{"gene":"CUBN","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":1998,"finding":"Human cubilin (CUBN) is a 3597 amino acid peripheral membrane protein that binds intrinsic factor-cobalamin (IF-Cbl) complex in a calcium- and cobalamin-dependent manner with high affinity, as demonstrated by surface plasmon resonance. The protein undergoes proteolytic processing via cleavage at a furin recognition site (Arg7-Glu8-Lys9-Arg) in the trans-Golgi apparatus.","method":"Surface plasmon resonance, complete cDNA cloning, amino-terminal sequencing, fluorescence in situ hybridization","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding assay with defined mechanism, direct sequencing of cleavage site, replicated by multiple methods","pmids":["9572993"],"is_preprint":false},{"year":1997,"finding":"Cubilin (gp280) functions as the intrinsic factor-cobalamin receptor (IFCR) in kidney, intestine, and yolk sac epithelium, binding IF-Cbl complex with an association constant of 0.3×10⁹ M⁻¹ and mediating its internalization. Anti-gp280 antibodies inhibited IF-[⁵⁷Co]Cbl binding at all three epithelial sites and blocked uptake and internalization of ¹²⁵IF-Cbl in yolk sac epithelial cells.","method":"Ligand binding assay, immunoblotting, immunoprecipitation, immunoelectron microscopy, radioligand uptake assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including radioligand uptake, co-localization by immunoelectron microscopy, and antibody inhibition of endocytosis","pmids":["9153271"],"is_preprint":false},{"year":1995,"finding":"Cubilin (gp280) is localized to clathrin-coated intermicrovillar areas of proximal tubule and yolk sac epithelial cells and is functionally required for endocytosis: antibodies against gp280 inhibited internalization of [¹⁴C]sucrose and peroxidase and disrupted the early endocytic pathway, resulting in accumulation of smaller, irregular vesicles rather than normal lysosomes.","method":"Indirect immunofluorescence, ultrastructural immunoelectron microscopy, endocytosis inhibition assay with tracers","journal":"European journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — direct localization with functional consequence (endocytosis disruption) using multiple orthogonal methods","pmids":["7664754"],"is_preprint":false},{"year":1995,"finding":"Cubilin (gp280) undergoes an unusual processing pathway: unlike the related receptor gp330, gp280 is initially targeted to the plasma membrane in an endoglycosidase H-sensitive (immature) form, and Golgi-mediated processing occurs mainly by recycling rather than prior to initial membrane delivery.","method":"Endoglycosidase H sensitivity assay, biosynthetic labeling, cell fractionation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical characterization of processing pathway with direct experimental evidence, single lab","pmids":["7626048"],"is_preprint":false},{"year":1998,"finding":"Cubilin (gp280) acts as a receptor for myeloma light chains in the kidney, mediating their endocytosis in renal proximal tubule cells. Evidence included: light chain co-elution during immunoaffinity purification of cubilin, anti-cubilin antisera displacement of light chain binding from brush-border membranes, surface plasmon resonance binding, and partial inhibition of light chain endocytosis in yolk sac epithelial cells by anti-cubilin antibody.","method":"Immunoaffinity purification, surface plasmon resonance, radioligand binding displacement, endocytosis inhibition assay","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 1–2 — four independent lines of evidence including surface plasmon resonance and functional endocytosis assay","pmids":["9691015"],"is_preprint":false},{"year":1999,"finding":"Loss-of-function mutations in CUBN cause hereditary megaloblastic anaemia 1 (MGA1/Imerslund-Gräsbeck syndrome), characterized by selective intestinal vitamin B12 malabsorption. Two independent disease-specific CUBN mutations were identified in Finnish MGA1 families by linkage disequilibrium mapping and molecular analysis.","method":"Linkage disequilibrium mapping, mutation identification, genetic analysis in affected families","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with defined molecular lesion and clinical phenotype, replicated across multiple families, highly cited foundational paper","pmids":["10080186"],"is_preprint":false},{"year":2007,"finding":"Cubilin forms the CUBAM complex together with amnionless (AMN), and this complex functions as the receptor for intrinsic factor-Cbl in the ileum and as a multi-ligand reabsorption receptor in renal proximal tubules. Mutations in either CUBN or AMN disrupt this complex and cause Imerslund-Gräsbeck syndrome with selective proteinuria.","method":"Genetic analysis, clinical phenotyping of patients with CUBN and AMN mutations","journal":"European journal of pediatrics","confidence":"Medium","confidence_rationale":"Tier 3 — complex function inferred from genetic evidence, consistent with prior biochemical data","pmids":["17668238"],"is_preprint":false},{"year":2013,"finding":"A CUBN frameshift mutation far C-terminal from the intrinsic factor-cobalamin binding site causes ~10-fold reduction in CUBN mRNA and ~20-fold reduction in cubilin protein in both ileum and kidney of affected border collies, leading to cobalamin malabsorption and proteinuria comprising CUBN ligands as demonstrated by radiolabeled cobalamin uptake studies and SDS-PAGE.","method":"Radiolabeled cobalamin uptake assay, SDS-PAGE of urine proteins, quantitative mRNA and protein expression analysis, DNA sequencing","journal":"Molecular genetics and metabolism","confidence":"High","confidence_rationale":"Tier 1–2 — direct functional assay (radiolabeled cobalamin uptake) plus molecular quantification, ortholog model","pmids":["23746554"],"is_preprint":false},{"year":2020,"finding":"C-terminal variants in CUBN (after the vitamin B12-binding domain) cause isolated chronic albuminuria/proteinuria without vitamin B12 malabsorption or impaired renal function, demonstrating that the C-terminal half of cubilin is specifically required for renal albumin reabsorption in the proximal tubule, while the N-terminal region (including the IF-Cbl binding