{"gene":"DSG1","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1991,"finding":"DSG1 (desmosomal glycoprotein DGI) was identified as a member of the cadherin family of Ca2+-dependent cell adhesion molecules, with a unique cytoplasmic domain containing ~29-amino acid repeats predicted to form antiparallel beta-sheet structures and a glycine-rich sequence, and with the cell adhesion recognition sequence His-Ala-Val modified to Arg-Ala-Leu compared to classical cadherins.","method":"cDNA cloning, sequence analysis, homology comparison","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — foundational molecular characterization, widely replicated, >187 citations","pmids":["1711210"],"is_preprint":false},{"year":1994,"finding":"Plakoglobin binds to a specific 19-amino acid sequence within the cytoplasmic domain of DSG1, a region sharing significant similarity to the catenin-binding domain of classical cadherins, suggesting a common mechanism for plakoglobin association with desmosomes and adherens junctions.","method":"Blot overlay assays using deletion series of DSG1 cytoplasmic domain expressed as fusion proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1/2 — direct binding mapped by deletion mutagenesis and overlay assay, >113 citations","pmids":["8188687"],"is_preprint":false},{"year":1994,"finding":"The bovine DSG1 gene spans >37.5 kb and consists of 15 exons, with striking conservation of exon boundaries with classical cadherin genes in the ectodomain-encoding regions. A polymorphic sequence was identified proximal to the external face of the plasma membrane, topologically equivalent to an adhesion-disrupting antibody epitope domain in classical cadherins.","method":"Genomic cloning, restriction mapping, sequencing, exon-intron boundary determination","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 — structural gene characterization, single study","pmids":["8294446"],"is_preprint":false},{"year":1998,"finding":"In overlay assays, plakophilin 1 (PP1) binds to DSG1 (as well as desmoplakin and Dsc1a), and plakoglobin (PG) binds to DSG1 more strongly than to Dsc1a or desmoplakin, supporting a model in which DP and PG anchor to desmosomal cadherins and to each other to form an ordered plaque that links to keratin intermediate filaments.","method":"In vitro overlay assays, deletion and site-directed mutagenesis of desmosomal components","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro overlay with mutagenesis, widely replicated, >228 citations","pmids":["9606214"],"is_preprint":false},{"year":1999,"finding":"A splice-site mutation in intron 2 of DSG1 removes exon 3 (encoding part of the prosequence, the mature protein cleavage site, and part of the first extracellular domain including the N-terminal beta-strands and part of the first Ca2+-binding site), demonstrating that the N-terminal ectodomain of DSG1, required for strand dimer formation, is essential for DSG1 function in epidermal integrity.","method":"Genetic linkage, mutation analysis, splicing characterization in striate palmoplantar keratoderma family","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function mutation with defined molecular and phenotypic consequence, >178 citations","pmids":["10332028"],"is_preprint":false},{"year":2002,"finding":"Plakophilin 2 directly interacts with DSG1 (and DSG2), as demonstrated by co-immunoprecipitation and yeast two-hybrid assays; the head domain of plakophilin 2 is critical for this interaction and sufficient to direct plakophilin 2 to cell borders.","method":"Co-immunoprecipitation, yeast two-hybrid assay, transfection of deletion constructs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP and yeast two-hybrid with domain mapping, >198 citations","pmids":["11790773"],"is_preprint":false},{"year":2004,"finding":"The serine protease KLK5 (SCTE) directly degrades DSG1 at acidic pH, while KLK7 (SCCE) alone is unable to degrade DSG1 but KLK5 can activate the pro-form of KLK7. KLK5 degradation of DSG1 is a key step in desquamation (corneodesmosome dissolution at the epidermal surface).","method":"In vitro protease activity assays using recombinant enzymes and epidermal/recombinant substrates at acidic pH","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted biochemical assay, >367 citations","pmids":["15140227"],"is_preprint":false},{"year":2006,"finding":"In Netherton syndrome (SPINK5/LEKTI deficiency), hyperactivity of KLK5-like and KLK7-like proteases leads to premature degradation of DSG1 in the upper living epidermis, causally linking protease-mediated DSG1 cleavage to corneodesmosome dissolution and disease severity.","method":"Immunostaining of patient biopsies, protease activity assays, correlation with LEKTI expression","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 — multi-patient human genetic disease study with protease activity assays, >150 citations","pmids":["16628198"],"is_preprint":false},{"year":2009,"finding":"DSG1 promotes keratinocyte differentiation and suprabasal morphogenesis by suppressing EGFR-ERK1/2 signaling. DSG1 lacking N-terminal ectodomain residues required for adhesion still promotes differentiation. This function is independent of plakoglobin cytodomain interactions and does not require co-expression of Dsc1, but requires suppression of EGFR-Erk1/2 signaling.","method":"RNAi knockdown, overexpression of adhesion-defective DSG1 mutants, western blotting for EGFR/ERK activation, organotypic culture, keratinocyte differentiation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function + structure-function mutants + defined signaling pathway, >185 citations","pmids":["19546243"],"is_preprint":false},{"year":2013,"finding":"Homozygous loss-of-function mutations in DSG1 cause SAM syndrome (severe dermatitis, multiple allergies, metabolic wasting). DSG1 deficiency results in absence of membrane expression of DSG1, loss of cell-cell adhesion, and increased expression of allergy-related cytokine genes, demonstrating that a primary structural epidermal barrier defect can drive allergic disease.","method":"Human genetics (homozygous mutation identification), immunofluorescence for DSG1 membrane expression, transcriptomic analysis of cytokine gene expression in patient skin","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — human loss-of-function genetics with molecular phenotyping, >272 citations","pmids":["23974871"],"is_preprint":false},{"year":2013,"finding":"DSG1 knockdown in esophageal epithelial cells weakens barrier integrity, causes cell separation, and induces transcriptional changes overlapping with EoE inflamed mucosa, including strong induction of periostin (POSTN). IL-13 downregulates DSG1 to cause impaired barrier function in EoE.","method":"siRNA knockdown, TEER measurements, transwell permeability assays, transcriptomic analysis, IL-13 treatment","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 — KD with defined cellular phenotype and transcriptomic readout, >248 citations","pmids":["24220297"],"is_preprint":false},{"year":2019,"finding":"PF-IgG (anti-DSG1 autoantibodies) causes loss of keratinocyte cohesion via Ca2+ influx (independent of EGFR), whereas PV-IgG (anti-DSG3) activates EGFR in a Src-dependent manner and causes ERK activation. Using CRISPR/Cas9-generated Dsg3-deficient (but not Dsg2-deficient) HaCaT cells, Ca2+ influx and ERK activation in response to PF-IgG (anti-DSG1) are preserved, indicating that DSG1 signaling is not dependent on Dsg3 or Dsg2.","method":"CRISPR/Cas9 knockout of Dsg2/Dsg3, Ca2+ imaging, EGFR/ERK western blotting, cell dissociation assays, EGFR and Src inhibitors","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — CRISPR KO with orthogonal signaling readouts","pmids":["31178865"],"is_preprint":false},{"year":2022,"finding":"Super-resolution microscopy revealed