{"gene":"TGM5","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":2005,"finding":"TGM5 encodes transglutaminase 5 (TG5), which is strongly expressed in epidermal granular cells and cross-links structural proteins during terminal epidermal differentiation to form the cornified cell envelope; the missense mutation G113C completely abolishes TG5 enzymatic activity in vitro, while T109M does not, demonstrating that TG5 protein cross-linking activity is essential for cell-cell adhesion between the outermost epidermal layers.","method":"In vitro biochemical cross-linking assay; 3D structural modeling; homozygosity mapping; mutation analysis in patients with acral peeling skin syndrome","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assay with mutagenesis, structural modeling, and disease-linked loss-of-function validation","pmids":["16380904"],"is_preprint":false},{"year":2012,"finding":"TGM5 mutations (p.M1T, p.L41P, p.L214CfsX15, p.S604IfsX9, and the recurrent p.G113C) impair TG5 function and alter expression and distribution of epidermal differentiation markers (keratin 1, keratin 10, involucrin, loricrin, and corneodesmosin) in APSS keratinocytes, indicating TG5 is required for normal terminal epidermal differentiation; upregulation of these markers appears to represent a compensatory mechanism for epidermal barrier stabilization.","method":"Quantitative real-time PCR, immunoblotting, immunofluorescence analysis of patient keratinocytes and skin; functional transglutaminase activity assay","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (activity assay, qPCR, immunoblot, immunofluorescence) in patient-derived material","pmids":["22622422"],"is_preprint":false},{"year":2015,"finding":"Novel TGM5 mutations (c.1001+2_1001+3del, c.1171G>A, c.1498C>T) were confirmed to abolish transglutaminase-5 activity using a functional transglutaminase activity assay, and alternative splicing consequences were demonstrated by RT-PCR, establishing pathogenicity at the molecular level.","method":"Transglutaminase activity assay; reverse-transcribed PCR for alternative splicing; in silico prediction tools","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — functional activity assay combined with RT-PCR, single study","pmids":["25644735"],"is_preprint":false}],"current_model":"TGM5 encodes transglutaminase 5 (TG5), an enzyme expressed in epidermal granular cells that cross-links structural proteins (including keratins, involucrin, loricrin, and corneodesmosin) to form the cornified cell envelope during terminal epidermal differentiation; loss of TG5 catalytic activity—caused by mutations such as G113C that lie close to the catalytic domain—disrupts protein cross-linking and cell-cell adhesion between the stratum granulosum and stratum corneum, leading to acral peeling skin syndrome."},"narrative":{"teleology":[{"year":2005,"claim":"The central question of whether TG5 enzymatic cross-linking activity is essential for epidermal cohesion was answered: the G113C mutation abolishes TG5 activity in vitro, establishing a direct causal link between TGM5 loss-of-function and acral peeling skin syndrome.","evidence":"In vitro biochemical cross-linking assay, 3D structural modeling, and homozygosity mapping in APSS families","pmids":["16380904"],"confidence":"High","gaps":["No in vivo animal model to confirm epidermal barrier defect is cell-autonomous","Structural basis of catalytic inactivation by G113C not resolved at atomic resolution","Relative contribution of TG5 versus other transglutaminases (TG1, TG3) to cornified envelope formation not delineated"]},{"year":2012,"claim":"The downstream consequences of TG5 deficiency in patient skin were characterized: multiple TGM5 mutations alter the expression and distribution of key differentiation markers (K1, K10, involucrin, loricrin, corneodesmosin), revealing compensatory upregulation that partially stabilizes the barrier.","evidence":"qPCR, immunoblotting, immunofluorescence, and transglutaminase activity assay in APSS patient keratinocytes and skin biopsies","pmids":["22622422"],"confidence":"High","gaps":["Whether compensatory upregulation is transcriptionally driven or reflects post-translational stabilization is unclear","Which specific cross-linked products are missing in TG5-deficient cornified envelopes has not been mapped"]},{"year":2015,"claim":"The allelic spectrum of pathogenic TGM5 variants was expanded with splice-site and missense mutations confirmed to abolish TG5 activity, reinforcing that catalytic loss is the unifying pathogenic mechanism.","evidence":"Transglutaminase activity assay and RT-PCR for aberrant splicing in patient samples","pmids":["25644735"],"confidence":"Medium","gaps":["Single study; independent replication of specific splice-site consequences not yet reported","Quantitative relationship between residual TG5 activity and disease severity not established"]},{"year":null,"claim":"The specific cross-linked protein products generated by TG5 in vivo, the structural determinants of substrate selectivity, and the functional interplay with TG1 and TG3 in cornified envelope assembly remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure or cryo-EM structure of TG5 available","No Tgm5-knockout mouse model reported","Genotype–phenotype correlation across the full mutation spectrum is incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["KRT1","KRT10","IVL","LOR","CDSN"],"other_free_text":[]},"mechanistic_narrative":"TGM5 encodes transglutaminase 5 (TG5), a calcium-dependent enzyme strongly expressed in epidermal granular cells that catalyzes protein cross-linking of structural substrates—including keratins 1 and 10, involucrin, loricrin, and corneodesmosin—during terminal differentiation to form the cornified cell envelope [PMID:16380904, PMID:22622422]. Loss-of-function mutations in TGM5, such as the recurrent G113C missense change that completely abolishes enzymatic activity in vitro, cause acral peeling skin syndrome (APSS) by disrupting cell–cell adhesion between the stratum granulosum and stratum corneum [PMID:16380904, PMID:25644735]. In APSS keratinocytes, compensatory upregulation of cornified envelope components occurs in response to TG5 deficiency, indicating a feedback mechanism for epidermal barrier stabilization [PMID:22622422]."