{"gene":"DSG1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1994,"finding":"A 19-amino acid sequence within the cytoplasmic domain of DSG1 is required for association with plakoglobin, and this region shows 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 binding assay with deletion series of DSG1 cytoplasmic domain expressed as fusion proteins","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro binding assay with deletion mapping, single lab, single method","pmids":["8188687"],"is_preprint":false},{"year":1994,"finding":"The DSG1 gene consists of 15 exons distributed over >37.5 kb of genomic DNA, with striking conservation of exon boundaries in regions encoding the ectodomain compared to classical cadherin genes, and polymorphism was identified in a region proximal to the external face of the plasma membrane topologically equivalent to an adhesion-disrupting epitope domain of classical cadherins.","method":"Genomic cloning, restriction mapping, sequencing, and exon structure determination of bovine DSG1 gene","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structural genomic analysis with functional implications, single lab, multiple methods (cloning, sequencing, comparative analysis)","pmids":["8294446"],"is_preprint":false},{"year":2019,"finding":"DSG1 (desmoglein 1) mediates Ca2+ influx independently of EGFR in response to pemphigus foliaceus IgG (PF-IgG), and EGFR inhibition does not block PF-IgG-induced loss of keratinocyte cohesion, in contrast to PV-IgG which requires Src-dependent EGFR activation.","method":"CRISPR/Cas9 knockout of Dsg3 and Dsg2 in HaCaT keratinocytes, Ca2+ chelation, EGFR inhibition, pharmacological signaling pathway dissection","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with functional adhesion readout and multiple pharmacological interventions, single lab","pmids":["31178865"],"is_preprint":false},{"year":2022,"finding":"DSG1 and DSG3 have distinct distributions within desmosomes across epidermal layers: an increasing DSG1/DSG3 ratio from basal to granular layer was observed; extradesmosomal DSG1 co-localizes with plakoglobin in all epidermal layers, and in pemphigus patient skin this extradesmosomal DSG1-plakoglobin co-localization is significantly reduced, supporting a role for DSG1 in desmosome assembly beyond structural adhesion.","method":"Super-resolution microscopy (STORM/STED) with co-localization analysis of DSG1, DSG3, desmoplakin, and plakoglobin in healthy and pemphigus patient skin","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence inference, single lab, super-resolution imaging","pmids":["35711465"],"is_preprint":false},{"year":2003,"finding":"FLAG-tagged Dsg1-beta (mouse desmoglein 1 paralog) localizes to the cell-cell border when transiently expressed in HaCaT epithelial cells, consistent with desmosomal localization.","method":"Transient expression of FLAG-tagged construct in HaCaT cells with immunofluorescence","journal":"Experimental dermatology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization experiment without functional consequence, single lab, single method; note this is mouse Dsg1-beta, a paralog","pmids":["12631242"],"is_preprint":false},{"year":2021,"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, demonstrating that intronic DSG1 mutations can cause loss-of-function through aberrant splicing.","method":"Mini-gene exon-trap assay, next-generation sequencing, RNA isolation and cDNA synthesis","journal":"European journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mini-gene functional splicing assay with mechanistic validation, single lab","pmids":["33818390"],"is_preprint":false},{"year":2026,"finding":"Loss-of-function DSG1 variants in the extracellular or transmembrane domains result in total absence of DSG1 protein at the cell surface (as shown by immunofluorescence staining), abolishing intercellular connecting and anchoring capability, whereas intracellular domain variants partially preserve adhesive function.","method":"Immunofluorescence staining of DSG1 protein expression in skin of SAM syndrome patients with characterized variants","journal":"Journal of dermatological science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein localization in patient skin tissue with domain-function correlation, single lab, multiple patients","pmids":["41781296"],"is_preprint":false},{"year":2025,"finding":"In STIM1/2 conditional knockout mouse epidermis, DSG1 levels are altered alongside elevated Kallikrein-related peptidases (Klk6 and Klk7), with increased serine protease activities correlating with compromised epidermal barrier function, suggesting that