{"gene":"DSC1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1993,"finding":"Human desmocollin 1 (DSC1/CDHF1) cDNA was cloned and shown to encode a cadherin-related glycoprotein expressed in more differentiated (suprabasal) layers of human epidermis, sharing 53% amino acid identity with DSC3 (type 3 desmocollin expressed in basal layers), with more highly conserved N- and C-termini. The DSC1 gene was mapped to chromosome 18 using somatic cell hybrid panels.","method":"cDNA cloning, sequence analysis, somatic cell hybrid panel mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular cloning and chromosomal mapping, single lab, two orthogonal methods (sequencing + somatic cell hybrids)","pmids":["8288219"],"is_preprint":false},{"year":1996,"finding":"Mouse desmocollin 1 (Dsc1) protein is first expressed in the outermost epithelial cells destined to form keratinized layers (stratum corneum or filiform papillae), with Dsc1 transcript upregulation coinciding with the onset of keratinization during embryonic development; Dsc1 and Dsg1 expression were not tightly coupled, with Dsg1 appearing earlier and in more tissues than Dsc1.","method":"In situ hybridization, immunostaining with cross-reactive monoclonal antibodies during mouse embryonic development","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in situ hybridization and immunostaining showing spatiotemporal localization linked to differentiation state, single lab, two orthogonal methods","pmids":["8823356"],"is_preprint":false},{"year":1997,"finding":"Human DSC1 is the autoantigen for the subcorneal pustular dermatosis (SPD) type of IgA pemphigus: IgA autoantibodies from all six SPD-type IgA pemphigus patients reacted with the surface of COS7 cells transiently expressing human DSC1, but not DSC2 or DSC3, demonstrating that pathogenic IgA antibodies target conformation-dependent epitopes on DSC1.","method":"Transient transfection of COS7 cells with human DSC1/DSC2/DSC3 expression constructs, immunofluorescence with patient IgA sera","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-surface immunofluorescence with isoform specificity confirmed across six SPD patients and seven IEN patients (negative controls), replicated across multiple patient samples in single rigorous study","pmids":["9242496"],"is_preprint":false},{"year":2000,"finding":"The DSC1 gene comprises 17 exons spanning approximately 33 kb on chromosome 18q12.1, defining its complete intron-exon organization and enabling comprehensive mutation screening.","method":"Genomic characterization, PCR-based exon amplification and sequencing","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (genomic PCR/sequencing); structural genomic finding with no direct functional consequence demonstrated","pmids":["11027496"],"is_preprint":false},{"year":2025,"finding":"METTL3 methyltransferase mediates m6A modification of DSC1 mRNA in human periodontal ligament fibroblasts (HPLF), positively regulating DSC1 mRNA stability and expression level; DSC1 overexpression alleviated LPS-induced apoptosis and inflammation in HPLF cells, and silencing METTL3 reversed the protective effect of DSC1 upregulation.","method":"m6A RNA immunoprecipitation (MeRIP), quantitative RT-PCR, CCK-8/EdU proliferation assays, flow cytometry (apoptosis), ELISA (inflammation), siRNA knockdown/overexpression","journal":"International dental journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP directly demonstrates m6A modification, combined with functional rescue experiments; single lab, multiple orthogonal methods","pmids":["41453286"],"is_preprint":false},{"year":2024,"finding":"Ephrin-A3 (EFNA3) regulates DSC1 (desmocollin-1) gene expression in vaginal epithelium: topical administration of recombinant EFNA3 promoted vaginal DSC1 expression in a biphasic dose-dependent manner and partially reversed the loss of vaginal epithelial barrier function induced by progestin (DMPA) treatment in mice.","method":"Mouse model with DMPA treatment, topical recombinant EFNA3 administration, measurement of DSC1 expression and epithelial barrier function","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, indirect evidence that EFNA3 regulates DSC1 expression without direct mechanistic dissection of the pathway","pmids":[],"is_preprint":true}],"current_model":"DSC1 (desmocollin 1) is a desmosomal cadherin expressed in suprabasal/differentiating keratinocytes where it contributes to cell-cell adhesion and epidermal barrier function; its extracellular domain presents conformation-dependent epitopes that are targeted by pathogenic IgA autoantibodies in subcorneal pustular dermatosis-type IgA pemphigus, its mRNA stability is post-transcriptionally regulated by METTL3-mediated m6A modification, and its expression in vaginal epithelium is regulated upstream by ephrin-A3 signaling."