA-ADD3 axis showed ADD3 levels modulate stem cell senescence, proliferation, and migration.","evidence":"Dual-luciferase miR-143-3p/ADD3 3'UTR assay, lncRNA SAN perturbation, EdU/transwell/SA-beta-gal and rescue assays","pmids":["37605290"],"confidence":"Medium","gaps":["Downstream effectors of ADD3 in senescence not identified","Single cell system"]},{"year":2024,"claim":"Necessity-and-sufficiency tests defined ADD3 as an actin-dependent regulator of glioblastoma stem cell morphology, intercellular connectivity, and chemoresistance.","evidence":"ADD3 loss- and gain-of-function in GSCs with live imaging, cell-cycle analysis, chemoresistance and actin perturbation assays","pmids":["39592188"],"confidence":"Medium","gaps":["Molecular partners mediating tumor-tumor connections unknown","Relationship to its membrane-skeletal scaffolding role unclear"]},{"year":2025,"claim":"Human organoid plus mouse knockouts established ADD3 as essential for cholangiocyte differentiation, betaII-spectrin recruitment, ciliogenesis, and epithelial barrier integrity, linking its scaffolding function to biliary atresia susceptibility.","evidence":"ADD3 knockout cholangiocyte organoids with TEER and immunofluorescence, electron microscopy of bile ducts, Add3 knockout mouse RRV-induced biliary atresia model","pmids":["41297070"],"confidence":"High","gaps":["How ADD3 directs betaII-spectrin recruitment mechanistically not resolved","Connection between cilia defect and barrier failure not dissected"]},{"year":null,"claim":"It remains unknown how the single ADD3 scaffolding activity is mechanistically partitioned across its diverse roles in membrane-skeleton stabilization, ion-channel regulation, epithelial barrier/cilia formation, and tumor cell behavior.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of ADD3 at the spectrin-actin junction in the corpus","Direct molecular substrates/effectors largely undefined","Isoform-specific functions not connected to phenotypes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,8,9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,9]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,8]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,9]}],"pathway":[],"complexes":["spectrin-actin membrane skeleton junction"],"partners":["ADD1","SPTBN1","QKI"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UEY8","full_name":"Gamma-adducin","aliases":["Adducin-like protein 70"],"length_aa":706,"mass_kda":79.2,"function":"Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network. Plays a role in actin filament capping (PubMed:23836506). Binds to calmodulin (Probable). Involved in myogenic reactivity of the renal afferent arteriole (Af-art), renal interlobular arteries and middle cerebral artery (MCA) to increased perfusion pressure. Involved in regulation of potassium channels in the vascular smooth muscle cells (VSMCs) of the Af-art and MCA ex vivo. Involved in regulation of glomerular capillary pressure, glomerular filtration rate (GFR) and glomerular nephrin expression in response to hypertension. Involved in renal blood flow (RBF) autoregulation. Plays a role in podocyte structure and function. Regulates globular monomer actin (G-actin) and filamentous polymer actin (F-actin) ratios in the primary podocytes affecting actin cytoskeleton organization. Regulates expression of synaptopodin, RhoA, Rac1 and CDC42 in the renal cortex and the primary podocytes. Regulates expression of nephrin in the glomeruli and in the primary podocytes, expression of nephrin and podocinin in the renal cortex, and expression of focal adhesion proteins integrin alpha-3 and integrin beta-1 in the glomeruli. Involved in cell migration and cell adhesion of podocytes, and in podocyte foot process effacement. Regulates expression of profibrotics markers MMP2, MMP9, TGF beta-1, tubular tight junction protein E-cadherin, and mesenchymal markers vimentin and alpha-SMA (By similarity). Promotes the growth of neurites (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton; Cell membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9UEY8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADD3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTG1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ADD3","total_profiled":1310},"omim":[{"mim_id":"617008","title":"CEREBRAL PALSY, SPASTIC QUADRIPLEGIC, 3; CPSQ3","url":"https://www.omim.org/entry/617008"},{"mim_id":"612900","title":"CEREBRAL PALSY, SPASTIC QUADRIPLEGIC, 2; CPSQ2","url":"https://www.omim.org/entry/612900"},{"mim_id":"602303","title":"LYSINE ACETYLTRANSFERASE 2B; KAT2B","url":"https://www.omim.org/entry/602303"},{"mim_id":"601568","title":"ADDUCIN 3; ADD3","url":"https://www.omim.org/entry/601568"},{"mim_id":"601021","title":"NUCLEOPORIN, 98-KD; NUP98","url":"https://www.omim.org/entry/601021"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ADD3"},"hgnc":{"alias_symbol":[],"prev_symbol":["ADDL"]},"alphafold":{"accession":"Q9UEY8","domains":[{"cath_id":"-","chopping":"34-102","consensus_level":"medium","plddt":77.3152,"start":34,"end":102},{"cath_id":"3.40.225.10","chopping":"127-382","consensus_level":"high","plddt":89.1636,"start":127,"end":382}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UEY8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UEY8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UEY8-F1-predicted_aligned_error_v6.png","plddt_mean":66.