site) is required for intestinal B12 uptake.","method":"Next-generation sequencing, bioinformatics, structural modeling, epidemiological cohort analysis, clinical phenotyping","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — genotype-phenotype dissection across 39 patients with biallelic variants, confirmed in large population cohorts, multiple orthogonal approaches","pmids":["31613795"],"is_preprint":false},{"year":2022,"finding":"Variants after the vitamin B12-binding domain of CUBN disrupt the association of cubilin with its co-receptor amnionless (AMN), causing aberrant AMN localization in the cell cytoplasm rather than at the membrane, and result in impaired reabsorption of albumin, transferrin, and α1-microglobulin in renal proximal tubules without affecting glomerular filtration or vitamin B12 absorption.","method":"Exome sequencing, Sanger sequencing, in vitro functional assay in HEK293T cells, in vivo mouse experiments, clinical biochemical analysis","journal":"Journal of translational medicine","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro and in vivo experiments demonstrating disrupted CUBN-AMN interaction and aberrant localization, multiple orthogonal methods","pmids":["36266725"],"is_preprint":false},{"year":2025,"finding":"A novel CUBN transcript encodes a truncated cubilin isoform with a unique C-terminus that is expressed in both kidney and small intestine, while full-length cubilin is expressed only in the kidney. C-terminal CUBN variants therefore do not affect the intestinal isoform, explaining why C-terminal mutations cause isolated proteinuria without vitamin B12 malabsorption.","method":"Transcriptome analysis, targeted panel sequencing of 52 patients from 42 families, identification of novel transcript isoform","journal":"Kidney international reports","confidence":"Medium","confidence_rationale":"Tier 2 — novel isoform discovery with mechanistic explanation, single lab but large cohort","pmids":["41624452"],"is_preprint":false},{"year":2025,"finding":"The genomic locus of lncRNA Gm26793 (chromosome 7) forms an inter-chromosomal interaction with Cubn (chromosome 2) via CTCF, restraining Cubn expression and maintaining epigenetic landscape to ensure proper primitive endoderm versus epiblast lineage specification during mouse embryogenesis.","method":"Genetic ablation of Gm26793, chromatin conformation capture, CTCF binding analysis, stem cell differentiation assays, mouse embryo analysis","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 — direct genetic manipulation with chromatin conformation data showing CTCF-mediated inter-chromosomal regulation of Cubn expression","pmids":["40461506"],"is_preprint":false}],"current_model":"Cubilin (CUBN) is a large peripheral membrane multiligand endocytic receptor expressed on the apical surface of intestinal epithelium, renal proximal tubules, and yolk sac; it binds intrinsic factor-cobalamin complex in a calcium-dependent manner via its N-terminal CUB domains to mediate intestinal vitamin B12 absorption, and uses its C-terminal CUB domains to reabsorb albumin, transferrin, light chains, and other filtered proteins in the renal proximal tubule, functioning as part of the CUBAM complex with its obligate co-receptor amnionless (AMN), whose membrane localization depends on proper CUBN association; loss-of-function mutations cause Imerslund-Gräsbeck syndrome, while C-terminal-specific variants selectively abolish renal albumin reabsorption without affecting intestinal B12 uptake because a truncated cubilin isoform expressed in the intestine lacks the C-terminal region."},"narrative":{"teleology":[{"year":1995,"claim":"Establishing that cubilin localizes to clathrin-coated intermicrovillar pits and is functionally required for apical endocytosis resolved its role as an active endocytic receptor rather than a passive surface marker.","evidence":"Immunoelectron microscopy and endocytosis inhibition assays with tracers in proximal tubule and yolk sac epithelial cells","pmids":["7664754"],"confidence":"High","gaps":["Mechanism of membrane anchoring unknown given absence of transmembrane domain","Identity of co-receptor mediating internalization not yet established"]},{"year":1995,"claim":"Demonstration that cubilin reaches the plasma membrane in an endoglycosidase H–sensitive form and undergoes Golgi processing mainly via recycling revealed an atypical biosynthetic trafficking pathway.","evidence":"Endoglycosidase H sensitivity assay and biosynthetic labeling in cultured cells","pmids":["7626048"],"confidence":"Medium","gaps":["Not independently replicated in a second system","Molecular determinants of recycling-dependent processing not identified"]},{"year":1997,"claim":"Identification of cubilin as the intrinsic factor–cobalamin receptor across kidney, intestine, and yolk sac unified previously separate observations of IF-Cbl binding at epithelial surfaces.","evidence":"Ligand binding assays, anti-gp280 antibody inhibition of radioligand uptake and internalization, immunoelectron microscopy","pmids":["9153271"],"confidence":"High","gaps":["Structural basis for IF-Cbl recognition not resolved","Whether cubilin alone suffices for internalization or requires a co-receptor unclear"]},{"year":1998,"claim":"Cloning of full-length human CUBN and demonstration of calcium-dependent IF-Cbl binding by surface plasmon resonance defined the molecular identity and binding requirements of the receptor, while furin cleavage at Arg7-Glu8-Lys9-Arg established a processing step in the trans-Golgi.","evidence":"cDNA cloning, surface plasmon resonance, amino-terminal sequencing, fluorescence in situ hybridization","pmids":["9572993"],"confidence":"High","gaps":["Which CUB domains mediate IF-Cbl versus other ligand binding not delineated","Functional significance of furin cleavage for receptor activity not tested"]},{"year":1998,"claim":"Demonstration that cubilin binds and mediates endocytosis of myeloma light chains expanded its role from a single-ligand IF-Cbl receptor to a multiligand endocytic receptor in the kidney.","evidence":"Immunoaffinity purification, surface plasmon resonance, radioligand displacement, and endocytosis inhibition in yolk