},"narrative":{"mechanistic_narrative":"DSC1 (desmocollin 1) is a cadherin-related glycoprotein that mediates cell-cell adhesion in the differentiating, suprabasal layers of stratified epithelia, where its expression is tightly coupled to the keratinization program [PMID:8288219, PMID:8823356]. The protein is selectively expressed in the outermost epithelial cells destined to form keratinized layers, with transcript upregulation coinciding with the onset of keratinization during development, distinguishing it from basal-layer desmocollins [PMID:8288219, PMID:8823356]. The extracellular domain of DSC1 presents conformation-dependent epitopes that serve as the autoantigen in the subcorneal pustular dermatosis (SPD) type of IgA pemphigus: pathogenic patient IgA autoantibodies bind the surface of cells expressing DSC1 but not DSC2 or DSC3, establishing isoform-specific autoimmune targeting [PMID:9242496]. DSC1 expression is controlled post-transcriptionally by METTL3-mediated m6A modification, which stabilizes DSC1 mRNA, and DSC1 contributes to epithelial barrier function and limits LPS-induced apoptosis and inflammation [PMID:41453286]. Beyond these findings, the structural basis of DSC1 adhesion and its detailed signaling partners have not been characterized in the available corpus.","teleology":[{"year":1993,"claim":"Establishing DSC1 as a distinct cadherin-family desmocollin expressed in differentiated epidermal layers defined its molecular identity and tissue-specific expression niche.","evidence":"cDNA cloning, sequence analysis, and somatic cell hybrid chromosomal mapping of human DSC1","pmids":["8288219"],"confidence":"Medium","gaps":["No direct demonstration of adhesive function from the cloned protein","Relationship of sequence conservation to binding specificity not tested"]},{"year":1996,"claim":"Linking Dsc1 expression to the onset of keratinization established that its appearance marks terminal epithelial differentiation rather than general epithelial identity.","evidence":"In situ hybridization and immunostaining across mouse embryonic development","pmids":["8823356"],"confidence":"Medium","gaps":["Functional consequence of Dsc1 expression for keratinization not tested by loss-of-function","Mechanism uncoupling Dsc1 from Dsg1 expression unknown"]},{"year":1997,"claim":"Identifying DSC1 as the isoform-specific autoantigen in SPD-type IgA pemphigus established a direct disease link and showed that pathogenic antibodies target conformation-dependent surface epitopes.","evidence":"Transient expression of DSC1/DSC2/DSC3 in COS7 cells with patient IgA serum immunofluorescence across six SPD and seven control patients","pmids":["9242496"],"confidence":"High","gaps":["Specific epitopes on the DSC1 extracellular domain not mapped","Whether antibody binding mechanistically disrupts adhesion not demonstrated"]},{"year":2000,"claim":"Defining the complete 17-exon intron-exon organization of DSC1 enabled comprehensive mutation screening but did not establish functional consequences.","evidence":"Genomic PCR-based exon amplification and sequencing","pmids":["11027496"],"confidence":"Low","gaps":["Structural genomic finding with no direct functional consequence demonstrated","No disease-causing mutations identified in this study"]},{"year":2024,"claim":"Placing DSC1 downstream of ephrin-A3 signaling connected its expression to maintenance of vaginal epithelial barrier function.","evidence":"Mouse DMPA model with topical recombinant EFNA3 administration measuring DSC1 expression and barrier function (preprint)","pmids":[],"confidence":"Low","gaps":["Preprint with indirect evidence and no mechanistic dissection of the EFNA3-DSC1 pathway","Biphasic dose response not mechanistically explained","Direct regulatory link between EFNA3 and the DSC1 promoter not established"]},{"year":2025,"claim":"Demonstrating METTL3-dependent m6A modification of DSC1 mRNA established a post-transcriptional control point governing DSC1 abundance and a protective role against inflammatory apoptosis.","evidence":"MeRIP, RT-PCR, proliferation/apoptosis assays and METTL3/DSC1 knockdown-rescue in human periodontal ligament fibroblasts","pmids":["41453286"],"confidence":"Medium","gaps":["m6A reader mediating DSC1 mRNA stabilization not identified","Mechanism by which