{"gene":"CDSN","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2003,"finding":"Nonsense mutations in CDSN (encoding corneodesmosin) cause hypotrichosis simplex of the scalp; truncated CDSN protein aggregates were detected in the superficial dermis and at the periphery of hair follicles, establishing corneodesmosin as a keratinocyte adhesion molecule important for normal scalp hair follicle physiology.","method":"DNA sequencing of affected families, immunohistochemistry/protein detection of truncated aggregates in skin biopsies","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mutations identified in multiple families with defined molecular and cellular phenotype, protein localization confirmed by tissue analysis","pmids":["12754508"],"is_preprint":false},{"year":2011,"finding":"Homozygous loss-of-function frameshift mutation in CDSN (c.164_167dupGCCT; p.Thr57ProfsX6) causes generalized peeling skin syndrome type B, demonstrating that corneodesmosin deficiency impairs cell-cell adhesion in the upper epidermis and leads to an abnormal inflammatory response due to epidermal barrier disruption.","method":"PCR amplification and direct sequencing; clinical phenotype characterization","journal":"Archives of dermatological research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, single method (sequencing), but functional inference (adhesion defect + barrier disruption) is supported by prior literature on CDSN function","pmids":["22146835"],"is_preprint":false},{"year":2013,"finding":"A novel homozygous nonsense mutation (p.Gly142*) in CDSN produces a stable truncated 16-kDa corneodesmosin protein detectable in upper epidermal layers by Western blot, whereas full-length protein is absent; this truncated protein is likely nonfunctional, establishing that peeling skin disease can result from expression of a truncated but stable CDSN protein (not only full loss).","method":"DNA sequencing, Western blot, immunohistochemistry, real-time PCR of skin biopsies","journal":"The British journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (sequencing, Western blot, IHC, qPCR) in single lab establishing protein truncation and loss of function","pmids":["23957618"],"is_preprint":false},{"year":2013,"finding":"A large homozygous genomic deletion (59.1 kb) encompassing the CDSN gene, mediated by Alu-S sequence recombination, abrogates corneodesmosin expression and causes peeling skin disease, demonstrating that complete loss of corneodesmosin alone is sufficient for the PSD phenotype even when several flanking genes are also deleted.","method":"PCR, QMPSF (quantitative multiplex PCR of short fluorescent fragments), breakpoint sequencing, microsatellite haplotyping","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple molecular methods to define deletion breakpoints and confirm absent protein expression, single lab","pmids":["24116970"],"is_preprint":false},{"year":2014,"finding":"Complete deletion of the CDSN gene results in undetectable corneodesmosin in epidermis and peeling skin syndrome type B, confirming that corneodesmosin is essential for epidermal integrity; loss of the five additional co-deleted PSORS1 region genes does not produce an additional cutaneous phenotype.","method":"Immunohistochemistry, PCR, QMPSF, CGH array, microsatellite haplotyping","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods confirming complete loss of CDSN and its protein, single lab with clear phenotypic readout","pmids":["24372652"],"is_preprint":false},{"year":2014,"finding":"A homozygous missense mutation (c.1358G>A) in CDSN is associated with peeling skin syndrome; electron microscopy of affected skin revealed statistically significant shortness and sparsity of corneodesmosomes compared to controls, suggesting that mutant corneodesmosin reduces corneodesmosome size and contributes to defective desquamation.","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; electron microscopy provides structural evidence but no direct functional assay of mutant protein activity","pmids":["25473393"],"is_preprint":false},{"year":2024,"finding":"Skin biopsy from a PSS1 patient with CDSN loss-of-function (p.Gln99*) showed absent corneodesmosin expression and overexpression of Th2-related cytokines IL-4 and IL-13; JAK1 inhibitor upadacitinib alleviated skin symptoms, implicating JAK1/Th2 signaling in the inflammatory pathogenesis downstream of corneodesmosin deficiency.","method":"Whole exome sequencing, immunohistochemistry for CDSN and cytokines, clinical response to JAK1 inhibitor","journal":"The Journal of dermatology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single case, IHC-based pathway inference, therapeutic response does not definitively establish molecular mechanism","pmids":["39377561"],"is_preprint":false},{"year":2025,"finding":"In a CDSN knockdown human epidermal equivalent model and in Cdsn/Klk5 double-knockout mice, deletion of the desquamation-initiating serine protease KLK5 unexpectedly aggravated the CDSN-nEDD phenotype: epidermal proteolysis was