sac epithelial cells","pmids":["9691015"],"confidence":"High","gaps":["Light chain binding domain not mapped","Relative contribution of cubilin versus megalin to light chain clearance in vivo not determined"]},{"year":1999,"claim":"Discovery of disease-causing CUBN mutations in Finnish families established the causal link between cubilin deficiency and Imerslund-Gräsbeck syndrome (hereditary megaloblastic anaemia with proteinuria).","evidence":"Linkage disequilibrium mapping and mutation identification in affected families","pmids":["10080186"],"confidence":"High","gaps":["Whether all IGS-associated mutations act through loss of IF-Cbl binding or through protein instability not distinguished","Role of co-receptor AMN mutations not yet recognized"]},{"year":2007,"claim":"Recognition that cubilin functions as the CUBAM complex with amnionless (AMN) explained how a peripheral membrane protein achieves membrane anchoring and endocytic signaling, and linked AMN mutations to the same disease.","evidence":"Genetic analysis and clinical phenotyping of patients with CUBN and AMN mutations","pmids":["17668238"],"confidence":"Medium","gaps":["Structural basis of CUBN–AMN interaction not defined","Whether AMN is required stoichiometrically or catalytically for cubilin surface delivery unknown"]},{"year":2013,"claim":"A canine model with a C-terminal CUBN frameshift showed that massive reduction of cubilin protein in both ileum and kidney produces combined cobalamin malabsorption and proteinuria, confirming in vivo that cubilin levels are rate-limiting for both functions.","evidence":"Radiolabeled cobalamin uptake, SDS-PAGE of urine proteins, quantitative mRNA/protein analysis in affected border collies","pmids":["23746554"],"confidence":"High","gaps":["Mechanism by which C-terminal frameshift destabilizes the entire transcript not resolved","Whether residual cubilin retains partial function not tested"]},{"year":2020,"claim":"Genotype-phenotype dissection across 39 patients showed that C-terminal CUBN variants cause isolated albuminuria without B12 malabsorption, mapping albumin reabsorption to the C-terminal CUB domains and demonstrating functional modularity of the receptor.","evidence":"Next-generation sequencing, structural modeling, epidemiological cohort analysis, clinical phenotyping","pmids":["31613795"],"confidence":"High","gaps":["Which specific C-terminal CUB domain(s) bind albumin not pinpointed","Crystal structure of cubilin C-terminal region lacking"]},{"year":2022,"claim":"Functional assays showed that C-terminal CUBN variants disrupt the CUBN–AMN interaction, trapping AMN in the cytoplasm and preventing apical membrane targeting, thus revealing the molecular mechanism underlying selective proteinuria.","evidence":"In vitro functional assays in HEK293T cells, in vivo mouse experiments, exome and Sanger sequencing","pmids":["36266725"],"confidence":"High","gaps":["Which residues at the CUBN–AMN interface are critical not mapped","Whether N-terminal CUBN–AMN interaction is structurally independent of C-terminal interaction unknown"]},{"year":2025,"claim":"Discovery of a truncated cubilin isoform with a unique C-terminus expressed in the intestine but not exclusively in the kidney explained why C-terminal variants spare intestinal B12 absorption — they affect only the full-length kidney isoform.","evidence":"Transcriptome analysis and targeted panel sequencing of 52 patients from 42 families","pmids":["41624452"],"confidence":"Medium","gaps":["Protein-level confirmation of truncated isoform expression not yet reported","Whether the truncated isoform retains AMN interaction capability not tested"]},{"year":2025,"claim":"Demonstration that the lncRNA Gm26793 restrains Cubn expression via CTCF-mediated inter-chromosomal interaction revealed an epigenetic layer of Cubn regulation important for primitive endoderm versus epiblast lineage specification.","evidence":"Genetic ablation, chromatin conformation capture, CTCF binding analysis, stem cell differentiation assays, and mouse embryo analysis","pmids":["40461506"],"confidence":"Medium","gaps":["Whether this regulatory mechanism operates in adult kidney or intestine not tested","Relevance to human CUBN regulation not established"]},{"year":null,"claim":"High-resolution structural data for cubilin or the CUBAM complex are lacking, and the precise CUB domain interfaces responsible for binding individual ligands (albumin, transferrin, light chains) and for AMN association remain unmapped.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of cubilin or the CUBAM complex","Ligand-specific binding sites across the 27 CUB domains not delineated","Mechanism of apical sorting and recycling of CUBAM not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,1,4,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3,9]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,5,7,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6,7,8]}],"complexes":["CUBAM"],"partners":["AMN"],"other_free_text":[]},"mechanistic_narrative":"Cubilin (CUBN) is a large peripheral membrane multiligand endocytic receptor that mediates vitamin B12 absorption in the ileum and protein reabsorption in the renal proximal tubule through its obligate partnership with the co-receptor amnionless (AMN) in the CUBAM complex. Cubilin binds intrinsic factor–cobalamin (IF-Cbl) complex in a calcium-dependent manner via its N-terminal CUB domains and mediates endocytic uptake of albumin, transferrin, light chains, and α1-microglobulin via C-terminal CUB domains at the apical clathrin-coated intermicrovillar surface of proximal tubule cells [PMID:9572993, PMID:9153271, PMID:7664754, PMID:9691015]. C-terminal CUBN variants disrupt CUBN–AMN association, causing aberrant cytoplasmic AMN retention and selective loss of renal albumin reabsorption without affecting intestinal B12 uptake, because the intestine expresses a truncated cubilin isoform lacking the C-terminal region [PMID:36266725, PMID:41624452]. Loss-of-function mutations in CUBN or AMN cause Imerslund-Gräsbeck syndrome (hereditary megaloblastic anaemia 1), characterized by selective intestinal vitamin B12 malabsorption and proteinuria [PMID:10080186, PMID:17668238]."