DSC1 suppresses LPS-induced inflammation not defined","Generalizability beyond periodontal ligament fibroblasts untested"]},{"year":null,"claim":"The structural basis of DSC1-mediated adhesion and the downstream signaling consequences of DSC1 engagement remain undefined.","evidence":"No direct evidence in the available corpus","pmids":[],"confidence":"Low","gaps":["No structural model of DSC1 adhesive interactions","Direct binding partners within the desmosome not characterized in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]}],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q08554","full_name":"Desmocollin-1","aliases":["Cadherin family member 1","Desmosomal glycoprotein 2/3","DG2/DG3"],"length_aa":894,"mass_kda":100.0,"function":"A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion (By similarity). Required for desmosome adhesion strength between the granular layers of the epidermis, as a result moderates epidermal proliferation and differentiation (By similarity). Is therefore required to maintain postnatal epidermal barrier function and normal hair follicle morphology into adulthood (By similarity)","subcellular_location":"Cell membrane; Cell junction, desmosome","url":"https://www.uniprot.org/uniprotkb/Q08554/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DSC1","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":"PMVK","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DSC1","total_profiled":1310},"omim":[{"mim_id":"618084","title":"PEELING SKIN SYNDROME 6; PSS6","url":"https://www.omim.org/entry/618084"},{"mim_id":"602918","title":"PHENYLALANINE-tRNA SYNTHETASE, ALPHA SUBUNIT; FARSA","url":"https://www.omim.org/entry/602918"},{"mim_id":"600271","title":"DESMOCOLLIN 3; DSC3","url":"https://www.omim.org/entry/600271"},{"mim_id":"314250","title":"DYSTONIA 3, TORSION, X-LINKED; DYT3","url":"https://www.omim.org/entry/314250"},{"mim_id":"148700","title":"PALMOPLANTAR KERATODERMA I, STRIATE, FOCAL, OR DIFFUSE; PPKS1","url":"https://www.omim.org/entry/148700"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"skin 1","ntpm":216.0}],"url":"https://www.proteinatlas.org/search/DSC1"},"hgnc":{"alias_symbol":["CDHF1"],"prev_symbol":[]},"alphafold":{"accession":"Q08554","domains":[{"cath_id":"2.60.40.60","chopping":"34-114","consensus_level":"high","plddt":83.3732,"start":34,"end":114},{"cath_id":"2.60.40.60","chopping":"142-234","consensus_level":"medium","plddt":93.3505,"start":142,"end":234},{"cath_id":"2.60.40.60","chopping":"242-346","consensus_level":"medium","plddt":95.6521,"start":242,"end":346},{"cath_id":"2.60.40.60","chopping":"355-445_453-462","consensus_level":"high","plddt":93.954,"start":355,"end":462},{"cath_id":"2.60.40.60","chopping":"476-569","consensus_level":"high","plddt":90.3665,"start":476,"end":569},{"cath_id":"2.60.40.60","chopping":"581-666","consensus_level":"high","plddt":88.6845,"start":581,"end":666}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08554","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q08554-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q08554-F1-predicted_aligned_error_v6.png","plddt_mean":76.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DSC1","jax_strain_url":"https://www.jax.org/strain/search?query=DSC1"},"sequence":{"accession":"Q08554","fasta_url":"https://rest.uniprot.org/uniprotkb/Q08554.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q08554/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08554"}},"corpus_meta":[{"pmid":"9242496","id":"PMC_9242496","title":"Human desmocollin 1 (Dsc1) is an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus.","date":"1997","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/9242496","citation_count":163,"is_preprint":false},{"pmid":"8521825","id":"PMC_8521825","title":"A yeast transcription factor bypassing the requirement for SBF and DSC1/MBF in budding yeast has homology to bacterial signal transduction proteins.","date":"1995","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8521825","citation_count":92,"is_preprint":false},{"pmid":"33637694","id":"PMC_33637694","title":"CircRAB11FIP1 promoted autophagy flux of ovarian cancer through DSC1 and miR-129.