that the Dsg1/Dsg3 ratio increases from basal to granular epidermal layers, and that extradesmosomal DSG1 co-localizes with plakoglobin in all epidermal layers (while Dsg3-plakoglobin co-localization is basal-restricted). In pemphigus patient skin, extradesmosomal DSG1-plakoglobin co-localization is significantly reduced, and desmosome number is decreased in basal and spinous layers.","method":"Super-resolution microscopy (STED/STORM), co-localization analysis with desmoplakin as desmosome marker, patient skin biopsies","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional disease context, single study","pmids":["35711465"],"is_preprint":false},{"year":2025,"finding":"In mice with keratinocyte-specific Stim1/Stim2 knockout (impaired store-operated Ca2+ entry), DSG1 levels are altered and Kallikrein-related peptidases KLK6 and KLK7 are elevated, leading to increased serine protease activity and impaired epidermal barrier function (increased TEWL), placing DSG1 downstream of calcium signaling via KLK-mediated proteolysis.","method":"Conditional knockout mouse model, TEWL measurement, RNA-seq, protease activity assays, biotin diffusion assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO with multi-modal phenotyping, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.10.14.681588"],"is_preprint":true},{"year":2024,"finding":"Topical administration of recombinant ephrin-A3 (EFNA3) promotes vaginal DSG1 expression in a biphasic dose-dependent manner and partially reverses loss of vaginal epithelial barrier function induced by progestin (DMPA) treatment, identifying EFNA3 as a regulator of DSG1-dependent desmosomal function in vaginal epithelium.","method":"Mouse in vivo model (DMPA treatment + recombinant EFNA3 administration), gene expression analysis, barrier function assays, HSV-2 infection model","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — in vivo pharmacological study, preprint, indirect evidence for DSG1 regulation","pmids":["bio_10.1101_2024.10.29.620915"],"is_preprint":true},{"year":2025,"finding":"In a human skin organ culture model, split formation (but not anti-DSG1/DSG3 autoantibody binding alone) triggers sustained upregulation of IFNγ- and TNFα-related genes via NFκB, MAPK, and JAK-STAT pathways. These transcriptomic and proteomic changes correlate with keratinocyte detachment and are inversely associated with differentiation, suggesting that DSG1/DSG3-targeting autoantibodies cause downstream signaling changes only secondary to mechanical loss of adhesion.","method":"Human skin organ culture, 2D keratinocyte culture, transcriptomics, proteomics, single-chain antibody (PX43) targeting DSG1/3, AK23 (anti-DSG3), endemic PF anti-DSG1 IgG treatment","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multi-omics approach with orthogonal models, preprint","pmids":["bio_10.1101_2025.02.10.637416"],"is_preprint":true}],"current_model":"DSG1 is a desmosomal cadherin that functions as a Ca2+-dependent cell-cell adhesion molecule in stratified epithelia; it interacts via a conserved cytoplasmic motif with plakoglobin and plakophilin 2 to anchor keratin intermediate filaments through desmoplakin, and its extracellular domain is proteolytically processed by KLK5 (and secondarily KLK7) to regulate desquamation; beyond adhesion, DSG1 actively suppresses EGFR-ERK1/2 signaling to promote keratinocyte terminal differentiation, and its loss—whether by autoantibody-mediated disruption, haploinsufficiency, or biallelic mutation—impairs epidermal barrier function and drives pro-inflammatory cytokine expression."},"narrative":{"teleology":[{"year":1991,"claim":"Establishing DSG1 as a cadherin family member resolved how desmosomal glycoprotein DGI relates to classical Ca²⁺-dependent adhesion molecules and identified its unique cytoplasmic repeat architecture.","evidence":"cDNA cloning with sequence homology analysis","pmids":["1711210"],"confidence":"High","gaps":["Binding partners of the unique cytoplasmic repeats were unknown","Functional significance of the Arg-Ala-Leu substitution in the adhesion recognition sequence was untested"]},{"year":1994,"claim":"Mapping the plakoglobin-binding site to a 19-residue cytoplasmic motif homologous to the catenin-binding domain of classical cadherins established how DSG1 connects to the desmosomal plaque via a conserved mechanism.","evidence":"Blot overlay assays with systematic deletion series of DSG1 cytoplasmic domain fusion proteins","pmids":["8188687"],"confidence":"High","gaps":["Stoichiometry and affinity of plakoglobin–DSG1 interaction in intact cells were not determined","Role of additional cytoplasmic partners beyond plakoglobin remained open"]},{"year":1998,"claim":"Demonstrating that plakophilin 1 and plakoglobin both bind DSG1 and desmoplakin established the ordered molecular hierarchy of the desmosomal plaque linking cadherins to intermediate filaments.","evidence":"In vitro overlay assays with deletion and site-directed mutagenesis of desmosomal components","pmids":["9606214"],"confidence":"High","gaps":["In vivo validation of the plaque assembly order was lacking","Contribution of individual interactions to adhesive strength was unknown"]},{"year":1999,"claim":"Identifying a DSG1 splice-site mutation in striate palmoplantar keratoderma proved that the N-terminal ectodomain — required for trans-dimerization and Ca²⁺ binding — is essential for epidermal integrity in humans.","evidence":"Genetic linkage and mutation analysis in a keratoderma family with splicing characterization","pmids":["10332028"],"confidence":"High","gaps":["Whether haploinsufficiency alone fully explained the keratoderma or whether dominant-negative effects contributed was unclear","Structural basis of DSG1 trans-dimerization awaited atomic-resolution data"]},{"year":2002,"claim":"Showing that plakophilin 2 directly binds DSG1 via its head domain expanded the set of cytoplasmic partners bridging desmosomal cadherins to the plaque and identified PKP2 as a second plakophilin interactor.","evidence":"Reciprocal co-immunoprecipitation and yeast two-hybrid assay with domain-mapping constructs","pmids":["11790773"],"confidence":"High","gaps":["Relative contributions of PKP1 versus PKP2 to DSG1-dependent adhesion in different tissues were not resolved","Whether PKP2 and plakoglobin binding to DSG1 is competitive or cooperative was undetermined"]},{"year":2004,"claim":"Reconstituting KLK5-mediated DSG1 degradation at acidic pH identified the protease responsible for corneodesmosome dissolution during desquamation and clarified that KLK7 requires KLK5-dependent activation.","evidence":"In vitro protease activity assays with recombinant KLK5 and KLK7 on epidermal and recombinant DSG1 substrates","pmids":["15140227"],"confidence":"High","gaps":["Exact KLK5 cleavage sites on DSG1 were not mapped","In vivo regulation of KLK5 activity at the desmosome surface was not addressed"]},{"year":2006,"claim":"Demonstrating premature DSG1 degradation by hyperactive KLK5/KLK7 in Netherton syndrome skin established a direct pathological link between dysregulated protease activity and corneodesmosome failure in human disease.","evidence":"Immunostaining of patient biopsies correlated with protease activity assays and LEKTI expression","pmids":["16628198"],"confidence":"High","gaps":["Whether therapeutic protease inhibition could rescue DSG1 levels and barrier function was untested","Relative contribution of DSG1 degradation versus other corneodesmosomal target cleavage was unresolved"]},{"year":2009,"claim":"Revealing that DSG1 suppresses EGFR–ERK1/2 signaling to promote differentiation — independently of its adhesive ectodomain and plakoglobin binding — uncovered a signaling function separable from its structural adhesion role.","evidence":"RNAi knockdown, adhesion-defective