Ca2+ signaling via SOCE regulates DSG1 through Klk-mediated proteolysis.","method":"Epithelial tissue-specific Stim1/2 knockout mice, RNA-seq, transepidermal water loss measurement, protease activity assays, biotinylated tracer diffusion assay","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect evidence for DSG1 regulation (not direct mechanistic study of DSG1 itself), single preprint, correlative","pmids":[],"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 DMPA-induced loss of vaginal epithelial barrier function, identifying EFNA3 as an upstream regulator of DSG1 expression in vaginal epithelium.","method":"Recombinant EFNA3 topical administration in DMPA-treated mice, DSG1 expression measurement, transepidermal/transmucosal barrier function assay, HSV-2 infection model","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — DSG1 regulation shown indirectly through expression changes, preprint, single lab, no direct mechanistic dissection of DSG1","pmids":[],"is_preprint":true},{"year":2025,"finding":"In a human skin organ culture pemphigus model, cell detachment/split formation (but not autoantibody binding to DSG1/DSG3 alone) induces sustained upregulation of IFNγ and TNFα-related genes via NFκB, MAPK, and JAK-STAT pathways, indicating DSG1-targeted autoantibodies do not directly trigger downstream transcriptomic or proteomic changes without physical disruption of adhesion.","method":"Human skin organ culture (HSOC) with anti-DSG1/3 single-chain antibody fragment (PX43), transcriptome and proteome quantification, comparison with 2D cell culture models","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, mechanistic conclusion about DSG1 signaling is negative (no direct downstream signaling from antibody binding alone), single lab","pmids":[],"is_preprint":true}],"current_model":"DSG1 (desmoglein 1) is a desmosomal transmembrane cadherin that mediates cell-cell adhesion in suprabasal epidermis by engaging plakoglobin through a conserved 19-amino acid cytoplasmic sequence homologous to the catenin-binding domain of classical cadherins; its extracellular domain is the target of pathogenic autoantibodies in pemphigus foliaceus, which disrupt adhesion through Ca2+-dependent signaling distinct from the EGFR/Src pathway triggered by anti-DSG3 antibodies; DSG1 is distributed in an increasing gradient from basal to granular epidermal layers and associates extradesomally with plakoglobin, with loss-of-function variants in the extracellular/transmembrane domains abolishing intercellular adhesion while intracellular domain variants partially preserve function."},"narrative":{"mechanistic_narrative":"DSG1 (desmoglein 1) is a desmosomal cadherin that mediates calcium-dependent intercellular adhesion in stratified epithelia, organized in an increasing basal-to-granular gradient across epidermal layers [PMID:35711465]. Its cytoplasmic domain engages plakoglobin through a 19-amino acid sequence homologous to the catenin-binding domain of classical cadherins, providing a shared molecular basis for plakoglobin recruitment to desmosomes and adherens junctions [PMID:8188687]. Beyond structural adhesion, an extradesmosomal pool of DSG1 co-localizes with plakoglobin throughout the epidermis, and this association is lost in pemphigus patient skin, implicating DSG1 in desmosome assembly [PMID:35711465]. DSG1 is the target of pemphigus foliaceus autoantibodies, which drive EGFR-independent Ca2+ influx and loss of keratinocyte cohesion, distinct from the Src/EGFR-dependent mechanism of anti-DSG3 pemphigus vulgaris antibodies [PMID:31178865]. Domain-resolved patient analyses establish a structure-function map: loss-of-function variants in the extracellular or transmembrane domains abolish surface DSG1 and intercellular adhesion, whereas intracellular-domain variants partially preserve adhesive function [PMID:41781296], and intronic variants can cause loss of function via aberrant splicing and nonsense-mediated decay [PMID:33818390].","teleology":[{"year":1994,"claim":"Established how DSG1 connects to the cytoskeletal/junctional plaque by mapping the cytoplasmic determinant for plakoglobin binding, unifying desmosomal and adherens-junction adhesion mechanisms.","evidence":"Blot overlay binding assay with a deletion series of the DSG1 cytoplasmic domain as fusion proteins","pmids":["8188687"],"confidence":"Medium","gaps":["In vitro binding only; affinity and stoichiometry in intact desmosomes not defined","Does not address how this binding is regulated in vivo"]},{"year":1994,"claim":"Defined the genomic architecture of DSG1 and showed conservation of ectodomain exon boundaries with