{"gene":"CDSN","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2003,"finding":"Nonsense mutations in CDSN (encoding corneodesmosin) cause hypotrichosis simplex of the scalp; truncated CDSN aggregates were detected in the superficial dermis and at the periphery of hair follicles, establishing CDSN as a keratinocyte adhesion molecule required for normal scalp hair physiology.","method":"Genetic sequencing of patient families; protein detection (immunohistochemistry/Western) showing truncated aggregates in dermis and hair follicle periphery","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple independent families, protein-level validation of truncation, replicated across labs","pmids":["12754508"],"is_preprint":false},{"year":2011,"finding":"Loss-of-function mutations in CDSN lead to deficiency of corneodesmosin, a major component of desmosomal junctions in the uppermost epidermal layers, impairing cell-cell adhesion in the upper epidermis and triggering an abnormal inflammatory response due to epidermal barrier disruption (peeling skin syndrome type B).","method":"PCR/direct sequencing identifying homozygous frameshift mutation; clinical and histological phenotype characterization (inflammatory peeling)","journal":"Archives of dermatological research","confidence":"Medium","confidence_rationale":"Tier 3 + Strong — multiple independent CDSN loss-of-function papers consistently show same adhesion/barrier phenotype","pmids":["22146835","23957618","24116970","24372652"],"is_preprint":false},{"year":2013,"finding":"A truncated corneodesmosin (p.Gly142*) is stably expressed as a 16-kDa protein in patient epidermis and is non-functional, demonstrating that full-length corneodesmosin is required for its adhesive function; total corneodesmosin loss underlies peeling skin disease.","method":"Western blot and immunohistochemistry of skin biopsies; DNA sequencing; real-time PCR","journal":"The British journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (Western, IHC, sequencing) in single study","pmids":["23957618"],"is_preprint":false},{"year":2014,"finding":"A homozygous missense mutation in CDSN (c.1358G>A) results in structurally shortened and sparse corneodesmosomes as measured by electron microscopy, linking CDSN protein to corneodesmosome structural integrity.","method":"Gene sequencing; electron microscopy with morphometric analysis of corneodesmosomes","journal":"Case reports in dermatology","confidence":"Low","confidence_rationale":"Tier 3 + Weak — single case, single lab, morphometric observation only","pmids":["25473393"],"is_preprint":false},{"year":2025,"finding":"Genetic epistasis experiments (Klk5 knockout crossed into Cdsn knockout mice, and shRNA knockdown in human epidermal equivalents) showed that deletion of the desquamation-initiating serine protease KLK5 aggravates rather than rescues the CDSN-nEDD phenotype, with elevated epidermal proteolysis, severe (corneo)desmosomal ultrastructural alterations, increased barrier permeability, and greater stratum corneum detachment — placing CDSN upstream of fine protease balance in the desquamation cascade.","method":"Genetic epistasis (double-knockout mouse model, shRNA in human epidermal equivalents); electron microscopy; barrier permeability assays","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1-2 — genetic epistasis in two independent models (mouse KO and human tissue equivalent) with multiple functional readouts","pmids":["40943523"],"is_preprint":false},{"year":2024,"finding":"Loss-of-function CDSN mutation (c.295C>T, p.Gln99*) leads to absence of corneodesmosin in skin, overexpression of Th2-related cytokines (IL-4 and IL-13), and JAK1-dependent signaling; JAK1 inhibition (upadacitinib) alleviated symptoms, implicating JAK1-Th2 signaling in CDSN-deficiency pathogenesis.","method":"Whole exome sequencing; immunohistochemistry confirming absent CDSN and elevated IL-4/IL-13; JAK1 inhibitor treatment with clinical outcome","journal":"The Journal of dermatology","confidence":"Low","confidence_rationale":"Tier 3 + Weak — single case, mechanistic inference from IHC and drug response without in vitro reconstitution","pmids":["39377561"],"is_preprint":false}],"current_model":"Corneodesmosin (CDSN) is a glycoprotein component of corneodesmosomes in the upper epidermis and inner root sheath of hair follicles that mediates keratinocyte cell-cell adhesion; loss-of-function mutations cause progressive epidermal barrier disruption, abnormal desquamation, and secondary inflammatory responses (involving Th2 cytokines and JAK1 signaling), while genetic epistasis places CDSN upstream of and in functional balance with the desquamation-initiating serine protease KLK5."