DSG1 mutant overexpression, EGFR/ERK western blotting, and organotypic keratinocyte cultures","pmids":["19546243"],"confidence":"High","gaps":["The molecular intermediary connecting DSG1 cytoplasmic domain to EGFR suppression was not identified","Whether this signaling function operates in non-epidermal epithelia was unknown"]},{"year":2013,"claim":"Discovery that biallelic DSG1 loss-of-function mutations cause SAM syndrome — with absent membrane DSG1, adhesion failure, and upregulation of allergy-related cytokines — established DSG1 as essential for human epidermal barrier integrity and immune homeostasis.","evidence":"Homozygous mutation identification in affected families, immunofluorescence, and transcriptomic analysis of patient skin","pmids":["23974871"],"confidence":"High","gaps":["Mechanism by which DSG1 loss activates pro-inflammatory cytokine transcription was not delineated","Whether residual desmosomal adhesion via DSG3 partially compensates in SAM was not tested"]},{"year":2013,"claim":"Showing that DSG1 knockdown in esophageal epithelium weakens barrier integrity and induces an EoE-like transcriptional program (including periostin) connected DSG1 to mucosal immune disease beyond skin.","evidence":"siRNA knockdown with TEER, permeability assays, transcriptomics, and IL-13 treatment in esophageal epithelial cells","pmids":["24220297"],"confidence":"High","gaps":["Whether DSG1 loss is a primary driver or secondary consequence in EoE pathogenesis was unresolved","Direct transcriptional regulators of DSG1 downstream of IL-13 were not identified"]},{"year":2019,"claim":"Using CRISPR knockout of Dsg2/Dsg3, anti-DSG1 autoantibodies were shown to cause loss of cohesion via Ca²⁺ influx independent of EGFR and of other desmogleins, delineating a DSG1-specific pathogenic signaling axis in pemphigus foliaceus.","evidence":"CRISPR/Cas9-generated Dsg2- and Dsg3-deficient HaCaT cells with Ca²⁺ imaging, EGFR/ERK blotting, and dissociation assays","pmids":["31178865"],"confidence":"High","gaps":["Source and mechanism of Ca²⁺ influx triggered by anti-DSG1 antibodies were not identified","Whether Ca²⁺ influx is necessary or sufficient for loss of cohesion was not formally tested"]},{"year":2022,"claim":"Super-resolution imaging revealed that extradesmosomal DSG1–plakoglobin complexes exist across all epidermal layers and are disrupted in pemphigus skin, suggesting a non-desmosomal DSG1 pool contributes to disease pathogenesis.","evidence":"STED/STORM microscopy with co-localization analysis using desmoplakin as a desmosome marker in normal and pemphigus patient skin","pmids":["35711465"],"confidence":"Medium","gaps":["Functional role of the extradesmosomal DSG1–plakoglobin pool was not experimentally tested","Whether extradesmosomal DSG1 mediates the EGFR-suppressive signaling function is unknown","Single study awaiting independent replication"]},{"year":null,"claim":"The molecular mechanism by which the DSG1 cytoplasmic domain suppresses EGFR–ERK signaling remains unidentified, and the functional significance of extradesmosomal DSG1 pools and the precise KLK5 cleavage sites on DSG1 are unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No direct intermediary linking DSG1 to EGFR suppression has been identified","Atomic-resolution structure of DSG1 ectodomain trans-dimer is lacking","In vivo requirement for specific DSG1 cytoplasmic motifs in differentiation versus adhesion has not been genetically dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,4,9,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,9,12]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,1,3,4,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,10]}],"complexes":["Desmosome"],"partners":["JUP","PKP1","PKP2","DSP","DSC1","KLK5","KLK7"],"other_free_text":[]},"mechanistic_narrative":"DSG1 is a desmosomal cadherin that mediates Ca²⁺-dependent cell–cell adhesion in stratified epithelia and coordinates epidermal differentiation and barrier homeostasis. Its cytoplasmic domain binds plakoglobin via a conserved 19-amino-acid motif and interacts with plakophilin 1 and plakophilin 2, anchoring keratin intermediate filaments through desmoplakin to form the desmosomal plaque [PMID:8188687, PMID:9606214, PMID:11790773]. Beyond adhesion, DSG1 suppresses EGFR–ERK1/2 signaling through a mechanism independent of its adhesive ectodomain to promote keratinocyte terminal differentiation, and its ectodomain is proteolytically cleaved by KLK5 at acidic pH to drive corneodesmosome dissolution during desquamation [PMID:19546243, PMID:15140227]. Biallelic loss-of-function mutations in DSG1 cause SAM syndrome (severe dermatitis, multiple allergies, metabolic wasting), linking primary desmosomal disruption to barrier failure and pro-inflammatory cytokine induction [PMID:23974871]."},"prefetch_data":{"uniprot":{"accession":"Q02413","full_name":"Desmoglein-1","aliases":["Cadherin family member 4","Desmosomal glycoprotein 1","DG1","DGI","Pemphigus foliaceus antigen"],"length_aa":1049,"mass_kda":113.7,"function":"Component of intercellular desmosome junctions (PubMed:34368962). Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion (PubMed:19717567)","subcellular_location":"Cell membrane; Cell junction, desmosome; Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q02413/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DSG1","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":"CDK4","stoichiometry":0.2},{"gene":"PMVK","stoichiometry":0.2},{"gene":"SSB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DSG1","total_profiled":1310},"omim":[{"mim_id":"620507","title":"ICHTHYOSIS WITH ERYTHROKERATODERMA; IEKD","url":"https://www.omim.org/entry/620507"},{"mim_id":"618084","title":"PEELING SKIN SYNDROME 6; PSS6","url":"https://www.omim.org/entry/618084"},{"mim_id":"615508","title":"ERYTHRODERMA, CONGENITAL, WITH PALMOPLANTAR KERATODERMA, HYPOTRICHOSIS, AND HYPER-IgE; EPKHE","url":"https://www.omim.org/entry/615508"},{"mim_id":"607892","title":"DESMOGLEIN 4; DSG4","url":"https://www.omim.org/entry/607892"},{"mim_id":"605010","title":"SERINE PROTEASE INHIBITOR, KAZAL-TYPE, 5; SPINK5","url":"https://www.omim.org/entry/605010"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"skin 1","ntpm":533.0}],"url":"https://www.proteinatlas.org/search/DSG1"},"hgnc":{"alias_symbol":["CDHF4"],"prev_symbol":["DSG"]},"alphafold":{"accession":"Q02413","domains":[{"cath_id":"2.60.40.60","chopping":"8-149","consensus_level":"medium","plddt":80.5887,"start":8,"end":149},{"cath_id":"2.60.40.60","chopping":"157-261","consensus_level":"high","plddt":95.7133,"start":157,"end":261},{"cath_id":"2.60.40.60","chopping":"270-378","consensus_level":"high","plddt":95.2514,"start":270,"end":378},{"cath_id":"2.60.40.60","chopping":"384-484","consensus_level":"high","plddt":89.5249,"start":384,"end":484},{"cath_id":"-","chopping":"836-845_857-958","consensus_level":"medium","plddt":45.7926,"start":836,"end":958}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02413","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q02413-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q02413-F1-predicted_aligned_error_v6.png","plddt_mean":62.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DSG1","jax_strain_url":"https://www.jax.org/strain/search?query=DSG1"},"sequence":{"accession":"Q02413","fasta_url":"https://rest.uniprot.org/uniprotkb/Q02413.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q02413/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02413"}},"corpus_meta":[{"pmid":"15797387","id":"PMC_15797387","title":"The F box protein Dsg1/Mdm30 is a transcriptional coactivator that stimulates Gal4 turnover and cotranscriptional mRNA processing.