elevated, corneodesmosomes showed severe ultrastructural alterations, epidermal barrier permeability increased, and stratum corneum detachment worsened — establishing that KLK5 does not compensate for corneodesmosin loss and that other proteases assume increased activity in the absence of KLK5.","method":"shRNA-mediated CDSN knockdown in human epidermal equivalents, Cdsn/Klk5 double-knockout mouse model, ultrastructural analysis, barrier permeability assays","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — genetic epistasis with double KO model and engineered human tissue equivalent, multiple orthogonal phenotypic readouts; single lab but rigorous multi-method approach","pmids":["40943523"],"is_preprint":false}],"current_model":"Corneodesmosin (CDSN) is a glycoprotein component of corneodesmosomes expressed in the epidermis and inner root sheath of hair follicles that functions as a keratinocyte adhesion molecule; loss-of-function mutations (nonsense, frameshift, or large deletions) cause complete corneodesmosin deficiency leading to impaired cell-cell adhesion in the upper epidermis, barrier disruption, and inflammatory skin peeling (peeling skin syndrome type 1/PSS-B), while dominant truncating mutations cause hypotrichosis simplex of the scalp, and genetic epistasis studies show that KLK5-mediated desquamation cannot compensate for corneodesmosin loss, with downstream Th2/JAK1 inflammatory signaling implicated in disease pathogenesis."},"narrative":{"mechanistic_narrative":"Corneodesmosin (CDSN) is a keratinocyte adhesion glycoprotein of the corneodesmosome that maintains cell-cell cohesion in the upper epidermis and is required for normal scalp hair follicle physiology [PMID:12754508]. Loss of corneodesmosin function—through nonsense or frameshift mutations, large genomic deletions, or expression of stable but nonfunctional truncated protein—abrogates epidermal integrity and produces peeling skin syndrome type B, with impaired upper-epidermal adhesion and barrier disruption [PMID:22146835, PMID:23957618, PMID:24116970]; complete deletion of CDSN alone is sufficient for this phenotype even when neighboring PSORS1-region genes are co-deleted [PMID:24372652]. Distinct truncating mutations instead cause hypotrichosis simplex of the scalp, where truncated corneodesmosin aggregates accumulate around hair follicles [PMID:12754508]. Genetic epistasis establishes that the desquamation-initiating serine protease KLK5 cannot compensate for corneodesmosin loss; its removal instead aggravates corneodesmosome ultrastructural defects and barrier permeability as other proteases assume increased activity [PMID:40943523]. Downstream of corneodesmosin deficiency, barrier disruption drives an inflammatory response in which Th2 cytokine (IL-4/IL-13) and JAK1 signaling are implicated [PMID:39377561].","teleology":[{"year":2003,"claim":"Established corneodesmosin as a keratinocyte adhesion molecule with a role in scalp follicle physiology by linking its loss to a defined human phenotype.","evidence":"DNA sequencing of affected families with immunohistochemical detection of truncated CDSN aggregates in scalp biopsies","pmids":["12754508"],"confidence":"High","gaps":["Molecular basis of adhesion (binding partners within the corneodesmosome) not defined","Why truncated protein aggregates rather than degrades unaddressed"]},{"year":2011,"claim":"Connected biallelic loss-of-function to generalized peeling skin syndrome, framing corneodesmosin deficiency as a cause of upper-epidermal adhesion failure and barrier-driven inflammation.","evidence":"PCR and direct sequencing identifying a homozygous frameshift, with clinical phenotyping","pmids":["22146835"],"confidence":"Medium","gaps":["Adhesion and barrier defects inferred clinically, not measured directly","Single family, single sequencing method"]},{"year":2013,"claim":"Distinguished two routes to disease—stable truncated protein versus complete absence—by showing a nonsense mutation yields a stable but nonfunctional 16-kDa fragment while a 59-kb Alu-mediated deletion abolishes expression entirely.","evidence":"Sequencing plus Western blot/IHC/qPCR for the truncation allele, and breakpoint sequencing/QMPSF/haplotyping for the deletion","pmids":["23957618","24116970"],"confidence":"Medium","gaps":["Direct functional assay of the truncated protein's residual adhesion activity absent","Contribution of co-deleted flanking genes not yet excluded at this stage"]},{"year":2014,"claim":"Demonstrated that loss of CDSN alone is sufficient for peeling skin syndrome, isolating it from neighboring PSORS1 genes, and provided ultrastructural evidence that mutant protein shortens and sparsifies corneodesmosomes.","evidence":"IHC/PCR/QMPSF/CGH array on a complete-deletion case showing no extra phenotype from co-deleted genes; electron microscopy with morphometry on a missense case","pmids":["24372652","25473393"],"confidence":"Medium","gaps":["Mechanism by which corneodesmosin sets corneodesmosome size unresolved","Missense-allele finding is a single low-confidence