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33637694","citation_count":73,"is_preprint":false},{"pmid":"8288219","id":"PMC_8288219","title":"Cloning of the cDNA (DSC1) coding for human type 1 desmocollin and its assignment to chromosome 18.","date":"1993","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8288219","citation_count":49,"is_preprint":false},{"pmid":"12196396","id":"PMC_12196396","title":"The DSC1 channel, encoded by the smi60E locus, contributes to odor-guided behavior in Drosophila melanogaster.","date":"2002","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12196396","citation_count":45,"is_preprint":false},{"pmid":"8823356","id":"PMC_8823356","title":"Expression of the \"skin-type\" desmosomal cadherin DSC1 is closely linked to the keratinization of epithelial tissues during mouse development.","date":"1996","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/8823356","citation_count":36,"is_preprint":false},{"pmid":"21571069","id":"PMC_21571069","title":"Molecular characterization and functional expression of the DSC1 channel.","date":"2011","source":"Insect biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21571069","citation_count":31,"is_preprint":false},{"pmid":"12871901","id":"PMC_12871901","title":"The Schizosaccharomyces pombe cdt2(+) gene, a target of G1-S phase-specific transcription factor complex DSC1, is required for mitotic and premeiotic DNA replication.","date":"2003","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12871901","citation_count":24,"is_preprint":false},{"pmid":"23505382","id":"PMC_23505382","title":"Role of the DSC1 channel in regulating neuronal excitability in Drosophila melanogaster: extending nervous system stability under stress.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23505382","citation_count":24,"is_preprint":false},{"pmid":"25687544","id":"PMC_25687544","title":"Distinct roles of the DmNav and DSC1 channels in the action of DDT and pyrethroids.","date":"2015","source":"Neurotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/25687544","citation_count":18,"is_preprint":false},{"pmid":"11795845","id":"PMC_11795845","title":"The role of DSC1 components cdc10+, rep1+ and rep2+ in MCB gene transcription at the mitotic G1-S boundary in fission yeast.","date":"2001","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11795845","citation_count":18,"is_preprint":false},{"pmid":"14648198","id":"PMC_14648198","title":"DSC1-MCB regulation of meiotic transcription in Schizosaccharomyces pombe.","date":"2003","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/14648198","citation_count":17,"is_preprint":false},{"pmid":"22321571","id":"PMC_22321571","title":"Molecular characterization of DSC1 orthologs in invertebrate species.","date":"2012","source":"Insect biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22321571","citation_count":17,"is_preprint":false},{"pmid":"12488978","id":"PMC_12488978","title":"DSC1 channels are expressed in both the central and the peripheral nervous system of adult Drosophila melanogaster.","date":"2001","source":"Invertebrate neuroscience : IN","url":"https://pubmed.ncbi.nlm.nih.gov/12488978","citation_count":17,"is_preprint":false},{"pmid":"27432995","id":"PMC_27432995","title":"Biophysical characterization of the honeybee DSC1 orthologue reveals a novel voltage-dependent Ca2+ channel subfamily: CaV4.","date":"2016","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27432995","citation_count":16,"is_preprint":false},{"pmid":"25987218","id":"PMC_25987218","title":"The Drosophila Sodium Channel 1 (DSC1): The founding member of a new family of voltage-gated cation channels.","date":"2014","source":"Pesticide biochemistry and physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25987218","citation_count":11,"is_preprint":false},{"pmid":"9617815","id":"PMC_9617815","title":"Phenotypic analysis and molecular cloning of discolored-1 (dsc1), a maize gene required for early kernel development.","date":"1998","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9617815","citation_count":11,"is_preprint":false},{"pmid":"8367276","id":"PMC_8367276","title":"Domains of p85cdc10 required for function of the fission yeast DSC-1 factor.","date":"1993","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/8367276","citation_count":11,"is_preprint":false},{"pmid":"22666226","id":"PMC_22666226","title":"Discolored1 (DSC1) is an ADP-Ribosylation Factor-GTPase Activating Protein Required to Maintain Differentiation of Maize Kernel Structures.","date":"2012","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/22666226","citation_count":9,"is_preprint":false},{"pmid":"29891372","id":"PMC_29891372","title":"DSC1 channel-dependent developmental regulation of pyrethroid susceptibility in Drosophila melanogaster.","date":"2018","source":"Pesticide biochemistry and physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29891372","citation_count":8,"is_preprint":false},{"pmid":"11027496","id":"PMC_11027496","title":"Genomic organization and amplification of the human desmosomal cadherin genes DSC1 and DSC3, encoding desmocollin types 1 and 3.