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing that CDSN is a disease gene: identification of nonsense mutations in CDSN as the cause of hereditary hypotrichosis simplex of the scalp demonstrated that this corneodesmosomal glycoprotein is required for normal hair follicle adhesion and physiology.","evidence":"Genetic sequencing of multiple affected families with immunohistochemical and Western blot detection of truncated CDSN aggregates in dermis and hair follicle periphery","pmids":["12754508"],"confidence":"High","gaps":["Mechanism by which truncated CDSN aggregates in the dermis rather than being degraded was unknown","Whether CDSN loss also affects interfollicular epidermal adhesion was not tested","Structural basis of CDSN adhesive function remained unresolved"]},{"year":2011,"claim":"Extending CDSN deficiency from hair loss to generalized skin disease: homozygous loss-of-function CDSN mutations were shown to cause peeling skin syndrome type B, establishing that corneodesmosin is essential for cell–cell adhesion across the entire upper epidermis and that its absence triggers inflammatory barrier disruption.","evidence":"PCR and direct sequencing identifying frameshift mutations; clinical, histological, and immunohistochemical phenotyping across multiple independent reports","pmids":["22146835","23957618","24116970","24372652"],"confidence":"Medium","gaps":["The molecular mechanism linking barrier disruption to the inflammatory response was not defined","Whether residual truncated CDSN retains partial function was unclear"]},{"year":2013,"claim":"Resolving whether truncated CDSN is functional: detection of a stable 16-kDa truncated corneodesmosin (p.Gly142*) in patient epidermis demonstrated that partial CDSN expression is insufficient and that full-length protein is required for adhesive function.","evidence":"Western blot and immunohistochemistry of patient skin biopsies combined with DNA sequencing and real-time PCR","pmids":["23957618"],"confidence":"Medium","gaps":["Which specific domains of full-length CDSN mediate adhesion was not mapped","No in vitro reconstitution of CDSN adhesive activity was performed"]},{"year":2014,"claim":"Linking CDSN mutation to corneodesmosome ultrastructure: electron microscopy of a missense CDSN mutant revealed structurally shortened and sparse corneodesmosomes, directly connecting CDSN protein to the structural integrity of these junctions.","evidence":"Electron microscopy with morphometric analysis in a single patient with homozygous CDSN missense mutation","pmids":["25473393"],"confidence":"Low","gaps":["Single case from one laboratory without replication","No biochemical characterization of how the missense mutation alters CDSN folding or incorporation","Whether the ultrastructural defect is a direct or indirect consequence of the mutation was not resolved"]},{"year":2024,"claim":"Identifying the downstream inflammatory pathway: CDSN-deficient skin showed elevated Th2 cytokines IL-4 and IL-13 and JAK1-dependent signaling, and JAK1 inhibition alleviated symptoms, linking CDSN loss mechanistically to a specific inflammatory axis.","evidence":"Whole exome sequencing, immunohistochemistry for CDSN and cytokines, and clinical response to JAK1 inhibitor (upadacitinib) in a single patient","pmids":["39377561"],"confidence":"Low","gaps":["Mechanistic inference from single case without in vitro reconstitution or controlled trial","Whether JAK1-Th2 signaling is a direct consequence of barrier disruption or involves additional intermediaries is unknown","Reproducibility across patients not established"]},{"year":2025,"claim":"Positioning CDSN in the desquamation protease hierarchy: genetic epistasis showed that KLK5 deletion aggravates rather than rescues the CDSN-null phenotype, revealing that CDSN functions upstream of a finely tuned protease balance required for controlled stratum corneum shedding.","evidence":"Double-knockout (Cdsn/Klk5) mouse model and shRNA knockdown in human epidermal equivalents with electron microscopy and barrier permeability assays","pmids":["40943523"],"confidence":"High","gaps":["Identity of compensatory proteases that become hyperactive upon combined CDSN/KLK5 loss is unknown","Whether CDSN directly inhibits or modulates protease access to corneodesmosomes versus acting purely as a structural substrate remains unresolved"]},{"year":null,"claim":"Key open question: the structural basis of CDSN adhesive function — which domains mediate homophilic or heterophilic corneodesmosomal interactions, and how CDSN mechanistically controls protease accessibility within the desquamation cascade — remains undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of CDSN or CDSN-containing corneodesmosome complexes exists","Direct binding partners of CDSN within the corneodesmosome (e.g., desmoglein 1, desmocollin 1) have not been biochemically reconstituted","Mechanism by which CDSN loss triggers compensatory protease upregulation is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1,2,4]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,1,3,4]}],"complexes":["corneodesmosome"],"partners":["KLK5"],"other_free_text":[]},"mechanistic_narrative":"Corneodesmosin (CDSN) is a secreted glycoprotein that serves as a major adhesive component of corneodesmosomes in the upper epidermis and inner root sheath of hair follicles, where it is