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADD3","jax_strain_url":"https://www.jax.org/strain/search?query=ADD3"},"sequence":{"accession":"Q9UEY8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UEY8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UEY8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UEY8"}},"corpus_meta":[{"pmid":"31497351","id":"PMC_31497351","title":"Circular RNA circ-ADD3 inhibits hepatocellular carcinoma metastasis through facilitating EZH2 degradation via CDK1-mediated ubiquitination.","date":"2019","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/31497351","citation_count":63,"is_preprint":false},{"pmid":"24104524","id":"PMC_24104524","title":"Replication of a GWAS signal in a Caucasian population implicates ADD3 in susceptibility to biliary atresia.","date":"2013","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24104524","citation_count":53,"is_preprint":false},{"pmid":"33196842","id":"PMC_33196842","title":"QKI-5 regulates the alternative splicing of cytoskeletal gene ADD3 in lung cancer.","date":"2021","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/33196842","citation_count":41,"is_preprint":false},{"pmid":"27927653","id":"PMC_27927653","title":"Knockdown of Add3 impairs the myogenic response of renal afferent arterioles and middle cerebral arteries.","date":"2016","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27927653","citation_count":40,"is_preprint":false},{"pmid":"28902846","id":"PMC_28902846","title":"Downregulation of microRNA-145 may contribute to liver fibrosis in biliary atresia by targeting ADD3.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28902846","citation_count":29,"is_preprint":false},{"pmid":"25285724","id":"PMC_25285724","title":"Association between single nucleotide polymorphisms in the ADD3 gene and susceptibility to biliary atresia.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25285724","citation_count":23,"is_preprint":false},{"pmid":"31958485","id":"PMC_31958485","title":"Loss of cytoskeleton protein ADD3 promotes tumor growth and angiogenesis in glioblastoma multiforme.","date":"2020","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/31958485","citation_count":21,"is_preprint":false},{"pmid":"29768408","id":"PMC_29768408","title":"A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies.","date":"2018","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29768408","citation_count":20,"is_preprint":false},{"pmid":"32315284","id":"PMC_32315284","title":"Association of common variation in ADD3 and GPC1 with biliary atresia susceptibility.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32315284","citation_count":18,"is_preprint":false},{"pmid":"8893809","id":"PMC_8893809","title":"Cloning, expression and chromosome mapping of adducin-like 70 (ADDL), a human cDNA highly homologous to human erythrocyte adducin.","date":"1996","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8893809","citation_count":18,"is_preprint":false},{"pmid":"37605290","id":"PMC_37605290","title":"Knockdown of long noncoding RNA SAN rejuvenates aged adipose-derived stem cells via miR-143-3p/ADD3 axis.","date":"2023","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37605290","citation_count":15,"is_preprint":false},{"pmid":"19425068","id":"PMC_19425068","title":"Targeted deletion of the gamma-adducin gene (Add3) in mice reveals differences in alpha-adducin interactions in erythroid and nonerythroid cells.","date":"2009","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/19425068","citation_count":14,"is_preprint":false},{"pmid":"37834180","id":"PMC_37834180","title":"Contribution of ADD3 and the HLA Genes to Biliary Atresia Risk in Chinese.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37834180","citation_count":10,"is_preprint":false},{"pmid":"36046955","id":"PMC_36046955","title":"Hereditary spastic paraparesis presenting as cerebral palsy due to ADD3 variant with mechanistic insight provided by a Drosophila γ-adducin model.","date":"2022","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36046955","citation_count":8,"is_preprint":false},{"pmid":"34970477","id":"PMC_34970477","title":"ADD3 Deletion in Glioblastoma Predicts Disease Status and Survival.