classical cadherins, localizing a polymorphic region to a topological position equivalent to an adhesion-disrupting cadherin epitope.","evidence":"Genomic cloning, restriction mapping, and comparative exon-structure analysis of the bovine DSG1 gene","pmids":["8294446"],"confidence":"Medium","gaps":["Functional consequence of the identified polymorphism not tested","Bovine gene; human exon structure inferred by homology"]},{"year":2019,"claim":"Distinguished DSG1-directed from DSG3-directed pemphigus signaling by showing PF-IgG drives EGFR-independent Ca2+ influx, separating the two autoantibody mechanisms.","evidence":"CRISPR/Cas9 Dsg3/Dsg2 knockout HaCaT keratinocytes with Ca2+ chelation, EGFR inhibition, and adhesion readouts","pmids":["31178865"],"confidence":"Medium","gaps":["Identity of the Ca2+ channel and downstream effectors not resolved","Single keratinocyte line; not validated in patient tissue"]},{"year":2022,"claim":"Revealed that DSG1 has an extradesmosomal, plakoglobin-associated pool and a layer-specific distribution gradient that is disrupted in pemphigus, supporting a role in desmosome assembly beyond adhesion.","evidence":"Super-resolution STORM/STED co-localization of DSG1, DSG3, desmoplakin, and plakoglobin in healthy and pemphigus skin","pmids":["35711465"],"confidence":"Medium","gaps":["Functional role of the extradesmosomal pool in assembly not directly tested","Co-localization does not establish direct binding in situ"]},{"year":2021,"claim":"Demonstrated that non-coding DSG1 variants can cause loss of function, expanding the mutational mechanisms beyond coding changes.","evidence":"Mini-gene exon-trap splicing assay with NGS and cDNA analysis of a deep-intronic variant","pmids":["33818390"],"confidence":"Medium","gaps":["Quantitative impact on residual protein not measured","Single variant; generality across introns unknown"]},{"year":2026,"claim":"Provided a domain-resolved structure-function map linking variant location to adhesive outcome: ectodomain/transmembrane loss abolishes surface DSG1 while intracellular variants retain partial function.","evidence":"Immunofluorescence of DSG1 in skin of SAM syndrome patients with characterized variants","pmids":["41781296"],"confidence":"Medium","gaps":["Mechanism of residual function for intracellular variants not dissected","Adhesion quantified indirectly via staining, not biophysical assay"]},{"year":2025,"claim":"Implicated SOCE/Ca2+ signaling in DSG1 regulation by linking STIM1/2 loss to altered DSG1 and elevated kallikrein protease activity with barrier defects.","evidence":"Epithelial Stim1/2 conditional knockout mice, RNA-seq, protease activity and barrier assays (preprint)","pmids":[],"confidence":"Low","gaps":["Correlative; direct Klk-mediated DSG1 proteolysis not demonstrated","Preprint, single lab","DSG1 not the direct subject of mechanistic dissection"]},{"year":2024,"claim":"Identified EFNA3 as an upstream inducer of DSG1 expression supporting epithelial barrier integrity in vaginal epithelium.","evidence":"Topical recombinant EFNA3 in DMPA-treated mice with DSG1 expression and barrier/HSV-2 infection readouts (preprint)","pmids":[],"confidence":"Low","gaps":["Regulatory link inferred from expression changes, not direct mechanism","Preprint, single lab","Pathway connecting EFNA3 to DSG1 unknown"]},{"year":2025,"claim":"Showed that anti-DSG1/3 antibody binding alone does not trigger downstream transcriptomic/proteomic changes; physical adhesion disruption is required to drive inflammatory signaling.","evidence":"Human skin organ culture pemphigus model with anti-DSG1/3 scFv (PX43), transcriptome/proteome profiling (preprint)","pmids":[],"confidence":"Low","gaps":["Negative result; does not exclude rapid pre-detachment signaling","Preprint, single lab","Does not isolate DSG1-specific from DSG3-specific effects"]},{"year":null,"claim":"The molecular events linking DSG1 ectodomain engagement to Ca2+ influx and to desmosome assembly versus disassembly remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No identified Ca2+ channel mediating PF-IgG response","No structural model of the DSG1-plakoglobin interface in situ","Mechanism coupling extradesmosomal DSG1 to assembly unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[3,6]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,4,6]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,6]}],"complexes":["desmosome"],"partners":["JUP"],"other_free_text":[]}},"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 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overlay binding assay with deletion series of DSG1 cytoplasmic domain expressed as fusion proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro binding assay with deletion mapping, single lab, single method\",\n      \"pmids\": [\"8188687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The DSG1 gene consists of 15 exons distributed over >37.5 kb of genomic DNA, with striking conservation of exon boundaries in regions encoding the ectodomain compared to classical cadherin genes, and polymorphism was identified in a region proximal to the external face of the plasma membrane topologically equivalent to an adhesion-disrupting epitope domain of classical cadherins.