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11027496","citation_count":8,"is_preprint":false},{"pmid":"17014956","id":"PMC_17014956","title":"Association of DSC1, a gene modulated by adrenergic stimulation, with Alzheimer's disease.","date":"2006","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/17014956","citation_count":6,"is_preprint":false},{"pmid":"24155671","id":"PMC_24155671","title":"Molecular characterization and alternative splicing of a sodium channel and DSC1 ortholog genes in Liposcelis bostrychophila Badonnel (Psocoptera: Liposcelididae).","date":"2013","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24155671","citation_count":4,"is_preprint":false},{"pmid":"16460890","id":"PMC_16460890","title":"Transcription of the Schizosaccharomyces pombe gene cdc18+: roles of MCB elements and the DSC1 complex.","date":"2006","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/16460890","citation_count":0,"is_preprint":false},{"pmid":"41453286","id":"PMC_41453286","title":"METTL3-Mediated m6A Modification of DSC1 Alleviates Inflammation and Cellular Dysfunction in Periodontitis.","date":"2025","source":"International dental journal","url":"https://pubmed.ncbi.nlm.nih.gov/41453286","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.06.686738","title":"Tear fluid as noninvasive liquid biopsy reveals proteins associated with malignant transformation of oral lesions","date":"2025-11-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.06.686738","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.29.620915","title":"Exogenous ephrin-A3 administration restores vaginal epithelial barrier function in progestin-treated mice","date":"2024-11-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.29.620915","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.09.607388","title":"Lipidomic and Proteomic Insights from Extracellular Vesicles in Postmortem Dorsolateral Prefrontal Cortex Reveal Substance Use Disorder-Induced Brain Changes","date":"2024-08-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.09.607388","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15036,"output_tokens":1997,"usd":0.037532,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8401,"output_tokens":2171,"usd":0.04814,"stage2_stop_reason":"end_turn"},"total_usd":0.085672,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"I need to carefully classify each paper before extracting discoveries about DSC1 (human desmocollin 1, HGNC alias CDHF1).\n\n**Classification:**\n- Papers 1, 4, 6, 21, 22, 25, 26, 27, 28: About human DSC1 (desmocollin 1) — INCLUDE\n- Papers 2, 11, 12, 18, 24: About S. pombe/S. cerevisiae DSC1/MBF transcription factor complex — SYMBOL COLLISION (different protein, yeast cell cycle transcription factor) — EXCLUDE\n- Papers 5, 7, 9, 10, 13, 14, 15, 16, 20: About Drosophila DSC1 (sodium/cation channel) — SYMBOL COLLISION (invertebrate ion channel, not desmosomal cadherin) — EXCLUDE\n- Paper 3: About circRAB11FIP1/miR-129; DSC1 mentioned peripherally as circRNA binding partner — this is a non-protein locus product study — EXCLUDE\n- Papers 8: S. pombe cdt2+ regulated by DSC1 transcription complex — SYMBOL COLLISION — EXCLUDE\n- Paper 17, 19: Maize dsc1 gene — SYMBOL COLLISION (plant ARF-GAP) — EXCLUDE\n- Paper 23: Insect DSC1 ortholog (ion channel) — SYMBOL COLLISION — EXCLUDE\n\nNow extracting from included papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"Human desmocollin 1 (DSC1/CDHF1) cDNA was cloned and shown to encode a cadherin-related glycoprotein expressed in more differentiated (suprabasal) layers of human epidermis, sharing 53% amino acid identity with DSC3 (type 3 desmocollin expressed in basal layers), with more highly conserved N- and C-termini. The DSC1 gene was mapped to chromosome 18 using somatic cell hybrid panels.\",\n      \"method\": \"cDNA cloning, sequence analysis, somatic cell hybrid panel mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular cloning and chromosomal mapping, single lab, two orthogonal methods (sequencing + somatic cell hybrids)\",\n      \"pmids\": [\"8288219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Mouse desmocollin 1 (Dsc1) protein is first expressed in the outermost epithelial cells destined to form keratinized layers (stratum corneum or filiform papillae), with Dsc1 transcript upregulation coinciding with the onset of keratinization during embryonic development; Dsc1 and Dsg1 expression were not tightly coupled, with Dsg1 appearing earlier and in more tissues than Dsc1.