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34970477","citation_count":5,"is_preprint":false},{"pmid":"10051165","id":"PMC_10051165","title":"De novo mosaic add(3) characterized to be trisomy 14q31-qter using spectral karyotyping and subtelomeric probes.","date":"1999","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10051165","citation_count":4,"is_preprint":false},{"pmid":"39592188","id":"PMC_39592188","title":"Morphoregulatory ADD3 underlies glioblastoma growth and formation of tumor-tumor connections.","date":"2024","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/39592188","citation_count":1,"is_preprint":false},{"pmid":"41297070","id":"PMC_41297070","title":"Loss of function of Adducin 3 (ADD3) causes abnormal development and impaired barrier function of human and mouse bile duct cells resulting in increased incidence and severity of Biliary Atresia.","date":"2025","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/41297070","citation_count":0,"is_preprint":false},{"pmid":"41589307","id":"PMC_41589307","title":"Multiple susceptibility enhancer variants increasing ADD3 expression predisposes to biliary atresia risk.","date":"2026","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41589307","citation_count":0,"is_preprint":false},{"pmid":"41168449","id":"PMC_41168449","title":"Venetoclax-based chemotherapy failure in adult T-cell acute lymphoblastic leukemia with NUP98::ADD3 fusion: a case report.","date":"2025","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/41168449","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12005,"output_tokens":2959,"usd":0.0402,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10454,"output_tokens":3470,"usd":0.06951,"stage2_stop_reason":"end_turn"},"total_usd":0.10971,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"ADD3 (ADDL) encodes a 674-amino acid protein highly homologous to alpha- and beta-adducin, implicated in cell membrane skeletal organization, and maps to chromosome 10q24.2–q24.3 by FISH.\",\n      \"method\": \"cDNA cloning, sequence homology analysis, Northern blot, fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cloning and chromosomal localization by FISH with Northern blot expression data, single lab, no functional reconstitution\",\n      \"pmids\": [\"8893809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In red blood cells, gamma-adducin (ADD3) localizes to the spectrin-actin junction of the peripheral membrane skeleton; deletion of ADD3 in mice reduces alpha-adducin levels by ~70% in platelets and ~50% in spleen/brain, demonstrating that alpha-adducin stability depends on a heterologous binding partner (beta- or gamma-adducin) in a tissue-specific manner. Loss of gamma-adducin alone does not exacerbate the beta-adducin null hereditary spherocytosis phenotype.\",\n      \"method\": \"Targeted gene deletion (knockout mouse), peripheral blood smear, scanning electron microscopy, Western blot quantification of membrane skeleton proteins, hematological parameter measurement, double-null (gamma/beta adducin) intercross\",\n      \"journal\": \"American journal of hematology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple orthogonal readouts, double-null epistasis cross, replicated across tissues\",\n      \"pmids\": [\"19425068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ADD3 (gamma-adducin) is required for the myogenic response of renal afferent arterioles and middle cerebral arteries; siRNA-mediated knockdown of Add3 abolished pressure-induced vasoconstriction and increased peak potassium currents approximately 3-fold in smooth muscle cells, indicating ADD3 regulates potassium channel function to maintain vascular reactivity.\",\n      \"method\": \"Dicer-substrate siRNA (DsiRNA) knockdown in ex vivo cultured arteries, pressure myography, electrophysiology (potassium current measurement) in isolated smooth muscle cells\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with two orthogonal physiological readouts (myogenic response and electrophysiology), single lab\",\n      \"pmids\": [\"27927653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mutations in ADD3 cause intellectual disability, microcephaly, cataracts, and skeletal defects; in Drosophila, the ADD3 ortholog hts mutant failed to fully rescue viability of hts null flies. Simultaneous knockdown of ADD3 and KAT2B synergistically impaired kidney and heart function in flies and impaired adhesion and migration of cultured human podocytes, indicating epistatic interaction between ADD3 and KAT2B in kidney/heart pathology.