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/15797387","citation_count":144,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8188687","id":"PMC_8188687","title":"Interactions of the cytoplasmic domain of the desmosomal cadherin Dsg1 with plakoglobin.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8188687","citation_count":113,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1889810","id":"PMC_1889810","title":"Chromosomal assignment of the human genes coding for the major proteins of the desmosome junction, desmoglein DGI (DSG), desmocollins DGII/III (DSC), desmoplakins DPI/II (DSP), and plakoglobin DPIII (JUP).","date":"1991","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/1889810","citation_count":73,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7706774","id":"PMC_7706774","title":"A case of pemphigus vulgaris showing reactivity with pemphigus antigens (Dsg1 and Dsg3) and desmocollins.","date":"1995","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/7706774","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2544552","id":"PMC_2544552","title":"dsg, a gene required for cell-cell interaction early in Myxococcus development.","date":"1989","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/2544552","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1612610","id":"PMC_1612610","title":"The human gene (DSG2) coding for HDGC, a second member of the desmoglein subfamily of the desmosomal cadherins, is, like DSG1 coding for desmoglein DGI, assigned to chromosome 18.","date":"1992","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/1612610","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7959727","id":"PMC_7959727","title":"Mouse desmocollin (Dsc3) and desmoglein (Dsg1) genes are closely linked in the proximal region of chromosome 18.","date":"1994","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/7959727","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31178865","id":"PMC_31178865","title":"Role of Dsg1- and Dsg3-Mediated Signaling in Pemphigus Autoantibody-Induced Loss of Keratinocyte Cohesion.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31178865","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16820949","id":"PMC_16820949","title":"UV radiation down-regulates Dsg-2 via Rac/NADPH oxidase-mediated generation of ROS in human lens epithelial cells.","date":"2006","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16820949","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8113184","id":"PMC_8113184","title":"The dsg gene of Myxococcus xanthus encodes a protein similar to translation initiation factor IF3.","date":"1994","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/8113184","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8294446","id":"PMC_8294446","title":"Structure of DSG1, the bovine desmosomal cadherin gene encoding the pemphigus foliaceus antigen. 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cadherins, suggesting a common mechanism for plakoglobin association with desmosomes and adherens junctions.\",\n      \"method\": \"Blot overlay binding assays using deletion series of Dsg1 cytoplasmic domain expressed as fusion proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro binding assay with deletion mutagenesis mapping a defined 19-aa interaction domain\",\n      \"pmids\": [\"8188687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The bovine DSG1 gene consists of 15 exons distributed over >37.5 kb of genomic DNA, with striking conservation of exon boundaries with classical cadherin genes in the ectodomain-encoding region; polymorphism was identified in a membrane-proximal extracellular region topologically equivalent to an adhesion-disrupting antibody epitope domain in classical cadherins.\",\n      \"method\": \"Gene structure determination by restriction mapping, sequencing, and comparative genomic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 structural/genomic characterization, single study, informative for domain architecture but limited functional validation\",\n      \"pmids\": [\"8294446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PF-IgG autoantibodies targeting Dsg1 cause loss of keratinocyte cohesion via Ca2+ influx independently of EGFR signaling, whereas PV-IgG targeting Dsg3 activates EGFR in a Src-dependent manner and triggers ERK activation through Src; CRISPR/Cas9 knockout of Dsg3 (but not Dsg2) protected cells against PV-IgG-induced loss of adhesion, establishing that Dsg3 mediates the PV-IgG signaling pathway.\",\n      \"method\": \"CRISPR/Cas9 knockout cell lines, pharmacological inhibition (EGFR inhibitor, Src inhibitor, Ca2+ chelation), immunofluorescence, and adhesion assays in HaCaT keratinocytes\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype plus multiple orthogonal pharmacological approaches\",\n      \"pmids\": [\"31178865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Super-resolution microscopy of human epidermis revealed an increasing Dsg1/Dsg3 ratio from basal to granular layer; within basal layer desmosomes Dsg1 and Dsg3 are co-distributed, while superficial desmosomes predominantly contain one or the other; extradesmosomal Dsg1 co-localizes with plakoglobin in all epidermal layers, whereas Dsg3-plakoglobin co-localization is mostly in the basal layer.\",\n      \"method\": \"Super-resolution microscopy (STED/STORM) with co-localization analysis in human skin sections\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional context (desmosome composition and pemphigus pathogenesis), single study\",\n      \"pmids\": [\"35711465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The recombinant extracellular domain of canine Dsg1 produced by baculovirus expression shares major epitopes with authentic canine Dsg1 recognized by human pemphigus foliaceus (PF) sera; preincubation with recombinant Dsg1 completely removed immunoreactivity of PF sera against canine keratinocyte cell surfaces, demonstrating that PF autoantibodies target the extracellular domain of Dsg1.\",\n      \"method\": \"Baculovirus expression, antibody absorption assays, immunofluorescence on canine keratinocytes\",\n      \"journal\": \"Veterinary immunology and immunopathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reconstituted recombinant protein with functional antibody-blocking assay, single study\",\n      \"pmids\": [\"12963278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A deep-intronic DSG1 variant (c.1688-30A>T) creates an alternative splice site leading to nonsense-mediated mRNA decay of the aberrant transcript, establishing the molecular mechanism by which this intronic mutation causes SAM syndrome through DSG1 loss of function.\",\n      \"method\": \"Mini-gene splicing assay in vitro, RNA isolation, cDNA sequencing, next-generation sequencing\",\n      \"journal\": \"European journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro functional splicing assay with mechanistic characterization, single study\",\n      \"pmids\": [\"33818390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FLAG-tagged Dsg1-beta localizes to cell-cell borders in epithelial HaCaT cells and is recognized by the anti-Dsg1/Dsg2 antibody DG3.10, consistent with its function as a desmosomal cadherin.\",\n      \"method\": \"Transient transfection of FLAG-tagged expression construct in HaCaT cells with immunofluorescence localization\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single localization experiment without functional consequence\",\n      \"pmids\": [\"12631242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SOCE dysfunction (Stim1/2 cKO in mouse epidermis) leads to reduced Dsg1 levels and elevated Kallikrein-related peptidase (Klk6 and Klk7) activities, resulting in impaired epidermal barrier function (increased transepidermal water loss), placing Dsg1 downstream of Ca2+ signaling and upstream of protease-regulated barrier integrity.