\",\n      \"method\": \"Genomic cloning, restriction mapping, sequencing, and exon structure determination of bovine DSG1 gene\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structural genomic analysis with functional implications, single lab, multiple methods (cloning, sequencing, comparative analysis)\",\n      \"pmids\": [\"8294446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DSG1 (desmoglein 1) mediates Ca2+ influx independently of EGFR in response to pemphigus foliaceus IgG (PF-IgG), and EGFR inhibition does not block PF-IgG-induced loss of keratinocyte cohesion, in contrast to PV-IgG which requires Src-dependent EGFR activation.\",\n      \"method\": \"CRISPR/Cas9 knockout of Dsg3 and Dsg2 in HaCaT keratinocytes, Ca2+ chelation, EGFR inhibition, pharmacological signaling pathway dissection\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with functional adhesion readout and multiple pharmacological interventions, single lab\",\n      \"pmids\": [\"31178865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DSG1 and DSG3 have distinct distributions within desmosomes across epidermal layers: an increasing DSG1/DSG3 ratio from basal to granular layer was observed; extradesmosomal DSG1 co-localizes with plakoglobin in all epidermal layers, and in pemphigus patient skin this extradesmosomal DSG1-plakoglobin co-localization is significantly reduced, supporting a role for DSG1 in desmosome assembly beyond structural adhesion.\",\n      \"method\": \"Super-resolution microscopy (STORM/STED) with co-localization analysis of DSG1, DSG3, desmoplakin, and plakoglobin in healthy and pemphigus patient skin\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence inference, single lab, super-resolution imaging\",\n      \"pmids\": [\"35711465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FLAG-tagged Dsg1-beta (mouse desmoglein 1 paralog) localizes to the cell-cell border when transiently expressed in HaCaT epithelial cells, consistent with desmosomal localization.\",\n      \"method\": \"Transient expression of FLAG-tagged construct in HaCaT cells with immunofluorescence\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization experiment without functional consequence, single lab, single method; note this is mouse Dsg1-beta, a paralog\",\n      \"pmids\": [\"12631242\"],\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, demonstrating that intronic DSG1 mutations can cause loss-of-function through aberrant splicing.\",\n      \"method\": \"Mini-gene exon-trap assay, next-generation sequencing, RNA isolation and cDNA synthesis\",\n      \"journal\": \"European journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mini-gene functional splicing assay with mechanistic validation, single lab\",\n      \"pmids\": [\"33818390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Loss-of-function DSG1 variants in the extracellular or transmembrane domains result in total absence of DSG1 protein at the cell surface (as shown by immunofluorescence staining), abolishing intercellular connecting and anchoring capability, whereas intracellular domain variants partially preserve adhesive function.\",\n      \"method\": \"Immunofluorescence staining of DSG1 protein expression in skin of SAM syndrome patients with characterized variants\",\n      \"journal\": \"Journal of dermatological science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein localization in patient skin tissue with domain-function correlation, single lab, multiple patients\",\n      \"pmids\": [\"41781296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In STIM1/2 conditional knockout mouse epidermis, DSG1 levels are altered alongside elevated Kallikrein-related peptidases (Klk6 and Klk7), with increased serine protease activities correlating with compromised epidermal barrier function, suggesting that Ca2+ signaling via SOCE regulates DSG1 through Klk-mediated proteolysis.