case without functional protein assay"]},{"year":2024,"claim":"Linked corneodesmosin deficiency to a specific inflammatory axis by showing Th2 cytokine overexpression and clinical benefit from JAK1 inhibition.","evidence":"Whole exome sequencing, IHC for CDSN and IL-4/IL-13, and clinical response to upadacitinib in a single PSS1 patient","pmids":["39377561"],"confidence":"Low","gaps":["Single case with IHC-based and therapeutic-response inference, not mechanistic proof","Causal chain from barrier loss to Th2/JAK1 activation not established"]},{"year":2025,"claim":"Resolved whether desquamation proteases compensate for corneodesmosin loss, showing via genetic epistasis that removing KLK5 worsens rather than rescues the phenotype.","evidence":"shRNA CDSN knockdown in human epidermal equivalents and Cdsn/Klk5 double-knockout mice with ultrastructural and barrier permeability readouts","pmids":["40943523"],"confidence":"High","gaps":["Identity of the compensating proteases that gain activity in KLK5 absence not determined","Single-lab study; direct biochemical substrate relationships not mapped"]},{"year":null,"claim":"The direct molecular binding partners of corneodesmosin within the corneodesmosome and the biochemical basis of its adhesive function remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No identified direct protein interactor or structural model in the corpus","Proteases responsible for normal corneodesmosin turnover not enumerated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,5,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0030312","term_label":"external encapsulating structure","supporting_discovery_ids":[2,3,7]}],"pathway":[],"complexes":["corneodesmosome"],"partners":[],"other_free_text":[]}},"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":36,"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":"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":"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":"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":"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":20,"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":"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":19,"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":2,"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":"42135622","id":"PMC_42135622","title":"Identification and functional assessment of CDSN gene variants associated with horn phenotypes in sheep.","date":"2026","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/42135622","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":13193,"output_tokens":2111,"usd":0.035622,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9136,"output_tokens":2403,"usd":0.052878,"stage2_stop_reason":"end_turn"},"total_usd":0.0885,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","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 protein aggregates were detected in the superficial dermis and at the periphery of hair follicles, establishing corneodesmosin as a keratinocyte adhesion molecule important for normal scalp hair follicle physiology.\",\n      \"method\": \"DNA sequencing of affected families, immunohistochemistry/protein detection of truncated aggregates in skin biopsies\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mutations identified in multiple families with defined molecular and cellular phenotype, protein localization confirmed by tissue analysis\",\n      \"pmids\": [\"12754508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Homozygous loss-of-function frameshift mutation in CDSN (c.164_167dupGCCT; p.Thr57ProfsX6) causes generalized peeling skin syndrome type B, demonstrating that corneodesmosin deficiency impairs cell-cell adhesion in the upper epidermis and leads to an abnormal inflammatory response due to epidermal barrier disruption.\",\n      \"method\": \"PCR amplification and direct sequencing; clinical phenotype characterization\",\n      \"journal\": \"Archives of dermatological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, single method (sequencing), but functional inference (adhesion defect + barrier disruption) is supported by prior literature on CDSN function\",\n      \"pmids\": [\"22146835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A novel homozygous nonsense mutation (p.Gly142*) in CDSN produces a stable truncated 16-kDa corneodesmosin protein detectable in upper epidermal layers by Western blot, whereas full-length protein is absent; this truncated protein is likely nonfunctional, establishing that peeling skin disease can result from expression of a truncated but stable CDSN protein (not only full loss).\",\n      \"method\": \"DNA sequencing, Western blot, immunohistochemistry, real-time PCR of skin biopsies\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (sequencing, Western blot, IHC, qPCR) in single lab establishing protein truncation and loss of function\",\n      \"pmids\": [\"23957618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A large homozygous genomic deletion (59.1 kb) encompassing the CDSN gene, mediated by Alu-S sequence recombination, abrogates corneodesmosin expression and causes peeling skin disease, demonstrating that complete loss of corneodesmosin alone is sufficient for the PSD phenotype even when several flanking genes are also deleted.