},"prefetch_data":{"uniprot":{"accession":"O60494","full_name":"Cubilin","aliases":["460 kDa receptor","Intestinal intrinsic factor receptor","Intrinsic factor-cobalamin receptor","Intrinsic factor-vitamin B12 receptor"],"length_aa":3623,"mass_kda":398.7,"function":"Endocytic receptor which plays a role in lipoprotein, vitamin and iron metabolism by facilitating their uptake (PubMed:10371504, PubMed:11606717, PubMed:11717447, PubMed:14576052, PubMed:9572993). Acts together with LRP2 to mediate endocytosis of high-density lipoproteins, GC, hemoglobin, ALB, TF and SCGB1A1. Acts together with AMN to mediate endocytosis of the CBLIF-cobalamin complex (PubMed:14576052, PubMed:9572993). Binds to ALB, MB, Kappa and lambda-light chains, TF, hemoglobin, GC, SCGB1A1, APOA1, high density lipoprotein, and the CBLIF-cobalamin complex. Ligand binding requires calcium (PubMed:9572993). Serves as important transporter in several absorptive epithelia, including intestine, renal proximal tubules and embryonic yolk sac. May play an important role in the development of the peri-implantation embryo through internalization of APOA1 and cholesterol. Binds to LGALS3 at the maternal-fetal interface","subcellular_location":"Apical cell membrane; Cell membrane; Membrane, coated pit; Endosome; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/O60494/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CUBN","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CUBN","total_profiled":1310},"omim":[{"mim_id":"619845","title":"RETINITIS PIGMENTOSA 93; RP93","url":"https://www.omim.org/entry/619845"},{"mim_id":"618884","title":"PROTEINURIA, CHRONIC BENIGN; PROCHOB","url":"https://www.omim.org/entry/618884"},{"mim_id":"618882","title":"IMERSLUND-GRASBECK SYNDROME 2; IGS2","url":"https://www.omim.org/entry/618882"},{"mim_id":"610528","title":"CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 8; CHD8","url":"https://www.omim.org/entry/610528"},{"mim_id":"609342","title":"COBALAMIN-BINDING INTRINSIC FACTOR; CBLIF","url":"https://www.omim.org/entry/609342"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":131.1}],"url":"https://www.proteinatlas.org/search/CUBN"},"hgnc":{"alias_symbol":["IFCR","gp280"],"prev_symbol":["MGA1"]},"alphafold":{"accession":"O60494","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60494","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CUBN","jax_strain_url":"https://www.jax.org/strain/search?query=CUBN"},"sequence":{"accession":"O60494","fasta_url":"https://rest.uniprot.org/uniprotkb/O60494.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60494/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60494"}},"corpus_meta":[{"pmid":"10080186","id":"PMC_10080186","title":"Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1.","date":"1999","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10080186","citation_count":194,"is_preprint":false},{"pmid":"21355061","id":"PMC_21355061","title":"CUBN is a gene locus for albuminuria.","date":"2011","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/21355061","citation_count":191,"is_preprint":false},{"pmid":"9572993","id":"PMC_9572993","title":"The human intrinsic factor-vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region.","date":"1998","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9572993","citation_count":114,"is_preprint":false},{"pmid":"9153271","id":"PMC_9153271","title":"Identification of rat yolk sac target protein of teratogenic antibodies, gp280, as intrinsic factor-cobalamin receptor.","date":"1997","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/9153271","citation_count":95,"is_preprint":false},{"pmid":"9691015","id":"PMC_9691015","title":"Myeloma light chains are ligands for cubilin (gp280).","date":"1998","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9691015","citation_count":91,"is_preprint":false},{"pmid":"31613795","id":"PMC_31613795","title":"Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.","date":"2020","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/31613795","citation_count":74,"is_preprint":false},{"pmid":"19161160","id":"PMC_19161160","title":"An association study of 45 folate-related genes in spina bifida: Involvement of cubilin (CUBN) and tRNA aspartic acid methyltransferase 1 (TRDMT1).","date":"2009","source":"Birth defects research. Part A, Clinical and molecular teratology","url":"https://pubmed.ncbi.nlm.nih.gov/19161160","citation_count":61,"is_preprint":false},{"pmid":"7664754","id":"PMC_7664754","title":"Immunofunctional properties of a yolk sac epithelial cell line expressing two proteins gp280 and gp330 of the intermicrovillar area of proximal tubule cells: inhibition of endocytosis by the specific antibodies.","date":"1995","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/7664754","citation_count":41,"is_preprint":false},{"pmid":"20500530","id":"PMC_20500530","title":"Identification of Mga1, a G-protein alpha-subunit gene involved in regulating citrinin and pigment production in Monascus ruber M7.","date":"2010","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/20500530","citation_count":33,"is_preprint":false},{"pmid":"23613799","id":"PMC_23613799","title":"A frameshift mutation in the cubilin gene (CUBN) in Border Collies with Imerslund-Gräsbeck syndrome (selective cobalamin malabsorption).","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23613799","citation_count":29,"is_preprint":false},{"pmid":"22574174","id":"PMC_22574174","title":"CUBN as a novel locus for end-stage renal disease: insights from renal transplantation.