\",\n      \"method\": \"Patient variant identification, Drosophila rescue assay (viability, cardiac/nephrocyte morphology and function), simultaneous RNAi knockdown in Drosophila, cell adhesion and migration assay in human podocytes\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Drosophila genetic rescue and epistasis with functional cellular readouts, single lab\",\n      \"pmids\": [\"29768408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ADD3 depletion in glioblastoma cells promotes tumor growth and angiogenesis in vivo, associated with increased PCNA, suppressed p53 and p21 expression, and activation of VEGF-VEGFR-2 pro-angiogenic signaling in endothelial cells; ADD3 expression is functionally dependent on cell-matrix interaction.\",\n      \"method\": \"ADD3 depletion in GBM cells, in vivo tumor growth assay, Western blot for PCNA/p53/p21/VEGF/VEGFR-2, correlative in vitro and clinical microarray data\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with multiple molecular readouts, single lab\",\n      \"pmids\": [\"31958485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"QKI-5 represses inclusion of ADD3 exon 14 by binding to multiple sites in the upstream intron region of ADD3 pre-mRNA (mapped by iCLIP-seq); increased exon 14 inclusion (promoted by loss of QKI-5) enhances lung cancer cell proliferation and migration, placing ADD3 exon 14 splicing downstream of QKI-5 in a tumor-suppressive pathway.\",\n      \"method\": \"iCLIP-seq genome-wide binding mapping, alternative splicing assays, QKI-5 knockdown/overexpression, cell proliferation and migration assays, tumor QKI mutation analysis\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — nucleotide-resolution binding mapping by iCLIP-seq combined with functional splicing and phenotypic assays, multiple orthogonal methods\",\n      \"pmids\": [\"33196842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A biallelic missense variant in ADD3 (p.Gly367Asp) causes hereditary spastic paraparesis/cerebral palsy; molecular modelling predicts loss of structural integrity. In Drosophila, pan-neuronal overexpression or knockdown of the ADD3 ortholog hts reduced lifespan and impaired locomotion, establishing neuronal requirement for ADD3 function.\",\n      \"method\": \"Whole exome sequencing, molecular modelling, Drosophila pan-neuronal overexpression and RNAi knockdown with lifespan and locomotion assays\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Drosophila gain- and loss-of-function with functional readouts, single lab, molecular modelling is computational\",\n      \"pmids\": [\"36046955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The lncRNA SAN acts as a sponge for miR-143-3p, which targets ADD3; SAN knockdown reduces ADD3 expression via increased miR-143-3p activity, inhibiting ASC senescence and improving cell proliferation and migration. Dual-luciferase assays confirmed miR-143-3p binding to ADD3 3'UTR.\",\n      \"method\": \"Dual-luciferase reporter assay (miR-143-3p/ADD3 3'UTR), lentiviral overexpression/knockdown, miRNA mimic/inhibitor, EdU proliferation, transwell migration, SA-β-gal senescence assay, rescue experiments\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct luciferase validation of miR-143-3p/ADD3 interaction plus functional rescue experiments, single lab\",\n      \"pmids\": [\"37605290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ADD3 is necessary and sufficient for maintaining glioblastoma stem cell (GSC) morphology, tumor-tumor connection (TTC) abundance, cell cycle progression, and chemoresistance; its effects on morphology and proliferation depend on actin cytoskeleton stability.\",\n      \"method\": \"ADD3 loss-of-function and gain-of-function in GSCs, live cell imaging of TTC/nanotube formation, cell cycle analysis, chemoresistance assays, actin cytoskeleton perturbation\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — necessity and sufficiency tested with multiple phenotypic readouts, actin dependency established, single lab\",\n      \"pmids\": [\"39592188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ADD3 knockout in human pluripotent stem cell-derived cholangiocyte organoids causes defective cholangiocyte differentiation, failure to recruit βII-spectrin to the cell membrane, abnormal primary cilia development, reduced tight junction protein expression, lower transepithelial electrical resistance (TEER), and increased paracellular permeability. In Add3 knockout mice, bile ducts show reduced tight junction numbers and enlarged paracellular spaces, and knockout animals develop more severe biliary atresia upon RRV challenge.