essential for intercellular cohesion and epidermal barrier integrity. Full-length CDSN is required for corneodesmosome structural integrity; truncating or loss-of-function mutations produce non-functional protein and result in shortened, sparse corneodesmosomes, impaired cell–cell adhesion, abnormal desquamation, and secondary Th2-driven inflammation involving IL-4/IL-13 and JAK1 signaling [PMID:12754508, PMID:23957618, PMID:39377561]. Loss-of-function CDSN mutations cause hypotrichosis simplex of the scalp and peeling skin disease type B [PMID:12754508, PMID:22146835]. Genetic epistasis experiments place CDSN upstream of the desquamation-initiating serine protease KLK5, demonstrating that CDSN loss disrupts the fine protease balance required for controlled stratum corneum shedding [PMID:40943523]."},"prefetch_data":{"uniprot":{"accession":"Q15517","full_name":"Corneodesmosin","aliases":["S protein"],"length_aa":529,"mass_kda":51.6,"function":"Important for the epidermal barrier integrity","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q15517/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDSN","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PDPK1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CDSN","total_profiled":1310},"omim":[{"mim_id":"618084","title":"PEELING SKIN SYNDROME 6; PSS6","url":"https://www.omim.org/entry/618084"},{"mim_id":"616295","title":"PEELING SKIN WITH LEUKONYCHIA, ACRAL PUNCTATE KERATOSES, CHEILITIS, AND KNUCKLE PADS; PLACK","url":"https://www.omim.org/entry/616295"},{"mim_id":"616284","title":"FILAGGRIN FAMILY MEMBER 2; FLG2","url":"https://www.omim.org/entry/616284"},{"mim_id":"613525","title":"SEEK1 GENE","url":"https://www.omim.org/entry/613525"},{"mim_id":"607936","title":"PEELING SKIN SYNDROME 4; PSS4","url":"https://www.omim.org/entry/607936"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"skin 1","ntpm":663.9}],"url":"https://www.proteinatlas.org/search/CDSN"},"hgnc":{"alias_symbol":["D6S586E"],"prev_symbol":[]},"alphafold":{"accession":"Q15517","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15517","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15517-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15517-F1-predicted_aligned_error_v6.png","plddt_mean":37.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDSN","jax_strain_url":"https://www.jax.org/strain/search?query=CDSN"},"sequence":{"accession":"Q15517","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15517.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15517/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15517"}},"corpus_meta":[{"pmid":"12754508","id":"PMC_12754508","title":"Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12754508","citation_count":134,"is_preprint":false},{"pmid":"15529278","id":"PMC_15529278","title":"Mapping of the major psoriasis-susceptibility locus (PSORS1) in a 70-Kb interval around the corneodesmosin gene (CDSN).","date":"2004","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15529278","citation_count":43,"is_preprint":false},{"pmid":"16965413","id":"PMC_16965413","title":"Psoriasis vulgaris in Chinese individuals is associated with PSORS1C3 and CDSN genes.","date":"2006","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/16965413","citation_count":34,"is_preprint":false},{"pmid":"18708502","id":"PMC_18708502","title":"Characterization of the putative type III secretion ATPase CdsN (Cpn0707) of Chlamydophila pneumoniae.","date":"2008","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/18708502","citation_count":33,"is_preprint":false},{"pmid":"22146835","id":"PMC_22146835","title":"Inflammatory peeling skin syndrome caused a novel mutation in CDSN.","date":"2011","source":"Archives of dermatological research","url":"https://pubmed.ncbi.nlm.nih.gov/22146835","citation_count":25,"is_preprint":false},{"pmid":"23957618","id":"PMC_23957618","title":"Identification of the first nonsense CDSN mutation with expression of a truncated protein causing peeling skin syndrome type B.","date":"2013","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/23957618","citation_count":25,"is_preprint":false},{"pmid":"21687413","id":"PMC_21687413","title":"Chlamydia Pneumoniae CdsL Regulates CdsN ATPase Activity, and Disruption with a Peptide Mimetic Prevents Bacterial Invasion.","date":"2011","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/21687413","citation_count":24,"is_preprint":false},{"pmid":"29589160","id":"PMC_29589160","title":"HLA-C*06:02-independent, gender-related association of PSORS1C3 and PSORS1C1/CDSN single-nucleotide polymorphisms with risk and severity of psoriasis.","date":"2018","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/29589160","citation_count":23,"is_preprint":false},{"pmid":"12472658","id":"PMC_12472658","title":"Psoriasis is associated with a SNP haplotype of the corneodesmosin gene (CDSN).","date":"2002","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/12472658","citation_count":19,"is_preprint":false},{"pmid":"24116970","id":"PMC_24116970","title":"Alu-mediated