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22574174","citation_count":27,"is_preprint":false},{"pmid":"30547231","id":"PMC_30547231","title":"A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria.","date":"2018","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/30547231","citation_count":26,"is_preprint":false},{"pmid":"17668238","id":"PMC_17668238","title":"Imerslund-Gräsbeck syndrome in a 15-year-old German girl caused by compound heterozygous mutations in CUBN.","date":"2007","source":"European journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/17668238","citation_count":23,"is_preprint":false},{"pmid":"24164695","id":"PMC_24164695","title":"A frameshift mutation in the cubilin gene (CUBN) in Beagles with Imerslund-Gräsbeck syndrome (selective cobalamin malabsorption).","date":"2013","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24164695","citation_count":22,"is_preprint":false},{"pmid":"27197912","id":"PMC_27197912","title":"Association Analysis of the Cubilin (CUBN) and Megalin (LRP2) Genes with ESRD in African Americans.","date":"2016","source":"Clinical journal of the American Society of Nephrology : CJASN","url":"https://pubmed.ncbi.nlm.nih.gov/27197912","citation_count":21,"is_preprint":false},{"pmid":"23746554","id":"PMC_23746554","title":"An exon 53 frameshift mutation in CUBN abrogates cubam function and causes Imerslund-Gräsbeck syndrome in dogs.","date":"2013","source":"Molecular genetics and 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and Transplant Association - European Renal Association","url":"https://pubmed.ncbi.nlm.nih.gov/34610128","citation_count":16,"is_preprint":false},{"pmid":"17462923","id":"PMC_17462923","title":"A novel gene MGA1 is required for appressorium formation in Magnaporthe grisea.","date":"2007","source":"Fungal genetics and biology : FG & B","url":"https://pubmed.ncbi.nlm.nih.gov/17462923","citation_count":16,"is_preprint":false},{"pmid":"31438875","id":"PMC_31438875","title":"Isolated proteinuria due to CUBN homozygous mutation - challenging the investigative paradigm.","date":"2019","source":"BMC nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/31438875","citation_count":12,"is_preprint":false},{"pmid":"31497480","id":"PMC_31497480","title":"Profound vitamin D deficiency in four siblings with Imerslund-Grasbeck syndrome with homozygous CUBN mutation.","date":"2019","source":"JIMD 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research","url":"https://pubmed.ncbi.nlm.nih.gov/32775008","citation_count":8,"is_preprint":false},{"pmid":"30591068","id":"PMC_30591068","title":"Inherited selective cobalamin malabsorption in Komondor dogs associated with a CUBN splice site variant.","date":"2018","source":"BMC veterinary research","url":"https://pubmed.ncbi.nlm.nih.gov/30591068","citation_count":8,"is_preprint":false},{"pmid":"34326275","id":"PMC_34326275","title":"CircSPIDR acts as a tumour suppressor in cervical adenocarcinoma by sponging miR-431-5p and regulating SORCS1 and CUBN expression.","date":"2021","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/34326275","citation_count":8,"is_preprint":false},{"pmid":"36266725","id":"PMC_36266725","title":"Novel pathogenic variants in CUBN uncouple proteinuria from renal function.","date":"2022","source":"Journal of translational 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European Dialysis and Transplant Association - European Renal Association","url":"https://pubmed.ncbi.nlm.nih.gov/24052458","citation_count":5,"is_preprint":false},{"pmid":"37312928","id":"PMC_37312928","title":"Isolated benign persistent proteinuria with novel association of CUBN (cubilin) variants.","date":"2023","source":"Clinical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/37312928","citation_count":5,"is_preprint":false},{"pmid":"39390623","id":"PMC_39390623","title":"To treat or not to treat: CUBN-associated persistent proteinuria.","date":"2024","source":"Kidney research and clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/39390623","citation_count":4,"is_preprint":false},{"pmid":"36926036","id":"PMC_36926036","title":"Four missense genetic variants in CUBN are associated with higher levels of eGFR in non-diabetes but not in diabetes mellitus or its subtypes: A genetic association study in Europeans.","date":"2023","source":"Frontiers in 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PDE4D, and CUBN in regulating podocyte injury in diabetic nephropathy: a single-cell RNA sequencing analysis.","date":"2024","source":"Translational andrology and urology","url":"https://pubmed.ncbi.nlm.nih.gov/39698573","citation_count":3,"is_preprint":false},{"pmid":"38488435","id":"PMC_38488435","title":"Identification of novel pathogenic variants of CUBN in patients with isolated proteinuria.","date":"2024","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38488435","citation_count":2,"is_preprint":false},{"pmid":"32803705","id":"PMC_32803705","title":"Tuberculosis risk is associated with genetic polymorphisms in the LRP2, CUBN, and VDR genes.","date":"2020","source":"Genes & genomics","url":"https://pubmed.ncbi.nlm.nih.gov/32803705","citation_count":2,"is_preprint":false},{"pmid":"33031161","id":"PMC_33031161","title":"Novel CUBN Mutation in a Young Child With Megaloblastic Anemia.","date":"2021","source":"Journal of pediatric 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epithelia","date":"2024-05-09","source":"bioRxiv","url":"https://doi.org/10.1101/2024.05.06.591758","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":26205,"output_tokens":3051,"usd":0.06219},"stage2":{"model":"claude-opus-4-6","input_tokens":6436,"output_tokens":2828,"usd":0.15432},"total_usd":0.21651,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Human cubilin (CUBN) is a 3597 amino acid peripheral membrane protein that binds intrinsic factor-cobalamin (IF-Cbl) complex in a calcium- and cobalamin-dependent manner with high affinity, as demonstrated by surface plasmon resonance. The protein undergoes proteolytic processing via cleavage at a furin recognition site (Arg7-Glu8-Lys9-Arg) in the trans-Golgi apparatus.\",\n      \"method\": \"Surface plasmon resonance, complete cDNA cloning, amino-terminal sequencing, fluorescence in situ hybridization\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding assay with defined mechanism, direct sequencing of cleavage site, replicated by multiple methods\",\n      \"pmids\": [\"9572993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Cubilin (gp280) functions as the intrinsic factor-cobalamin receptor (IFCR) in kidney, intestine, and yolk sac epithelium, binding IF-Cbl complex with an association constant of 0.3×10⁹ M⁻¹ and mediating its internalization. Anti-gp280 antibodies inhibited IF-[⁵⁷Co]Cbl binding at all three epithelial sites and blocked uptake and internalization of ¹²⁵IF-Cbl in yolk sac epithelial cells.