\",\n      \"method\": \"Epithelial tissue-specific Stim1/2 knockout mice, RNA-seq, transepidermal water loss measurement, protease activity assays, biotinylated tracer diffusion assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect evidence for DSG1 regulation (not direct mechanistic study of DSG1 itself), single preprint, correlative\",\n      \"pmids\": [],\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 DMPA-induced loss of vaginal epithelial barrier function, identifying EFNA3 as an upstream regulator of DSG1 expression in vaginal epithelium.\",\n      \"method\": \"Recombinant EFNA3 topical administration in DMPA-treated mice, DSG1 expression measurement, transepidermal/transmucosal barrier function assay, HSV-2 infection model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — DSG1 regulation shown indirectly through expression changes, preprint, single lab, no direct mechanistic dissection of DSG1\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a human skin organ culture pemphigus model, cell detachment/split formation (but not autoantibody binding to DSG1/DSG3 alone) induces sustained upregulation of IFNγ and TNFα-related genes via NFκB, MAPK, and JAK-STAT pathways, indicating DSG1-targeted autoantibodies do not directly trigger downstream transcriptomic or proteomic changes without physical disruption of adhesion.\",\n      \"method\": \"Human skin organ culture (HSOC) with anti-DSG1/3 single-chain antibody fragment (PX43), transcriptome and proteome quantification, comparison with 2D cell culture models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, mechanistic conclusion about DSG1 signaling is negative (no direct downstream signaling from antibody binding alone), single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DSG1 (desmoglein 1) is a desmosomal transmembrane cadherin that mediates cell-cell adhesion in suprabasal epidermis by engaging plakoglobin through a conserved 19-amino acid cytoplasmic sequence homologous to the catenin-binding domain of classical cadherins; its extracellular domain is the target of pathogenic autoantibodies in pemphigus foliaceus, which disrupt adhesion through Ca2+-dependent signaling distinct from the EGFR/Src pathway triggered by anti-DSG3 antibodies; DSG1 is distributed in an increasing gradient from basal to granular epidermal layers and associates extradesomally with plakoglobin, with loss-of-function variants in the extracellular/transmembrane domains abolishing intercellular adhesion while intracellular domain variants partially preserve function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DSG1 (desmoglein 1) is a desmosomal cadherin that mediates calcium-dependent intercellular adhesion in stratified epithelia, organized in an increasing basal-to-granular gradient across epidermal layers [#3]. Its cytoplasmic domain engages plakoglobin through a 19-amino acid sequence homologous to the catenin-binding domain of classical cadherins, providing a shared molecular basis for plakoglobin recruitment to desmosomes and adherens junctions [#0]. Beyond structural adhesion, an extradesmosomal pool of DSG1 co-localizes with plakoglobin throughout the epidermis, and this association is lost in pemphigus patient skin, implicating DSG1 in desmosome assembly [#3]. DSG1 is the target of pemphigus foliaceus autoantibodies, which drive EGFR-independent Ca2+ influx and loss of keratinocyte cohesion, distinct from the Src/EGFR-dependent mechanism of anti-DSG3 pemphigus vulgaris antibodies [#2]. Domain-resolved patient analyses establish a structure-function map: loss-of-function variants in the extracellular or transmembrane domains abolish surface DSG1 and intercellular adhesion, whereas intracellular-domain variants partially preserve adhesive function [#6], and intronic variants can cause loss of function via aberrant splicing and nonsense-mediated decay [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established how DSG1 connects to the cytoskeletal/junctional plaque by mapping the cytoplasmic determinant for plakoglobin binding, unifying desmosomal and adherens-junction adhesion mechanisms.\",\n      \"evidence\": \"Blot overlay binding assay with a deletion series of the DSG1 cytoplasmic domain as fusion proteins\",\n      \"pmids\": [\"8188687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro binding only; affinity and stoichiometry in intact desmosomes not defined\", \"Does not address how this binding is regulated in vivo\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Defined the genomic architecture of DSG1 and showed conservation of ectodomain exon boundaries with classical cadherins, localizing a polymorphic region to a topological position equivalent to an adhesion-disrupting cadherin epitope.