\",\n      \"method\": \"ADD3 knockout human pluripotent stem cell-derived cholangiocyte organoids, TEER measurement, immunofluorescence for βII-spectrin/tight junction proteins/primary cilia, electron microscopy of bile ducts, Add3 knockout mouse RRV-induced BA model, serum bilirubin and histological analysis\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — human organoid knockout plus in vivo mouse knockout with multiple orthogonal mechanistic readouts including βII-spectrin recruitment, barrier function, and ciliogenesis\",\n      \"pmids\": [\"41297070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-145-5p directly targets the 3'UTR of ADD3 mRNA (validated by luciferase reporter assay); miR-145 overexpression in hepatic stellate cells (LX-2) decreases ADD3 protein and mRNA levels and suppresses p-Akt expression.\",\n      \"method\": \"Luciferase 3'UTR reporter assay, lentiviral miR-145 overexpression/inhibition in LX-2 cells, qPCR, Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct luciferase validation plus protein-level functional follow-up, single lab\",\n      \"pmids\": [\"28902846\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADD3 (gamma-adducin) is a cytoskeletal scaffolding protein that localizes to the spectrin-actin junction of the cell membrane skeleton, where it stabilizes alpha-adducin in a tissue-dependent manner; it regulates vascular smooth muscle potassium channel function and myogenic responses, is required for cholangiocyte differentiation, βII-spectrin membrane recruitment, tight junction integrity, and primary cilia development in bile ducts, modulates glioblastoma stem cell morphology and tumor-tumor connections via actin cytoskeleton stability, and its alternative splicing (exon 14 inclusion controlled by QKI-5) promotes lung cancer cell proliferation and migration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADD3 encodes gamma-adducin, a membrane-skeletal scaffolding protein homologous to alpha- and beta-adducin that localizes to the spectrin-actin junction of the peripheral membrane skeleton [#0, #1]. In erythroid and other tissues it stabilizes alpha-adducin in a tissue-specific manner, with its loss reducing alpha-adducin levels without exacerbating the beta-adducin-null spherocytosis phenotype, indicating partial functional redundancy among adducin paralogs [#1]. Through its actin-cytoskeletal scaffolding role, ADD3 supports epithelial barrier organization: in cholangiocytes it is required for recruitment of betaII-spectrin to the membrane, tight junction integrity, transepithelial barrier function, and primary cilia development, and its loss in mice predisposes to severe biliary atresia [#9]. ADD3 also regulates the myogenic response of resistance arteries by controlling smooth-muscle potassium channel function [#2], and modulates glioblastoma stem cell morphology, tumor-tumor connections, cell-cycle progression, and chemoresistance in an actin-dependent manner [#8]. ADD3 expression is post-transcriptionally controlled, with QKI-5 repressing inclusion of exon 14 to limit lung cancer cell proliferation and migration [#5] and multiple miRNAs (miR-145-5p, miR-143-3p) targeting its 3'UTR [#10, #7]. Biallelic ADD3 variants cause a neurodevelopmental syndrome encompassing intellectual disability, microcephaly, and spastic paraparesis/cerebral palsy [#3, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing ADD3 as a third adducin paralog defined its candidate role in membrane-skeletal organization before any function was tested.\",\n      \"evidence\": \"cDNA cloning, sequence homology analysis, and FISH mapping to 10q24\",\n      \"pmids\": [\"8893809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional assay or interaction partner demonstrated\", \"Tissue distribution beyond Northern blot not characterized\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic knockout resolved whether gamma-adducin is functionally redundant, showing it stabilizes alpha-adducin in a tissue-specific way and is dispensable for the spherocytosis phenotype.\",\n      \"evidence\": \"Add3 knockout mouse with membrane skeleton protein quantification, electron microscopy, and beta/gamma double-null epistasis cross\",\n      \"pmids\": [\"19425068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of tissue-specific alpha-adducin stabilization unresolved\", \"Direct binding stoichiometry at the spectrin-actin junction not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Knockdown in resistance arteries linked ADD3 to vascular reactivity through potassium channel control, extending its role beyond a passive scaffold.\",\n      \"evidence\": \"DsiRNA knockdown in ex vivo arteries with pressure myography and potassium current electrophysiology\",\n      \"pmids\": [\"27927653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which potassium channel ADD3 acts on is not identified\", \"Whether regulation is direct or via cytoskeletal coupling is unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Patient variants plus Drosophila genetics established ADD3 as a disease gene and uncovered an epistatic interaction with KAT2B in kidney/heart pathology.