large deletion of the CDSN gene as a cause of peeling skin disease.","date":"2013","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24116970","citation_count":19,"is_preprint":false},{"pmid":"24372652","id":"PMC_24372652","title":"Inflammatory peeling skin syndrome caused by homozygous genomic deletion in the PSORS1 region encompassing the CDSN gene.","date":"2014","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/24372652","citation_count":18,"is_preprint":false},{"pmid":"12929169","id":"PMC_12929169","title":"Dimorphic Alu element located between the TFIIH and CDSN genes within the major histocompatibility complex.","date":"2003","source":"Electrophoresis","url":"https://pubmed.ncbi.nlm.nih.gov/12929169","citation_count":17,"is_preprint":false},{"pmid":"15953084","id":"PMC_15953084","title":"Corneodesmosin (CDSN) gene association with psoriasis vulgaris in Caucasian but not in Japanese populations.","date":"2005","source":"Clinical and experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/15953084","citation_count":15,"is_preprint":false},{"pmid":"31663161","id":"PMC_31663161","title":"Mutations in the CDSN gene cause peeling skin disease and hypotrichosis simplex of the scalp.","date":"2019","source":"The Journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/31663161","citation_count":12,"is_preprint":false},{"pmid":"22033905","id":"PMC_22033905","title":"Association of -619C/T polymorphism in CDSN gene and psoriasis risk: a meta-analysis.","date":"2011","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/22033905","citation_count":5,"is_preprint":false},{"pmid":"22875505","id":"PMC_22875505","title":"[Clinical investigation of a Chinese family with hypotrichosis simplex of the scalp and mutational analysis of CDSN gene].","date":"2012","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22875505","citation_count":4,"is_preprint":false},{"pmid":"25473393","id":"PMC_25473393","title":"A Case of Inflammatory Generalized Type of Peeling Skin Syndrome Possibly Caused by a Homozygous Missense Mutation of CDSN.","date":"2014","source":"Case reports in dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/25473393","citation_count":3,"is_preprint":false},{"pmid":"37453912","id":"PMC_37453912","title":"Identification of B-cell-related HSPG2 and CDSN as susceptibility loci for Kawasaki disease.","date":"2023","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37453912","citation_count":2,"is_preprint":false},{"pmid":"39377561","id":"PMC_39377561","title":"A case of peeling skin syndrome type 1 with novel CDSN gene variation successfully treated with upadacitinib.","date":"2024","source":"The Journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/39377561","citation_count":1,"is_preprint":false},{"pmid":"40943523","id":"PMC_40943523","title":"Deletion of the Epidermal Protease KLK5 Aggravates the Symptoms of Congenital Ichthyosis CDSN-nEDD.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40943523","citation_count":0,"is_preprint":false},{"pmid":"37199725","id":"PMC_37199725","title":"Overcoming Limitations in Water-Ethanol Sprayed Superstrate Solar Cells by Compositional Engineering of Cu2CdSn(S,Se)4.","date":"2023","source":"ACS applied materials & interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/37199725","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12006,"output_tokens":1505,"usd":0.029296},"stage2":{"model":"claude-opus-4-6","input_tokens":4750,"output_tokens":2032,"usd":0.111825},"total_usd":0.141121,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Nonsense mutations in CDSN (encoding corneodesmosin) cause hypotrichosis simplex of the scalp; truncated CDSN aggregates were detected in the superficial dermis and at the periphery of hair follicles, establishing CDSN as a keratinocyte adhesion molecule required for normal scalp hair physiology.\",\n      \"method\": \"Genetic sequencing of patient families; protein detection (immunohistochemistry/Western) showing truncated aggregates in dermis and hair follicle periphery\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple independent families, protein-level validation of truncation, replicated across labs\",\n      \"pmids\": [\"12754508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss-of-function mutations in CDSN lead to deficiency of corneodesmosin, a major component of desmosomal junctions in the uppermost epidermal layers, impairing cell-cell adhesion in the upper epidermis and triggering an abnormal inflammatory response due to epidermal barrier disruption (peeling skin syndrome type B).\",\n      \"method\": \"PCR/direct sequencing identifying homozygous frameshift mutation; clinical and histological phenotype characterization (inflammatory peeling)\",\n      \"journal\": \"Archives of dermatological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 + Strong — multiple independent CDSN loss-of-function papers consistently show same adhesion/barrier phenotype\",\n      \"pmids\": [\"22146835\", \"23957618\", \"24116970\", \"24372652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A truncated corneodesmosin (p.Gly142*) is stably expressed as a 16-kDa protein in patient epidermis and is non-functional, demonstrating that full-length corneodesmosin is required for its adhesive function; total corneodesmosin loss underlies peeling skin disease.