\",\n      \"method\": \"PCR, QMPSF (quantitative multiplex PCR of short fluorescent fragments), breakpoint sequencing, microsatellite haplotyping\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple molecular methods to define deletion breakpoints and confirm absent protein expression, single lab\",\n      \"pmids\": [\"24116970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Complete deletion of the CDSN gene results in undetectable corneodesmosin in epidermis and peeling skin syndrome type B, confirming that corneodesmosin is essential for epidermal integrity; loss of the five additional co-deleted PSORS1 region genes does not produce an additional cutaneous phenotype.\",\n      \"method\": \"Immunohistochemistry, PCR, QMPSF, CGH array, microsatellite haplotyping\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods confirming complete loss of CDSN and its protein, single lab with clear phenotypic readout\",\n      \"pmids\": [\"24372652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A homozygous missense mutation (c.1358G>A) in CDSN is associated with peeling skin syndrome; electron microscopy of affected skin revealed statistically significant shortness and sparsity of corneodesmosomes compared to controls, suggesting that mutant corneodesmosin reduces corneodesmosome size and contributes to defective desquamation.\",\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; electron microscopy provides structural evidence but no direct functional assay of mutant protein activity\",\n      \"pmids\": [\"25473393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Skin biopsy from a PSS1 patient with CDSN loss-of-function (p.Gln99*) showed absent corneodesmosin expression and overexpression of Th2-related cytokines IL-4 and IL-13; JAK1 inhibitor upadacitinib alleviated skin symptoms, implicating JAK1/Th2 signaling in the inflammatory pathogenesis downstream of corneodesmosin deficiency.\",\n      \"method\": \"Whole exome sequencing, immunohistochemistry for CDSN and cytokines, clinical response to JAK1 inhibitor\",\n      \"journal\": \"The Journal of dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single case, IHC-based pathway inference, therapeutic response does not definitively establish molecular mechanism\",\n      \"pmids\": [\"39377561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a CDSN knockdown human epidermal equivalent model and in Cdsn/Klk5 double-knockout mice, deletion of the desquamation-initiating serine protease KLK5 unexpectedly aggravated the CDSN-nEDD phenotype: epidermal proteolysis was elevated, corneodesmosomes showed severe ultrastructural alterations, epidermal barrier permeability increased, and stratum corneum detachment worsened — establishing that KLK5 does not compensate for corneodesmosin loss and that other proteases assume increased activity in the absence of KLK5.\",\n      \"method\": \"shRNA-mediated CDSN knockdown in human epidermal equivalents, Cdsn/Klk5 double-knockout mouse model, ultrastructural analysis, barrier permeability assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — genetic epistasis with double KO model and engineered human tissue equivalent, multiple orthogonal phenotypic readouts; single lab but rigorous multi-method approach\",\n      \"pmids\": [\"40943523\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Corneodesmosin (CDSN) is a glycoprotein component of corneodesmosomes expressed in the epidermis and inner root sheath of hair follicles that functions as a keratinocyte adhesion molecule; loss-of-function mutations (nonsense, frameshift, or large deletions) cause complete corneodesmosin deficiency leading to impaired cell-cell adhesion in the upper epidermis, barrier disruption, and inflammatory skin peeling (peeling skin syndrome type 1/PSS-B), while dominant truncating mutations cause hypotrichosis simplex of the scalp, and genetic epistasis studies show that KLK5-mediated desquamation cannot compensate for corneodesmosin loss, with downstream Th2/JAK1 inflammatory signaling implicated in disease pathogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Corneodesmosin (CDSN) is a keratinocyte adhesion glycoprotein of the corneodesmosome that maintains cell-cell cohesion in the upper epidermis and is required for normal scalp hair follicle physiology [#0]. Loss of corneodesmosin function—through nonsense or frameshift mutations, large genomic deletions, or expression of stable but nonfunctional truncated protein—abrogates epidermal integrity and produces peeling skin syndrome type B, with impaired upper-epidermal adhesion and barrier disruption [#1, #2, #3]; complete deletion of CDSN alone is sufficient for this phenotype even when neighboring PSORS1-region genes are co-deleted [#4]. Distinct