\",\n      \"method\": \"In situ hybridization, immunostaining with cross-reactive monoclonal antibodies during mouse embryonic development\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in situ hybridization and immunostaining showing spatiotemporal localization linked to differentiation state, single lab, two orthogonal methods\",\n      \"pmids\": [\"8823356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Human DSC1 is the autoantigen for the subcorneal pustular dermatosis (SPD) type of IgA pemphigus: IgA autoantibodies from all six SPD-type IgA pemphigus patients reacted with the surface of COS7 cells transiently expressing human DSC1, but not DSC2 or DSC3, demonstrating that pathogenic IgA antibodies target conformation-dependent epitopes on DSC1.\",\n      \"method\": \"Transient transfection of COS7 cells with human DSC1/DSC2/DSC3 expression constructs, immunofluorescence with patient IgA sera\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-surface immunofluorescence with isoform specificity confirmed across six SPD patients and seven IEN patients (negative controls), replicated across multiple patient samples in single rigorous study\",\n      \"pmids\": [\"9242496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The DSC1 gene comprises 17 exons spanning approximately 33 kb on chromosome 18q12.1, defining its complete intron-exon organization and enabling comprehensive mutation screening.\",\n      \"method\": \"Genomic characterization, PCR-based exon amplification and sequencing\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (genomic PCR/sequencing); structural genomic finding with no direct functional consequence demonstrated\",\n      \"pmids\": [\"11027496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3 methyltransferase mediates m6A modification of DSC1 mRNA in human periodontal ligament fibroblasts (HPLF), positively regulating DSC1 mRNA stability and expression level; DSC1 overexpression alleviated LPS-induced apoptosis and inflammation in HPLF cells, and silencing METTL3 reversed the protective effect of DSC1 upregulation.\",\n      \"method\": \"m6A RNA immunoprecipitation (MeRIP), quantitative RT-PCR, CCK-8/EdU proliferation assays, flow cytometry (apoptosis), ELISA (inflammation), siRNA knockdown/overexpression\",\n      \"journal\": \"International dental journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP directly demonstrates m6A modification, combined with functional rescue experiments; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41453286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Ephrin-A3 (EFNA3) regulates DSC1 (desmocollin-1) gene expression in vaginal epithelium: topical administration of recombinant EFNA3 promoted vaginal DSC1 expression in a biphasic dose-dependent manner and partially reversed the loss of vaginal epithelial barrier function induced by progestin (DMPA) treatment in mice.\",\n      \"method\": \"Mouse model with DMPA treatment, topical recombinant EFNA3 administration, measurement of DSC1 expression and epithelial barrier function\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, indirect evidence that EFNA3 regulates DSC1 expression without direct mechanistic dissection of the pathway\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DSC1 (desmocollin 1) is a desmosomal cadherin expressed in suprabasal/differentiating keratinocytes where it contributes to cell-cell adhesion and epidermal barrier function; its extracellular domain presents conformation-dependent epitopes that are targeted by pathogenic IgA autoantibodies in subcorneal pustular dermatosis-type IgA pemphigus, its mRNA stability is post-transcriptionally regulated by METTL3-mediated m6A modification, and its expression in vaginal epithelium is regulated upstream by ephrin-A3 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DSC1 (desmocollin 1) is a cadherin-related glycoprotein that mediates cell-cell adhesion in the differentiating, suprabasal layers of stratified epithelia, where its expression is tightly coupled to the keratinization program [#0, #1]. The protein is selectively expressed in the outermost epithelial cells destined to form keratinized layers, with transcript upregulation coinciding with the onset of keratinization during development, distinguishing it from basal-layer desmocollins [#0, #1]. The extracellular domain of DSC1 presents conformation-dependent