\",\n      \"method\": \"Western blot and immunohistochemistry of skin biopsies; DNA sequencing; real-time PCR\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Western, IHC, sequencing) in single study\",\n      \"pmids\": [\"23957618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A homozygous missense mutation in CDSN (c.1358G>A) results in structurally shortened and sparse corneodesmosomes as measured by electron microscopy, linking CDSN protein to corneodesmosome structural integrity.\",\n      \"method\": \"Gene sequencing; electron microscopy with morphometric analysis of corneodesmosomes\",\n      \"journal\": \"Case reports in dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 + Weak — single case, single lab, morphometric observation only\",\n      \"pmids\": [\"25473393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Genetic epistasis experiments (Klk5 knockout crossed into Cdsn knockout mice, and shRNA knockdown in human epidermal equivalents) showed that deletion of the desquamation-initiating serine protease KLK5 aggravates rather than rescues the CDSN-nEDD phenotype, with elevated epidermal proteolysis, severe (corneo)desmosomal ultrastructural alterations, increased barrier permeability, and greater stratum corneum detachment — placing CDSN upstream of fine protease balance in the desquamation cascade.\",\n      \"method\": \"Genetic epistasis (double-knockout mouse model, shRNA in human epidermal equivalents); electron microscopy; barrier permeability assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic epistasis in two independent models (mouse KO and human tissue equivalent) with multiple functional readouts\",\n      \"pmids\": [\"40943523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss-of-function CDSN mutation (c.295C>T, p.Gln99*) leads to absence of corneodesmosin in skin, overexpression of Th2-related cytokines (IL-4 and IL-13), and JAK1-dependent signaling; JAK1 inhibition (upadacitinib) alleviated symptoms, implicating JAK1-Th2 signaling in CDSN-deficiency pathogenesis.\",\n      \"method\": \"Whole exome sequencing; immunohistochemistry confirming absent CDSN and elevated IL-4/IL-13; JAK1 inhibitor treatment with clinical outcome\",\n      \"journal\": \"The Journal of dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 + Weak — single case, mechanistic inference from IHC and drug response without in vitro reconstitution\",\n      \"pmids\": [\"39377561\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Corneodesmosin (CDSN) is a glycoprotein component of corneodesmosomes in the upper epidermis and inner root sheath of hair follicles that mediates keratinocyte cell-cell adhesion; loss-of-function mutations cause progressive epidermal barrier disruption, abnormal desquamation, and secondary inflammatory responses (involving Th2 cytokines and JAK1 signaling), while genetic epistasis places CDSN upstream of and in functional balance with the desquamation-initiating serine protease KLK5.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Corneodesmosin (CDSN) is a secreted glycoprotein that serves as a major adhesive component of corneodesmosomes in the upper epidermis and inner root sheath of hair follicles, where it is essential for intercellular cohesion and epidermal barrier integrity. Full-length CDSN is required for corneodesmosome structural integrity; truncating or loss-of-function mutations produce non-functional protein and result in shortened, sparse corneodesmosomes, impaired cell–cell adhesion, abnormal desquamation, and secondary Th2-driven inflammation involving IL-4/IL-13 and JAK1 signaling [PMID:12754508, PMID:23957618, PMID:39377561]. Loss-of-function CDSN mutations cause hypotrichosis simplex of the scalp and peeling skin disease type B [PMID:12754508, PMID:22146835]. Genetic epistasis experiments place CDSN upstream of the desquamation-initiating serine protease KLK5, demonstrating that CDSN loss disrupts the fine protease balance required for controlled stratum corneum shedding [PMID:40943523].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that CDSN is a disease gene: identification of nonsense mutations in CDSN as the cause of hereditary hypotrichosis simplex of the scalp demonstrated that this corneodesmosomal glycoprotein is required for normal hair follicle adhesion and physiology.