\",\n      \"evidence\": \"Genomic cloning, restriction mapping, and comparative exon-structure analysis of the bovine DSG1 gene\",\n      \"pmids\": [\"8294446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the identified polymorphism not tested\", \"Bovine gene; human exon structure inferred by homology\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Distinguished DSG1-directed from DSG3-directed pemphigus signaling by showing PF-IgG drives EGFR-independent Ca2+ influx, separating the two autoantibody mechanisms.\",\n      \"evidence\": \"CRISPR/Cas9 Dsg3/Dsg2 knockout HaCaT keratinocytes with Ca2+ chelation, EGFR inhibition, and adhesion readouts\",\n      \"pmids\": [\"31178865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the Ca2+ channel and downstream effectors not resolved\", \"Single keratinocyte line; not validated in patient tissue\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed that DSG1 has an extradesmosomal, plakoglobin-associated pool and a layer-specific distribution gradient that is disrupted in pemphigus, supporting a role in desmosome assembly beyond adhesion.\",\n      \"evidence\": \"Super-resolution STORM/STED co-localization of DSG1, DSG3, desmoplakin, and plakoglobin in healthy and pemphigus skin\",\n      \"pmids\": [\"35711465\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of the extradesmosomal pool in assembly not directly tested\", \"Co-localization does not establish direct binding in situ\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that non-coding DSG1 variants can cause loss of function, expanding the mutational mechanisms beyond coding changes.\",\n      \"evidence\": \"Mini-gene exon-trap splicing assay with NGS and cDNA analysis of a deep-intronic variant\",\n      \"pmids\": [\"33818390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative impact on residual protein not measured\", \"Single variant; generality across introns unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided a domain-resolved structure-function map linking variant location to adhesive outcome: ectodomain/transmembrane loss abolishes surface DSG1 while intracellular variants retain partial function.\",\n      \"evidence\": \"Immunofluorescence of DSG1 in skin of SAM syndrome patients with characterized variants\",\n      \"pmids\": [\"41781296\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of residual function for intracellular variants not dissected\", \"Adhesion quantified indirectly via staining, not biophysical assay\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated SOCE/Ca2+ signaling in DSG1 regulation by linking STIM1/2 loss to altered DSG1 and elevated kallikrein protease activity with barrier defects.\",\n      \"evidence\": \"Epithelial Stim1/2 conditional knockout mice, RNA-seq, protease activity and barrier assays (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative; direct Klk-mediated DSG1 proteolysis not demonstrated\", \"Preprint, single lab\", \"DSG1 not the direct subject of mechanistic dissection\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified EFNA3 as an upstream inducer of DSG1 expression supporting epithelial barrier integrity in vaginal epithelium.\",\n      \"evidence\": \"Topical recombinant EFNA3 in DMPA-treated mice with DSG1 expression and barrier/HSV-2 infection readouts (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Regulatory link inferred from expression changes, not direct mechanism\", \"Preprint, single lab\", \"Pathway connecting EFNA3 to DSG1 unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that anti-DSG1/3 antibody binding alone does not trigger downstream transcriptomic/proteomic changes; physical adhesion disruption is required to drive inflammatory signaling.\",\n      \"evidence\": \"Human skin organ culture pemphigus model with anti-DSG1/3 scFv (PX43), transcriptome/proteome profiling (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Negative result; does not exclude rapid pre-detachment signaling\", \"Preprint, single lab\", \"Does not isolate DSG1-specific from DSG3-specific effects\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular events linking DSG1 ectodomain engagement to Ca2+ influx and to desmosome assembly versus disassembly remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No identified Ca2+ channel mediating PF-IgG response\", \"No structural model of the DSG1-plakoglobin interface in situ\", \"Mechanism coupling extradesmosomal DSG1 to assembly unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"complexes\": [\"desmosome\"],\n    \"partners\": [\"JUP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}