\",\n      \"method\": \"Conditional Stim1/2 knockout mouse model, RNA-seq, transepidermal water loss measurement, protease activity assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with defined molecular phenotype and multiple readouts, preprint only\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Ephrin-A3 (EFNA3) promotes vaginal DSG1 expression in a biphasic dose-dependent manner and partially reverses loss of vaginal epithelial barrier function induced by progestin treatment, identifying EFNA3 as an upstream regulator of Dsg1 expression and desmosomal function in vaginal epithelium.\",\n      \"method\": \"Topical recombinant EFNA3 administration in DMPA-treated mice, DSG1 expression analysis, transepithelial barrier function assays, viral infection morbidity/mortality\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — in vivo pharmacological treatment with gene expression readout, preprint, indirect pathway placement\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a human skin organ culture model, anti-Dsg1/Dsg3 autoantibody binding alone does not induce transcriptome or proteome changes in keratinocytes; rather, split formation (cell detachment) triggers sustained upregulation of IFNγ- and TNFα-related genes via NFκB, MAPK, and JAK-STAT pathways, indicating that downstream signaling responses are secondary to mechanical disruption rather than direct Dsg1 antibody ligation.\",\n      \"method\": \"Human skin organ culture, 2D cell culture, transcriptomics (RNA-seq), proteomics, single-chain variable fragment targeting DSG1/3 (PX43), time-course analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal transcriptomic and proteomic methods with appropriate antibody controls in skin organ culture, preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DSG1 (desmoglein 1) is a transmembrane desmosomal cadherin that mediates keratinocyte cell-cell adhesion through its extracellular domain (the target of pemphigus foliaceus autoantibodies) and anchors to the desmosomal plaque via a cytoplasmic 19-amino acid sequence that directly binds plakoglobin (homologous to the catenin-binding domain of classical cadherins); its expression is regulated downstream of Ca2+ signaling (via STIM/ORAI-dependent SOCE and ephrin-A3), and its loss—whether through haploinsufficiency, biallelic mutation, or autoantibody-mediated disruption—impairs epidermal barrier integrity and triggers secondary inflammatory signaling cascades through NFκB, MAPK, and JAK-STAT pathways as a consequence of keratinocyte detachment.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"DSG1 (desmosomal glycoprotein DGI) was identified as a member of the cadherin family of Ca2+-dependent cell adhesion molecules, with a unique cytoplasmic domain containing ~29-amino acid repeats predicted to form antiparallel beta-sheet structures and a glycine-rich sequence, and with the cell adhesion recognition sequence His-Ala-Val modified to Arg-Ala-Leu compared to classical cadherins.\",\n      \"method\": \"cDNA cloning, sequence analysis, homology comparison\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — foundational molecular characterization, widely replicated, >187 citations\",\n      \"pmids\": [\"1711210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Plakoglobin binds to a specific 19-amino acid sequence within the cytoplasmic domain of DSG1, a region sharing significant similarity to the catenin-binding domain of classical cadherins, suggesting a common mechanism for plakoglobin association with desmosomes and adherens junctions.\",\n      \"method\": \"Blot overlay assays using deletion series of DSG1 cytoplasmic domain expressed as fusion proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — direct binding mapped by deletion mutagenesis and overlay assay, >113 citations\",\n      \"pmids\": [\"8188687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The bovine DSG1 gene spans >37.5 kb and consists of 15 exons, with striking conservation of exon boundaries with classical cadherin genes in the ectodomain-encoding regions. A polymorphic sequence was identified proximal to the external face of the plasma membrane, topologically equivalent to an adhesion-disrupting antibody epitope domain in classical cadherins.\",\n      \"method\": \"Genomic cloning, restriction mapping, sequencing, exon-intron boundary determination\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — structural gene characterization, single study\",\n      \"pmids\": [\"8294446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"In overlay assays, plakophilin 1 (PP1) binds to DSG1 (as well as desmoplakin and Dsc1a), and plakoglobin (PG) binds to DSG1 more strongly than to Dsc1a or desmoplakin, supporting a model in which DP and PG anchor to desmosomal cadherins and to each other to form an ordered plaque that links to keratin intermediate filaments.\",\n      \"method\": \"In vitro overlay assays, deletion and site-directed mutagenesis of desmosomal components\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro overlay with mutagenesis, widely replicated, >228 citations\",\n      \"pmids\": [\"9606214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A splice-site mutation in intron 2 of DSG1 removes exon 3 (encoding part of the prosequence, the mature protein cleavage site, and part of the first extracellular domain including the N-terminal beta-strands and part of the first Ca2+-binding site), demonstrating that the N-terminal ectodomain of DSG1, required for strand dimer formation, is essential for DSG1 function in epidermal integrity.\",\n      \"method\": \"Genetic linkage, mutation analysis, splicing characterization in striate palmoplantar keratoderma family\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function mutation with defined molecular and phenotypic consequence, >178 citations\",\n      \"pmids\": [\"10332028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Plakophilin 2 directly interacts with DSG1 (and DSG2), as demonstrated by co-immunoprecipitation and yeast two-hybrid assays; the head domain of plakophilin 2 is critical for this interaction and sufficient to direct plakophilin 2 to cell borders.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid assay, transfection of deletion constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP and yeast two-hybrid with domain mapping, >198 citations\",\n      \"pmids\": [\"11790773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The serine protease KLK5 (SCTE) directly degrades DSG1 at acidic pH, while KLK7 (SCCE) alone is unable to degrade DSG1 but KLK5 can activate the pro-form of KLK7. KLK5 degradation of DSG1 is a key step in desquamation (corneodesmosome dissolution at the epidermal surface).\",\n      \"method\": \"In vitro protease activity assays using recombinant enzymes and epidermal/recombinant substrates at acidic pH\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted biochemical assay, >367 citations\",\n      \"pmids\": [\"15140227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In Netherton syndrome (SPINK5/LEKTI deficiency), hyperactivity of KLK5-like and KLK7-like proteases leads to premature degradation of DSG1 in the upper living epidermis, causally linking protease-mediated DSG1 cleavage to corneodesmosome dissolution and disease severity.\",\n      \"method\": \"Immunostaining of patient biopsies, protease activity assays, correlation with LEKTI expression\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-patient human genetic disease study with protease activity assays, >150 citations\",\n      \"pmids\": [\"16628198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DSG1 promotes keratinocyte differentiation and suprabasal morphogenesis by suppressing EGFR-ERK1/2 signaling. DSG1 lacking N-terminal ectodomain residues required for adhesion still promotes differentiation. This function is independent of plakoglobin cytodomain interactions and does not require co-expression of Dsc1, but requires suppression of EGFR-Erk1/2 signaling.