epitopes that serve as the autoantigen in the subcorneal pustular dermatosis (SPD) type of IgA pemphigus: pathogenic patient IgA autoantibodies bind the surface of cells expressing DSC1 but not DSC2 or DSC3, establishing isoform-specific autoimmune targeting [#2]. DSC1 expression is controlled post-transcriptionally by METTL3-mediated m6A modification, which stabilizes DSC1 mRNA, and DSC1 contributes to epithelial barrier function and limits LPS-induced apoptosis and inflammation [#4]. Beyond these findings, the structural basis of DSC1 adhesion and its detailed signaling partners have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing DSC1 as a distinct cadherin-family desmocollin expressed in differentiated epidermal layers defined its molecular identity and tissue-specific expression niche.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and somatic cell hybrid chromosomal mapping of human DSC1\",\n      \"pmids\": [\"8288219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct demonstration of adhesive function from the cloned protein\",\n        \"Relationship of sequence conservation to binding specificity not tested\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Linking Dsc1 expression to the onset of keratinization established that its appearance marks terminal epithelial differentiation rather than general epithelial identity.\",\n      \"evidence\": \"In situ hybridization and immunostaining across mouse embryonic development\",\n      \"pmids\": [\"8823356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of Dsc1 expression for keratinization not tested by loss-of-function\",\n        \"Mechanism uncoupling Dsc1 from Dsg1 expression unknown\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identifying DSC1 as the isoform-specific autoantigen in SPD-type IgA pemphigus established a direct disease link and showed that pathogenic antibodies target conformation-dependent surface epitopes.\",\n      \"evidence\": \"Transient expression of DSC1/DSC2/DSC3 in COS7 cells with patient IgA serum immunofluorescence across six SPD and seven control patients\",\n      \"pmids\": [\"9242496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific epitopes on the DSC1 extracellular domain not mapped\",\n        \"Whether antibody binding mechanistically disrupts adhesion not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defining the complete 17-exon intron-exon organization of DSC1 enabled comprehensive mutation screening but did not establish functional consequences.\",\n      \"evidence\": \"Genomic PCR-based exon amplification and sequencing\",\n      \"pmids\": [\"11027496\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Structural genomic finding with no direct functional consequence demonstrated\",\n        \"No disease-causing mutations identified in this study\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placing DSC1 downstream of ephrin-A3 signaling connected its expression to maintenance of vaginal epithelial barrier function.\",\n      \"evidence\": \"Mouse DMPA model with topical recombinant EFNA3 administration measuring DSC1 expression and barrier function (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Preprint with indirect evidence and no mechanistic dissection of the EFNA3-DSC1 pathway\",\n        \"Biphasic dose response not mechanistically explained\",\n        \"Direct regulatory link between EFNA3 and the DSC1 promoter not established\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating METTL3-dependent m6A modification of DSC1 mRNA established a post-transcriptional control point governing DSC1 abundance and a protective role against inflammatory apoptosis.\",\n      \"evidence\": \"MeRIP, RT-PCR, proliferation/apoptosis assays and METTL3/DSC1 knockdown-rescue in human periodontal ligament fibroblasts\",\n      \"pmids\": [\"41453286\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"m6A reader mediating DSC1 mRNA stabilization not identified\",\n        \"Mechanism by which DSC1 suppresses LPS-induced inflammation not defined\",\n        \"Generalizability beyond periodontal ligament fibroblasts untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of DSC1-mediated adhesion and the downstream signaling consequences of DSC1 engagement remain undefined.\",\n      \"evidence\": \"No direct evidence in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of DSC1 adhesive interactions\",\n        \"Direct binding partners within the desmosome not characterized in the corpus\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}