\",\n      \"method\": \"Ligand binding assay, immunoblotting, immunoprecipitation, immunoelectron microscopy, radioligand uptake assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including radioligand uptake, co-localization by immunoelectron microscopy, and antibody inhibition of endocytosis\",\n      \"pmids\": [\"9153271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Cubilin (gp280) is localized to clathrin-coated intermicrovillar areas of proximal tubule and yolk sac epithelial cells and is functionally required for endocytosis: antibodies against gp280 inhibited internalization of [¹⁴C]sucrose and peroxidase and disrupted the early endocytic pathway, resulting in accumulation of smaller, irregular vesicles rather than normal lysosomes.\",\n      \"method\": \"Indirect immunofluorescence, ultrastructural immunoelectron microscopy, endocytosis inhibition assay with tracers\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional consequence (endocytosis disruption) using multiple orthogonal methods\",\n      \"pmids\": [\"7664754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Cubilin (gp280) undergoes an unusual processing pathway: unlike the related receptor gp330, gp280 is initially targeted to the plasma membrane in an endoglycosidase H-sensitive (immature) form, and Golgi-mediated processing occurs mainly by recycling rather than prior to initial membrane delivery.\",\n      \"method\": \"Endoglycosidase H sensitivity assay, biosynthetic labeling, cell fractionation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical characterization of processing pathway with direct experimental evidence, single lab\",\n      \"pmids\": [\"7626048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Cubilin (gp280) acts as a receptor for myeloma light chains in the kidney, mediating their endocytosis in renal proximal tubule cells. Evidence included: light chain co-elution during immunoaffinity purification of cubilin, anti-cubilin antisera displacement of light chain binding from brush-border membranes, surface plasmon resonance binding, and partial inhibition of light chain endocytosis in yolk sac epithelial cells by anti-cubilin antibody.\",\n      \"method\": \"Immunoaffinity purification, surface plasmon resonance, radioligand binding displacement, endocytosis inhibition assay\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — four independent lines of evidence including surface plasmon resonance and functional endocytosis assay\",\n      \"pmids\": [\"9691015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Loss-of-function mutations in CUBN cause hereditary megaloblastic anaemia 1 (MGA1/Imerslund-Gräsbeck syndrome), characterized by selective intestinal vitamin B12 malabsorption. Two independent disease-specific CUBN mutations were identified in Finnish MGA1 families by linkage disequilibrium mapping and molecular analysis.\",\n      \"method\": \"Linkage disequilibrium mapping, mutation identification, genetic analysis in affected families\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined molecular lesion and clinical phenotype, replicated across multiple families, highly cited foundational paper\",\n      \"pmids\": [\"10080186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cubilin forms the CUBAM complex together with amnionless (AMN), and this complex functions as the receptor for intrinsic factor-Cbl in the ileum and as a multi-ligand reabsorption receptor in renal proximal tubules. Mutations in either CUBN or AMN disrupt this complex and cause Imerslund-Gräsbeck syndrome with selective proteinuria.\",\n      \"method\": \"Genetic analysis, clinical phenotyping of patients with CUBN and AMN mutations\",\n      \"journal\": \"European journal of pediatrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — complex function inferred from genetic evidence, consistent with prior biochemical data\",\n      \"pmids\": [\"17668238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A CUBN frameshift mutation far C-terminal from the intrinsic factor-cobalamin binding site causes ~10-fold reduction in CUBN mRNA and ~20-fold reduction in cubilin protein in both ileum and kidney of affected border collies, leading to cobalamin malabsorption and proteinuria comprising CUBN ligands as demonstrated by radiolabeled cobalamin uptake studies and SDS-PAGE.\",\n      \"method\": \"Radiolabeled cobalamin uptake assay, SDS-PAGE of urine proteins, quantitative mRNA and protein expression analysis, DNA sequencing\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct functional assay (radiolabeled cobalamin uptake) plus molecular quantification, ortholog model\",\n      \"pmids\": [\"23746554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"C-terminal variants in CUBN (after the vitamin B12-binding domain) cause isolated chronic albuminuria/proteinuria without vitamin B12 malabsorption or impaired renal function, demonstrating that the C-terminal half of cubilin is specifically required for renal albumin reabsorption in the proximal tubule, while the N-terminal region (including the IF-Cbl binding site) is required for intestinal B12 uptake.\",\n      \"method\": \"Next-generation sequencing, bioinformatics, structural modeling, epidemiological cohort analysis, clinical phenotyping\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genotype-phenotype dissection across 39 patients with biallelic variants, confirmed in large population cohorts, multiple orthogonal approaches\",\n      \"pmids\": [\"31613795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Variants after the vitamin B12-binding domain of CUBN disrupt the association of cubilin with its co-receptor amnionless (AMN), causing aberrant AMN localization in the cell cytoplasm rather than at the membrane, and result in impaired reabsorption of albumin, transferrin, and α1-microglobulin in renal proximal tubules without affecting glomerular filtration or vitamin B12 absorption.