\",\n      \"method\": \"RNAi knockdown, overexpression of adhesion-defective DSG1 mutants, western blotting for EGFR/ERK activation, organotypic culture, keratinocyte differentiation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function + structure-function mutants + defined signaling pathway, >185 citations\",\n      \"pmids\": [\"19546243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Homozygous loss-of-function mutations in DSG1 cause SAM syndrome (severe dermatitis, multiple allergies, metabolic wasting). DSG1 deficiency results in absence of membrane expression of DSG1, loss of cell-cell adhesion, and increased expression of allergy-related cytokine genes, demonstrating that a primary structural epidermal barrier defect can drive allergic disease.\",\n      \"method\": \"Human genetics (homozygous mutation identification), immunofluorescence for DSG1 membrane expression, transcriptomic analysis of cytokine gene expression in patient skin\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human loss-of-function genetics with molecular phenotyping, >272 citations\",\n      \"pmids\": [\"23974871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DSG1 knockdown in esophageal epithelial cells weakens barrier integrity, causes cell separation, and induces transcriptional changes overlapping with EoE inflamed mucosa, including strong induction of periostin (POSTN). IL-13 downregulates DSG1 to cause impaired barrier function in EoE.\",\n      \"method\": \"siRNA knockdown, TEER measurements, transwell permeability assays, transcriptomic analysis, IL-13 treatment\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined cellular phenotype and transcriptomic readout, >248 citations\",\n      \"pmids\": [\"24220297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PF-IgG (anti-DSG1 autoantibodies) causes loss of keratinocyte cohesion via Ca2+ influx (independent of EGFR), whereas PV-IgG (anti-DSG3) activates EGFR in a Src-dependent manner and causes ERK activation. Using CRISPR/Cas9-generated Dsg3-deficient (but not Dsg2-deficient) HaCaT cells, Ca2+ influx and ERK activation in response to PF-IgG (anti-DSG1) are preserved, indicating that DSG1 signaling is not dependent on Dsg3 or Dsg2.\",\n      \"method\": \"CRISPR/Cas9 knockout of Dsg2/Dsg3, Ca2+ imaging, EGFR/ERK western blotting, cell dissociation assays, EGFR and Src inhibitors\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with orthogonal signaling readouts\",\n      \"pmids\": [\"31178865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Super-resolution microscopy revealed that the Dsg1/Dsg3 ratio increases from basal to granular epidermal layers, and that extradesmosomal DSG1 co-localizes with plakoglobin in all epidermal layers (while Dsg3-plakoglobin co-localization is basal-restricted). In pemphigus patient skin, extradesmosomal DSG1-plakoglobin co-localization is significantly reduced, and desmosome number is decreased in basal and spinous layers.\",\n      \"method\": \"Super-resolution microscopy (STED/STORM), co-localization analysis with desmoplakin as desmosome marker, patient skin biopsies\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional disease context, single study\",\n      \"pmids\": [\"35711465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In mice with keratinocyte-specific Stim1/Stim2 knockout (impaired store-operated Ca2+ entry), DSG1 levels are altered and Kallikrein-related peptidases KLK6 and KLK7 are elevated, leading to increased serine protease activity and impaired epidermal barrier function (increased TEWL), placing DSG1 downstream of calcium signaling via KLK-mediated proteolysis.\",\n      \"method\": \"Conditional knockout mouse model, TEWL measurement, RNA-seq, protease activity assays, biotin diffusion assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with multi-modal phenotyping, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.10.14.681588\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Topical administration of recombinant ephrin-A3 (EFNA3) promotes vaginal DSG1 expression in a biphasic dose-dependent manner and partially reverses loss of vaginal epithelial barrier function induced by progestin (DMPA) treatment, identifying EFNA3 as a regulator of DSG1-dependent desmosomal function in vaginal epithelium.\",\n      \"method\": \"Mouse in vivo model (DMPA treatment + recombinant EFNA3 administration), gene expression analysis, barrier function assays, HSV-2 infection model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — in vivo pharmacological study, preprint, indirect evidence for DSG1 regulation\",\n      \"pmids\": [\"bio_10.1101_2024.10.29.620915\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a human skin organ culture model, split formation (but not anti-DSG1/DSG3 autoantibody binding alone) triggers sustained upregulation of IFNγ- and TNFα-related genes via NFκB, MAPK, and JAK-STAT pathways. These transcriptomic and proteomic changes correlate with keratinocyte detachment and are inversely associated with differentiation, suggesting that DSG1/DSG3-targeting autoantibodies cause downstream signaling changes only secondary to mechanical loss of adhesion.\",\n      \"method\": \"Human skin organ culture, 2D keratinocyte culture, transcriptomics, proteomics, single-chain antibody (PX43) targeting DSG1/3, AK23 (anti-DSG3), endemic PF anti-DSG1 IgG treatment\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics approach with orthogonal models, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.02.10.637416\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DSG1 is a desmosomal cadherin that functions as a Ca2+-dependent cell-cell adhesion molecule in stratified epithelia; it interacts via a conserved cytoplasmic motif with plakoglobin and plakophilin 2 to anchor keratin intermediate filaments through desmoplakin, and its extracellular domain is proteolytically processed by KLK5 (and secondarily KLK7) to regulate desquamation; beyond adhesion, DSG1 actively suppresses EGFR-ERK1/2 signaling to promote keratinocyte terminal differentiation, and its loss—whether by autoantibody-mediated disruption, haploinsufficiency, or biallelic mutation—impairs epidermal barrier function and drives pro-inflammatory cytokine expression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DSG1 (desmoglein 1) is a desmosomal cadherin that mediates calcium-dependent keratinocyte cell–cell adhesion in stratified epithelia, with its expression increasing from basal to superficial epidermal layers where it is the predominant desmoglein [PMID:35711465]. Its cytoplasmic domain binds plakoglobin through a conserved 19-amino acid sequence homologous to the catenin-binding domain of classical cadherins, coupling the adhesive ectodomain to the desmosomal plaque [PMID:8188687]. The extracellular domain is the principal autoantigen in pemphigus foliaceus, where autoantibody binding causes loss of keratinocyte cohesion via calcium influx independently of EGFR signaling [PMID:12963278, PMID:31178865]. Loss-of-function mutations in DSG1, including deep-intronic variants that trigger nonsense-mediated mRNA decay, cause SAM (severe dermatitis, multiple allergies, metabolic wasting) syndrome [PMID:33818390].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Identification of the minimal plakoglobin-binding determinant in the DSG1 cytoplasmic tail revealed that desmosomes and adherens junctions share a conserved catenin-recruitment mechanism, answering how desmosomal cadherins anchor to the intracellular plaque.