truncating mutations instead cause hypotrichosis simplex of the scalp, where truncated corneodesmosin aggregates accumulate around hair follicles [#0]. Genetic epistasis establishes that the desquamation-initiating serine protease KLK5 cannot compensate for corneodesmosin loss; its removal instead aggravates corneodesmosome ultrastructural defects and barrier permeability as other proteases assume increased activity [#7]. Downstream of corneodesmosin deficiency, barrier disruption drives an inflammatory response in which Th2 cytokine (IL-4/IL-13) and JAK1 signaling are implicated [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established corneodesmosin as a keratinocyte adhesion molecule with a role in scalp follicle physiology by linking its loss to a defined human phenotype.\",\n      \"evidence\": \"DNA sequencing of affected families with immunohistochemical detection of truncated CDSN aggregates in scalp biopsies\",\n      \"pmids\": [\"12754508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular basis of adhesion (binding partners within the corneodesmosome) not defined\",\n        \"Why truncated protein aggregates rather than degrades unaddressed\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected biallelic loss-of-function to generalized peeling skin syndrome, framing corneodesmosin deficiency as a cause of upper-epidermal adhesion failure and barrier-driven inflammation.\",\n      \"evidence\": \"PCR and direct sequencing identifying a homozygous frameshift, with clinical phenotyping\",\n      \"pmids\": [\"22146835\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Adhesion and barrier defects inferred clinically, not measured directly\",\n        \"Single family, single sequencing method\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Distinguished two routes to disease—stable truncated protein versus complete absence—by showing a nonsense mutation yields a stable but nonfunctional 16-kDa fragment while a 59-kb Alu-mediated deletion abolishes expression entirely.\",\n      \"evidence\": \"Sequencing plus Western blot/IHC/qPCR for the truncation allele, and breakpoint sequencing/QMPSF/haplotyping for the deletion\",\n      \"pmids\": [\"23957618\", \"24116970\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct functional assay of the truncated protein's residual adhesion activity absent\",\n        \"Contribution of co-deleted flanking genes not yet excluded at this stage\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that loss of CDSN alone is sufficient for peeling skin syndrome, isolating it from neighboring PSORS1 genes, and provided ultrastructural evidence that mutant protein shortens and sparsifies corneodesmosomes.\",\n      \"evidence\": \"IHC/PCR/QMPSF/CGH array on a complete-deletion case showing no extra phenotype from co-deleted genes; electron microscopy with morphometry on a missense case\",\n      \"pmids\": [\"24372652\", \"25473393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which corneodesmosin sets corneodesmosome size unresolved\",\n        \"Missense-allele finding is a single low-confidence case without functional protein assay\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked corneodesmosin deficiency to a specific inflammatory axis by showing Th2 cytokine overexpression and clinical benefit from JAK1 inhibition.\",\n      \"evidence\": \"Whole exome sequencing, IHC for CDSN and IL-4/IL-13, and clinical response to upadacitinib in a single PSS1 patient\",\n      \"pmids\": [\"39377561\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single case with IHC-based and therapeutic-response inference, not mechanistic proof\",\n        \"Causal chain from barrier loss to Th2/JAK1 activation not established\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved whether desquamation proteases compensate for corneodesmosin loss, showing via genetic epistasis that removing KLK5 worsens rather than rescues the phenotype.\",\n      \"evidence\": \"shRNA CDSN knockdown in human epidermal equivalents and Cdsn/Klk5 double-knockout mice with ultrastructural and barrier permeability readouts\",\n      \"pmids\": [\"40943523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the compensating proteases that gain activity in KLK5 absence not determined\",\n        \"Single-lab study; direct biochemical substrate relationships not mapped\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular binding partners of corneodesmosin within the corneodesmosome and the biochemical basis of its adhesive function remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No identified direct protein interactor or structural model in the corpus\",\n        \"Proteases responsible for normal corneodesmosin turnover not enumerated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0030312\", \"supporting_discovery_ids\": [2, 3, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:1266738\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"corneodesmosome\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}