\",\n      \"method\": \"Exome sequencing, Sanger sequencing, in vitro functional assay in HEK293T cells, in vivo mouse experiments, clinical biochemical analysis\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro and in vivo experiments demonstrating disrupted CUBN-AMN interaction and aberrant localization, multiple orthogonal methods\",\n      \"pmids\": [\"36266725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A novel CUBN transcript encodes a truncated cubilin isoform with a unique C-terminus that is expressed in both kidney and small intestine, while full-length cubilin is expressed only in the kidney. C-terminal CUBN variants therefore do not affect the intestinal isoform, explaining why C-terminal mutations cause isolated proteinuria without vitamin B12 malabsorption.\",\n      \"method\": \"Transcriptome analysis, targeted panel sequencing of 52 patients from 42 families, identification of novel transcript isoform\",\n      \"journal\": \"Kidney international reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — novel isoform discovery with mechanistic explanation, single lab but large cohort\",\n      \"pmids\": [\"41624452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The genomic locus of lncRNA Gm26793 (chromosome 7) forms an inter-chromosomal interaction with Cubn (chromosome 2) via CTCF, restraining Cubn expression and maintaining epigenetic landscape to ensure proper primitive endoderm versus epiblast lineage specification during mouse embryogenesis.\",\n      \"method\": \"Genetic ablation of Gm26793, chromatin conformation capture, CTCF binding analysis, stem cell differentiation assays, mouse embryo analysis\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genetic manipulation with chromatin conformation data showing CTCF-mediated inter-chromosomal regulation of Cubn expression\",\n      \"pmids\": [\"40461506\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Cubilin (CUBN) is a large peripheral membrane multiligand endocytic receptor expressed on the apical surface of intestinal epithelium, renal proximal tubules, and yolk sac; it binds intrinsic factor-cobalamin complex in a calcium-dependent manner via its N-terminal CUB domains to mediate intestinal vitamin B12 absorption, and uses its C-terminal CUB domains to reabsorb albumin, transferrin, light chains, and other filtered proteins in the renal proximal tubule, functioning as part of the CUBAM complex with its obligate co-receptor amnionless (AMN), whose membrane localization depends on proper CUBN association; loss-of-function mutations cause Imerslund-Gräsbeck syndrome, while C-terminal-specific variants selectively abolish renal albumin reabsorption without affecting intestinal B12 uptake because a truncated cubilin isoform expressed in the intestine lacks the C-terminal region.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Cubilin (CUBN) is a large peripheral membrane multiligand endocytic receptor that mediates vitamin B12 absorption in the ileum and protein reabsorption in the renal proximal tubule through its obligate partnership with the co-receptor amnionless (AMN) in the CUBAM complex. Cubilin binds intrinsic factor–cobalamin (IF-Cbl) complex in a calcium-dependent manner via its N-terminal CUB domains and mediates endocytic uptake of albumin, transferrin, light chains, and α1-microglobulin via C-terminal CUB domains at the apical clathrin-coated intermicrovillar surface of proximal tubule cells [PMID:9572993, PMID:9153271, PMID:7664754, PMID:9691015]. C-terminal CUBN variants disrupt CUBN–AMN association, causing aberrant cytoplasmic AMN retention and selective loss of renal albumin reabsorption without affecting intestinal B12 uptake, because the intestine expresses a truncated cubilin isoform lacking the C-terminal region [PMID:36266725, PMID:41624452]. Loss-of-function mutations in CUBN or AMN cause Imerslund-Gräsbeck syndrome (hereditary megaloblastic anaemia 1), characterized by selective intestinal vitamin B12 malabsorption and proteinuria [PMID:10080186, PMID:17668238].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that cubilin localizes to clathrin-coated intermicrovillar pits and is functionally required for apical endocytosis resolved its role as an active endocytic receptor rather than a passive surface marker.\",\n      \"evidence\": \"Immunoelectron microscopy and endocytosis inhibition assays with tracers in proximal tubule and yolk sac epithelial cells\",\n      \"pmids\": [\"7664754\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of membrane anchoring unknown given absence of transmembrane domain\", \"Identity of co-receptor mediating internalization not yet established\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Demonstration that cubilin reaches the plasma membrane in an endoglycosidase H–sensitive form and undergoes Golgi processing mainly via recycling revealed an atypical biosynthetic trafficking pathway.\",\n      \"evidence\": \"Endoglycosidase H sensitivity assay and biosynthetic labeling in cultured cells\",\n      \"pmids\": [\"7626048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not independently replicated in a second system\", \"Molecular determinants of recycling-dependent processing not identified\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of cubilin as the intrinsic factor–cobalamin receptor across kidney, intestine, and yolk sac unified previously separate observations of IF-Cbl binding at epithelial surfaces.\",\n      \"evidence\": \"Ligand binding assays, anti-gp280 antibody inhibition of radioligand uptake and internalization, immunoelectron microscopy\",\n      \"pmids\": [\"9153271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for IF-Cbl recognition not resolved\", \"Whether cubilin alone suffices for internalization or requires a co-receptor unclear\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Cloning of full-length human CUBN and demonstration of calcium-dependent IF-Cbl binding by surface plasmon resonance defined the molecular identity and binding requirements of the receptor, while furin cleavage at Arg7-Glu8-Lys9-Arg established a processing step in the trans-Golgi.