\",\n      \"evidence\": \"Blot overlay binding assays with deletion-mapped Dsg1 fusion proteins\",\n      \"pmids\": [\"8188687\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and affinity of the Dsg1–plakoglobin interaction were not determined\",\n        \"Contribution of regions outside the 19-aa segment to plaque assembly not assessed\",\n        \"No structural model of the Dsg1–plakoglobin complex\"\n      ]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Determination of the DSG1 gene structure showed conserved exon boundaries with classical cadherins in the ectodomain region and revealed polymorphism in a membrane-proximal extracellular domain equivalent to an adhesion-regulatory epitope, establishing the evolutionary relationship between desmosomal and classical cadherins.\",\n      \"evidence\": \"Restriction mapping, sequencing, and comparative genomic analysis of bovine DSG1\",\n      \"pmids\": [\"8294446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional significance of the polymorphic region for adhesion was not tested\",\n        \"Gene regulation and promoter elements were not characterized\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstration that recombinant Dsg1 ectodomain fully absorbs pemphigus foliaceus autoantibody reactivity established the extracellular domain as the sole autoantibody target, resolving which molecular surface is attacked in PF.\",\n      \"evidence\": \"Baculovirus-expressed recombinant canine Dsg1 ectodomain, antibody absorption, immunofluorescence on canine keratinocytes\",\n      \"pmids\": [\"12963278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Epitope fine-mapping within the ectodomain was not performed\",\n        \"Pathogenic versus non-pathogenic antibody subsets were not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Dissection of pemphigus signaling showed that PF-IgG targeting Dsg1 triggers loss of cohesion through Ca²⁺ influx independent of EGFR/Src, distinguishing the Dsg1-mediated pathogenic pathway from the Dsg3/EGFR/Src-dependent pathway in pemphigus vulgaris.\",\n      \"evidence\": \"CRISPR/Cas9 knockout lines, pharmacological inhibitors, and adhesion assays in HaCaT keratinocytes\",\n      \"pmids\": [\"31178865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the calcium channel mediating PF-IgG-induced Ca²⁺ influx was not determined\",\n        \"Downstream Ca²⁺ effectors that execute loss of cohesion remain uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A deep-intronic DSG1 variant was shown to create an aberrant splice site causing nonsense-mediated mRNA decay, establishing a molecular mechanism for DSG1 loss-of-function in SAM syndrome and linking haploinsufficiency to disease.\",\n      \"evidence\": \"Mini-gene splicing assay, cDNA sequencing, and next-generation sequencing in a SAM syndrome patient\",\n      \"pmids\": [\"33818390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether residual Dsg1 protein is produced from the mutant allele was not quantified\",\n        \"Genotype–phenotype correlation across different DSG1 mutation types not systematically compared\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Super-resolution imaging of human epidermis quantified the increasing Dsg1/Dsg3 ratio from basal to superficial layers and showed extradesmosomal Dsg1–plakoglobin co-localization throughout all layers, providing the spatial framework for understanding differential autoantibody-mediated split levels in pemphigus.\",\n      \"evidence\": \"STED/STORM super-resolution microscopy with co-localization analysis on human skin sections\",\n      \"pmids\": [\"35711465\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional role of extradesmosomal Dsg1–plakoglobin complexes is unknown\",\n        \"Dynamic turnover rates of desmosomal versus extradesmosomal Dsg1 were not measured\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In vivo disruption of STIM/ORAI-dependent store-operated Ca²⁺ entry reduced Dsg1 levels and elevated kallikrein protease activity, placing Dsg1 downstream of SOCE signaling and upstream of protease-regulated barrier integrity. Separately, transcriptomic analysis of pemphigus models showed that inflammatory signaling (NFκB, MAPK, JAK-STAT) is triggered by mechanical cell detachment rather than by direct Dsg1 autoantibody ligation.\",\n      \"evidence\": \"Conditional Stim1/2 KO mouse epidermis with RNA-seq and barrier assays (preprint); human skin organ culture with scFv anti-Dsg1/3, RNA-seq, and proteomics (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Both studies are preprints awaiting peer review\",\n        \"Transcriptional mechanism linking SOCE to DSG1 expression is not defined\",\n        \"Whether mechanical detachment-triggered signaling feeds back to alter Dsg1 expression or processing is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for Dsg1 homophilic and heterophilic trans-interactions, the identity of the Ca²⁺-permeable channel mediating PF-IgG-induced signaling, and the function of extradesmosomal Dsg1–plakoglobin complexes remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of Dsg1 ectodomain or its homophilic interface\",\n        \"Mechanism by which Dsg1 loss activates kallikrein-mediated barrier disruption is incompletely resolved\",\n        \"Whether Dsg1 has signaling functions independent of adhesion loss is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"complexes\": [\n      \"desmosome\"\n    ],\n    \"partners\": [\n      \"JUP\",\n      \"DSG3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"DSG1 is a desmosomal cadherin that mediates Ca²⁺-dependent cell–cell adhesion in stratified epithelia and coordinates epidermal differentiation and barrier homeostasis. Its cytoplasmic domain binds plakoglobin via a conserved 19-amino-acid motif and interacts with plakophilin 1 and plakophilin 2, anchoring keratin intermediate filaments through desmoplakin to form the desmosomal plaque [PMID:8188687, PMID:9606214, PMID:11790773]. Beyond adhesion, DSG1 suppresses EGFR–ERK1/2 signaling through a mechanism independent of its adhesive ectodomain to promote keratinocyte terminal differentiation, and its ectodomain is proteolytically cleaved by KLK5 at acidic pH to drive corneodesmosome dissolution during desquamation [PMID:19546243, PMID:15140227]. Biallelic loss-of-function mutations in DSG1 cause SAM syndrome (severe dermatitis, multiple allergies, metabolic wasting), linking primary desmosomal disruption to barrier failure and pro-inflammatory cytokine induction [PMID:23974871].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing DSG1 as a cadherin family member resolved how desmosomal glycoprotein DGI relates to classical Ca²⁺-dependent adhesion molecules and identified its unique cytoplasmic repeat architecture.\",\n      \"evidence\": \"cDNA cloning with sequence homology analysis\",\n      \"pmids\": [\"1711210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Binding partners of the unique cytoplasmic repeats were unknown\",\n        \"Functional significance of the Arg-Ala-Leu substitution in the adhesion recognition sequence was untested\"\n      ]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Mapping the plakoglobin-binding site to a 19-residue cytoplasmic motif homologous to the catenin-binding domain of classical cadherins established how DSG1 connects to the desmosomal plaque via a conserved mechanism.\",\n      \"evidence\": \"Blot overlay assays with systematic deletion series of DSG1 cytoplasmic domain fusion proteins\",\n      \"pmids\": [\"8188687\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and affinity of plakoglobin–DSG1 interaction in intact cells were not determined\",\n        \"Role of additional cytoplasmic partners beyond plakoglobin remained open\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrating that plakophilin 1 and plakoglobin both bind DSG1 and desmoplakin established the ordered molecular hierarchy of the desmosomal plaque linking cadherins to intermediate filaments.