\",\n      \"evidence\": \"Patient variant identification, Drosophila hts rescue and double-RNAi assays, podocyte adhesion/migration assays\",\n      \"pmids\": [\"29768408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking ADD3 to KAT2B not defined\", \"Causality of individual variants relies partly on fly orthology\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of miR-145-5p targeting established post-transcriptional control of ADD3 abundance in hepatic stellate cells.\",\n      \"evidence\": \"Luciferase 3'UTR reporter, miR-145 overexpression/inhibition in LX-2 cells with qPCR and Western blot\",\n      \"pmids\": [\"28902846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of ADD3 loss for stellate cell biology not directly tested\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Loss-of-function in glioblastoma showed ADD3 restrains tumor growth and angiogenesis, tying its expression to cell-matrix interaction.\",\n      \"evidence\": \"ADD3 depletion in GBM cells with in vivo tumor assays, Western blot for PCNA/p53/p21/VEGF/VEGFR-2\",\n      \"pmids\": [\"31958485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting ADD3 to p53/p21 and VEGF signaling unresolved\", \"Direct molecular partners in this context unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapping QKI-5 binding to ADD3 pre-mRNA placed exon 14 alternative splicing in a defined tumor-suppressive regulatory pathway.\",\n      \"evidence\": \"iCLIP-seq binding mapping, splicing assays, QKI-5 perturbation, proliferation/migration assays\",\n      \"pmids\": [\"33196842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional difference between exon 14-included and -skipped isoforms at the protein level not defined\", \"Whether splice isoforms differ in spectrin/actin binding unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A biallelic missense variant and neuronal Drosophila assays extended ADD3 disease association to spastic paraparesis/cerebral palsy and established a neuronal requirement.\",\n      \"evidence\": \"Whole exome sequencing, molecular modelling, Drosophila pan-neuronal overexpression and RNAi with lifespan/locomotion readouts\",\n      \"pmids\": [\"36046955\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural prediction is computational\", \"Neuronal molecular role of ADD3 not mechanistically defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A lncRNA-miRNA-ADD3 axis showed ADD3 levels modulate stem cell senescence, proliferation, and migration.\",\n      \"evidence\": \"Dual-luciferase miR-143-3p/ADD3 3'UTR assay, lncRNA SAN perturbation, EdU/transwell/SA-beta-gal and rescue assays\",\n      \"pmids\": [\"37605290\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of ADD3 in senescence not identified\", \"Single cell system\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Necessity-and-sufficiency tests defined ADD3 as an actin-dependent regulator of glioblastoma stem cell morphology, intercellular connectivity, and chemoresistance.\",\n      \"evidence\": \"ADD3 loss- and gain-of-function in GSCs with live imaging, cell-cycle analysis, chemoresistance and actin perturbation assays\",\n      \"pmids\": [\"39592188\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners mediating tumor-tumor connections unknown\", \"Relationship to its membrane-skeletal scaffolding role unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Human organoid plus mouse knockouts established ADD3 as essential for cholangiocyte differentiation, betaII-spectrin recruitment, ciliogenesis, and epithelial barrier integrity, linking its scaffolding function to biliary atresia susceptibility.\",\n      \"evidence\": \"ADD3 knockout cholangiocyte organoids with TEER and immunofluorescence, electron microscopy of bile ducts, Add3 knockout mouse RRV-induced biliary atresia model\",\n      \"pmids\": [\"41297070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ADD3 directs betaII-spectrin recruitment mechanistically not resolved\", \"Connection between cilia defect and barrier failure not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how the single ADD3 scaffolding activity is mechanistically partitioned across its diverse roles in membrane-skeleton stabilization, ion-channel regulation, epithelial barrier/cilia formation, and tumor cell behavior.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of ADD3 at the spectrin-actin junction in the corpus\", \"Direct molecular substrates/effectors largely undefined\", \"Isoform-specific functions not connected to phenotypes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 8, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [\"spectrin-actin membrane skeleton junction\"],\n    \"partners\": [\"ADD1\", \"SPTBN1\", \"QKI\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}