\",\n      \"evidence\": \"cDNA cloning, surface plasmon resonance, amino-terminal sequencing, fluorescence in situ hybridization\",\n      \"pmids\": [\"9572993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which CUB domains mediate IF-Cbl versus other ligand binding not delineated\", \"Functional significance of furin cleavage for receptor activity not tested\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstration that cubilin binds and mediates endocytosis of myeloma light chains expanded its role from a single-ligand IF-Cbl receptor to a multiligand endocytic receptor in the kidney.\",\n      \"evidence\": \"Immunoaffinity purification, surface plasmon resonance, radioligand displacement, and endocytosis inhibition in yolk sac epithelial cells\",\n      \"pmids\": [\"9691015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Light chain binding domain not mapped\", \"Relative contribution of cubilin versus megalin to light chain clearance in vivo not determined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Discovery of disease-causing CUBN mutations in Finnish families established the causal link between cubilin deficiency and Imerslund-Gräsbeck syndrome (hereditary megaloblastic anaemia with proteinuria).\",\n      \"evidence\": \"Linkage disequilibrium mapping and mutation identification in affected families\",\n      \"pmids\": [\"10080186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all IGS-associated mutations act through loss of IF-Cbl binding or through protein instability not distinguished\", \"Role of co-receptor AMN mutations not yet recognized\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Recognition that cubilin functions as the CUBAM complex with amnionless (AMN) explained how a peripheral membrane protein achieves membrane anchoring and endocytic signaling, and linked AMN mutations to the same disease.\",\n      \"evidence\": \"Genetic analysis and clinical phenotyping of patients with CUBN and AMN mutations\",\n      \"pmids\": [\"17668238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of CUBN–AMN interaction not defined\", \"Whether AMN is required stoichiometrically or catalytically for cubilin surface delivery unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"A canine model with a C-terminal CUBN frameshift showed that massive reduction of cubilin protein in both ileum and kidney produces combined cobalamin malabsorption and proteinuria, confirming in vivo that cubilin levels are rate-limiting for both functions.\",\n      \"evidence\": \"Radiolabeled cobalamin uptake, SDS-PAGE of urine proteins, quantitative mRNA/protein analysis in affected border collies\",\n      \"pmids\": [\"23746554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which C-terminal frameshift destabilizes the entire transcript not resolved\", \"Whether residual cubilin retains partial function not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genotype-phenotype dissection across 39 patients showed that C-terminal CUBN variants cause isolated albuminuria without B12 malabsorption, mapping albumin reabsorption to the C-terminal CUB domains and demonstrating functional modularity of the receptor.\",\n      \"evidence\": \"Next-generation sequencing, structural modeling, epidemiological cohort analysis, clinical phenotyping\",\n      \"pmids\": [\"31613795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific C-terminal CUB domain(s) bind albumin not pinpointed\", \"Crystal structure of cubilin C-terminal region lacking\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Functional assays showed that C-terminal CUBN variants disrupt the CUBN–AMN interaction, trapping AMN in the cytoplasm and preventing apical membrane targeting, thus revealing the molecular mechanism underlying selective proteinuria.\",\n      \"evidence\": \"In vitro functional assays in HEK293T cells, in vivo mouse experiments, exome and Sanger sequencing\",\n      \"pmids\": [\"36266725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which residues at the CUBN–AMN interface are critical not mapped\", \"Whether N-terminal CUBN–AMN interaction is structurally independent of C-terminal interaction unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery of a truncated cubilin isoform with a unique C-terminus expressed in the intestine but not exclusively in the kidney explained why C-terminal variants spare intestinal B12 absorption — they affect only the full-length kidney isoform.\",\n      \"evidence\": \"Transcriptome analysis and targeted panel sequencing of 52 patients from 42 families\",\n      \"pmids\": [\"41624452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protein-level confirmation of truncated isoform expression not yet reported\", \"Whether the truncated isoform retains AMN interaction capability not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstration that the lncRNA Gm26793 restrains Cubn expression via CTCF-mediated inter-chromosomal interaction revealed an epigenetic layer of Cubn regulation important for primitive endoderm versus epiblast lineage specification.\",\n      \"evidence\": \"Genetic ablation, chromatin conformation capture, CTCF binding analysis, stem cell differentiation assays, and mouse embryo analysis\",\n      \"pmids\": [\"40461506\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this regulatory mechanism operates in adult kidney or intestine not tested\", \"Relevance to human CUBN regulation not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"High-resolution structural data for cubilin or the CUBAM complex are lacking, and the precise CUB domain interfaces responsible for binding individual ligands (albumin, transferrin, light chains) and for AMN association remain unmapped.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of cubilin or the CUBAM complex\", \"Ligand-specific binding sites across the 27 CUB domains not delineated\", \"Mechanism of apical sorting and recycling of CUBAM not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1, 4, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 9]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005773\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 5, 7, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6, 7, 8]}\n    ],\n    \"complexes\": [\n      \"CUBAM\"\n    ],\n    \"partners\": [\n      \"AMN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}