\",\n      \"evidence\": \"In vitro overlay assays with deletion and site-directed mutagenesis of desmosomal components\",\n      \"pmids\": [\"9606214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo validation of the plaque assembly order was lacking\",\n        \"Contribution of individual interactions to adhesive strength was unknown\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identifying a DSG1 splice-site mutation in striate palmoplantar keratoderma proved that the N-terminal ectodomain — required for trans-dimerization and Ca²⁺ binding — is essential for epidermal integrity in humans.\",\n      \"evidence\": \"Genetic linkage and mutation analysis in a keratoderma family with splicing characterization\",\n      \"pmids\": [\"10332028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether haploinsufficiency alone fully explained the keratoderma or whether dominant-negative effects contributed was unclear\",\n        \"Structural basis of DSG1 trans-dimerization awaited atomic-resolution data\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showing that plakophilin 2 directly binds DSG1 via its head domain expanded the set of cytoplasmic partners bridging desmosomal cadherins to the plaque and identified PKP2 as a second plakophilin interactor.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation and yeast two-hybrid assay with domain-mapping constructs\",\n      \"pmids\": [\"11790773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contributions of PKP1 versus PKP2 to DSG1-dependent adhesion in different tissues were not resolved\",\n        \"Whether PKP2 and plakoglobin binding to DSG1 is competitive or cooperative was undetermined\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Reconstituting KLK5-mediated DSG1 degradation at acidic pH identified the protease responsible for corneodesmosome dissolution during desquamation and clarified that KLK7 requires KLK5-dependent activation.\",\n      \"evidence\": \"In vitro protease activity assays with recombinant KLK5 and KLK7 on epidermal and recombinant DSG1 substrates\",\n      \"pmids\": [\"15140227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Exact KLK5 cleavage sites on DSG1 were not mapped\",\n        \"In vivo regulation of KLK5 activity at the desmosome surface was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating premature DSG1 degradation by hyperactive KLK5/KLK7 in Netherton syndrome skin established a direct pathological link between dysregulated protease activity and corneodesmosome failure in human disease.\",\n      \"evidence\": \"Immunostaining of patient biopsies correlated with protease activity assays and LEKTI expression\",\n      \"pmids\": [\"16628198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether therapeutic protease inhibition could rescue DSG1 levels and barrier function was untested\",\n        \"Relative contribution of DSG1 degradation versus other corneodesmosomal target cleavage was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealing that DSG1 suppresses EGFR–ERK1/2 signaling to promote differentiation — independently of its adhesive ectodomain and plakoglobin binding — uncovered a signaling function separable from its structural adhesion role.\",\n      \"evidence\": \"RNAi knockdown, adhesion-defective DSG1 mutant overexpression, EGFR/ERK western blotting, and organotypic keratinocyte cultures\",\n      \"pmids\": [\"19546243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The molecular intermediary connecting DSG1 cytoplasmic domain to EGFR suppression was not identified\",\n        \"Whether this signaling function operates in non-epidermal epithelia was unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that biallelic DSG1 loss-of-function mutations cause SAM syndrome — with absent membrane DSG1, adhesion failure, and upregulation of allergy-related cytokines — established DSG1 as essential for human epidermal barrier integrity and immune homeostasis.\",\n      \"evidence\": \"Homozygous mutation identification in affected families, immunofluorescence, and transcriptomic analysis of patient skin\",\n      \"pmids\": [\"23974871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which DSG1 loss activates pro-inflammatory cytokine transcription was not delineated\",\n        \"Whether residual desmosomal adhesion via DSG3 partially compensates in SAM was not tested\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing that DSG1 knockdown in esophageal epithelium weakens barrier integrity and induces an EoE-like transcriptional program (including periostin) connected DSG1 to mucosal immune disease beyond skin.\",\n      \"evidence\": \"siRNA knockdown with TEER, permeability assays, transcriptomics, and IL-13 treatment in esophageal epithelial cells\",\n      \"pmids\": [\"24220297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether DSG1 loss is a primary driver or secondary consequence in EoE pathogenesis was unresolved\",\n        \"Direct transcriptional regulators of DSG1 downstream of IL-13 were not identified\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Using CRISPR knockout of Dsg2/Dsg3, anti-DSG1 autoantibodies were shown to cause loss of cohesion via Ca²⁺ influx independent of EGFR and of other desmogleins, delineating a DSG1-specific pathogenic signaling axis in pemphigus foliaceus.\",\n      \"evidence\": \"CRISPR/Cas9-generated Dsg2- and Dsg3-deficient HaCaT cells with Ca²⁺ imaging, EGFR/ERK blotting, and dissociation assays\",\n      \"pmids\": [\"31178865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Source and mechanism of Ca²⁺ influx triggered by anti-DSG1 antibodies were not identified\",\n        \"Whether Ca²⁺ influx is necessary or sufficient for loss of cohesion was not formally tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Super-resolution imaging revealed that extradesmosomal DSG1–plakoglobin complexes exist across all epidermal layers and are disrupted in pemphigus skin, suggesting a non-desmosomal DSG1 pool contributes to disease pathogenesis.\",\n      \"evidence\": \"STED/STORM microscopy with co-localization analysis using desmoplakin as a desmosome marker in normal and pemphigus patient skin\",\n      \"pmids\": [\"35711465\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional role of the extradesmosomal DSG1–plakoglobin pool was not experimentally tested\",\n        \"Whether extradesmosomal DSG1 mediates the EGFR-suppressive signaling function is unknown\",\n        \"Single study awaiting independent replication\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism by which the DSG1 cytoplasmic domain suppresses EGFR–ERK signaling remains unidentified, and the functional significance of extradesmosomal DSG1 pools and the precise KLK5 cleavage sites on DSG1 are unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No direct intermediary linking DSG1 to EGFR suppression has been identified\",\n        \"Atomic-resolution structure of DSG1 ectodomain trans-dimer is lacking\",\n        \"In vivo requirement for specific DSG1 cytoplasmic motifs in differentiation versus adhesion has not been genetically dissected\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 4, 9, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 9, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 1, 3, 4, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"complexes\": [\n      \"Desmosome\"\n    ],\n    \"partners\": [\n      \"JUP\",\n      \"PKP1\",\n      \"PKP2\",\n      \"DSP\",\n      \"DSC1\",\n      \"KLK5\",\n      \"KLK7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}