\",\n      \"evidence\": \"Genetic sequencing of multiple affected families with immunohistochemical and Western blot detection of truncated CDSN aggregates in dermis and hair follicle periphery\",\n      \"pmids\": [\"12754508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which truncated CDSN aggregates in the dermis rather than being degraded was unknown\",\n        \"Whether CDSN loss also affects interfollicular epidermal adhesion was not tested\",\n        \"Structural basis of CDSN adhesive function remained unresolved\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extending CDSN deficiency from hair loss to generalized skin disease: homozygous loss-of-function CDSN mutations were shown to cause peeling skin syndrome type B, establishing that corneodesmosin is essential for cell–cell adhesion across the entire upper epidermis and that its absence triggers inflammatory barrier disruption.\",\n      \"evidence\": \"PCR and direct sequencing identifying frameshift mutations; clinical, histological, and immunohistochemical phenotyping across multiple independent reports\",\n      \"pmids\": [\"22146835\", \"23957618\", \"24116970\", \"24372652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The molecular mechanism linking barrier disruption to the inflammatory response was not defined\",\n        \"Whether residual truncated CDSN retains partial function was unclear\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolving whether truncated CDSN is functional: detection of a stable 16-kDa truncated corneodesmosin (p.Gly142*) in patient epidermis demonstrated that partial CDSN expression is insufficient and that full-length protein is required for adhesive function.\",\n      \"evidence\": \"Western blot and immunohistochemistry of patient skin biopsies combined with DNA sequencing and real-time PCR\",\n      \"pmids\": [\"23957618\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which specific domains of full-length CDSN mediate adhesion was not mapped\",\n        \"No in vitro reconstitution of CDSN adhesive activity was performed\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linking CDSN mutation to corneodesmosome ultrastructure: electron microscopy of a missense CDSN mutant revealed structurally shortened and sparse corneodesmosomes, directly connecting CDSN protein to the structural integrity of these junctions.\",\n      \"evidence\": \"Electron microscopy with morphometric analysis in a single patient with homozygous CDSN missense mutation\",\n      \"pmids\": [\"25473393\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single case from one laboratory without replication\",\n        \"No biochemical characterization of how the missense mutation alters CDSN folding or incorporation\",\n        \"Whether the ultrastructural defect is a direct or indirect consequence of the mutation was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying the downstream inflammatory pathway: CDSN-deficient skin showed elevated Th2 cytokines IL-4 and IL-13 and JAK1-dependent signaling, and JAK1 inhibition alleviated symptoms, linking CDSN loss mechanistically to a specific inflammatory axis.\",\n      \"evidence\": \"Whole exome sequencing, immunohistochemistry for CDSN and cytokines, and clinical response to JAK1 inhibitor (upadacitinib) in a single patient\",\n      \"pmids\": [\"39377561\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Mechanistic inference from single case without in vitro reconstitution or controlled trial\",\n        \"Whether JAK1-Th2 signaling is a direct consequence of barrier disruption or involves additional intermediaries is unknown\",\n        \"Reproducibility across patients not established\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Positioning CDSN in the desquamation protease hierarchy: genetic epistasis showed that KLK5 deletion aggravates rather than rescues the CDSN-null phenotype, revealing that CDSN functions upstream of a finely tuned protease balance required for controlled stratum corneum shedding.\",\n      \"evidence\": \"Double-knockout (Cdsn/Klk5) mouse model and shRNA knockdown in human epidermal equivalents with electron microscopy and barrier permeability assays\",\n      \"pmids\": [\"40943523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of compensatory proteases that become hyperactive upon combined CDSN/KLK5 loss is unknown\",\n        \"Whether CDSN directly inhibits or modulates protease access to corneodesmosomes versus acting purely as a structural substrate remains unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open question: the structural basis of CDSN adhesive function — which domains mediate homophilic or heterophilic corneodesmosomal interactions, and how CDSN mechanistically controls protease accessibility within the desquamation cascade — remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of CDSN or CDSN-containing corneodesmosome complexes exists\",\n        \"Direct binding partners of CDSN within the corneodesmosome (e.g., desmoglein 1, desmocollin 1) have not been biochemically reconstituted\",\n        \"Mechanism by which CDSN loss triggers compensatory protease upregulation is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 1, 3, 4]}\n    ],\n    \"complexes\": [\n      \"corneodesmosome\"\n    ],\n    \"partners\": [\n      \"KLK5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}