},"prefetch_data":{"uniprot":{"accession":"O43548","full_name":"Protein-glutamine gamma-glutamyltransferase 5","aliases":["Transglutaminase X","TG(X)","TGX","TGase X","Transglutaminase-5","TGase-5"],"length_aa":720,"mass_kda":80.8,"function":"Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Contributes to the formation of the cornified cell envelope of keratinocytes","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O43548/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TGM5","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":[],"url":"https://opencell.sf.czbiohub.org/search/TGM5","total_profiled":1310},"omim":[{"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":"609796","title":"PEELING SKIN SYNDROME 2; PSS2","url":"https://www.omim.org/entry/609796"},{"mim_id":"607936","title":"PEELING SKIN SYNDROME 4; PSS4","url":"https://www.omim.org/entry/607936"},{"mim_id":"606776","title":"TRANSGLUTAMINASE 7; TGM7","url":"https://www.omim.org/entry/606776"},{"mim_id":"603805","title":"TRANSGLUTAMINASE 5; TGM5","url":"https://www.omim.org/entry/603805"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"esophagus","ntpm":11.4},{"tissue":"skin 1","ntpm":37.4}],"url":"https://www.proteinatlas.org/search/TGM5"},"hgnc":{"alias_symbol":["TGX","TGMX"],"prev_symbol":[]},"alphafold":{"accession":"O43548","domains":[{"cath_id":"2.60.40.10","chopping":"8-140","consensus_level":"high","plddt":93.2374,"start":8,"end":140},{"cath_id":"3.90.260.10","chopping":"155-468","consensus_level":"medium","plddt":95.2113,"start":155,"end":468},{"cath_id":"2.60.40.10","chopping":"508-617","consensus_level":"high","plddt":94.0694,"start":508,"end":617},{"cath_id":"2.60.40.10","chopping":"624-717","consensus_level":"high","plddt":95.878,"start":624,"end":717}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43548","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43548-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43548-F1-predicted_aligned_error_v6.png","plddt_mean":91.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TGM5","jax_strain_url":"https://www.jax.org/strain/search?query=TGM5"},"sequence":{"accession":"O43548","fasta_url":"https://rest.uniprot.org/uniprotkb/O43548.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43548/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43548"}},"corpus_meta":[{"pmid":"16380904","id":"PMC_16380904","title":"A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.","date":"2005","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16380904","citation_count":97,"is_preprint":false},{"pmid":"22494444","id":"PMC_22494444","title":"Prodrug strategy for PSMA-targeted delivery of TGX-221 to prostate cancer cells.","date":"2012","source":"Molecular pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/22494444","citation_count":42,"is_preprint":false},{"pmid":"30488505","id":"PMC_30488505","title":"Assessment of the performance of the TGx-DDI biomarker to detect DNA damage-inducing agents using quantitative RT-PCR in TK6 cells.","date":"2018","source":"Environmental and molecular mutagenesis","url":"https://pubmed.ncbi.nlm.nih.gov/30488505","citation_count":36,"is_preprint":false},{"pmid":"33693359","id":"PMC_33693359","title":"TGx-DDI, a Transcriptomic Biomarker for Genotoxicity Hazard Assessment 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peeling skin syndrome.","date":"2012","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/22622422","citation_count":31,"is_preprint":false},{"pmid":"32042365","id":"PMC_32042365","title":"Flow cytometric micronucleus assay and TGx-DDI transcriptomic biomarker analysis of ten genotoxic and non-genotoxic chemicals in human HepaRG™ cells.","date":"2020","source":"Genes and environment : the official journal of the Japanese Environmental Mutagen Society","url":"https://pubmed.ncbi.nlm.nih.gov/32042365","citation_count":29,"is_preprint":false},{"pmid":"29048665","id":"PMC_29048665","title":"TGX-221 inhibits proliferation and induces apoptosis in human glioblastoma cells.","date":"2017","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/29048665","citation_count":19,"is_preprint":false},{"pmid":"28766826","id":"PMC_28766826","title":"The TGx-28.65 biomarker online application for analysis of transcriptomics data to identify DNA damage-inducing chemicals in human cell cultures.","date":"2017","source":"Environmental and molecular mutagenesis","url":"https://pubmed.ncbi.nlm.nih.gov/28766826","citation_count":17,"is_preprint":false},{"pmid":"33770205","id":"PMC_33770205","title":"Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells.","date":"2021","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/33770205","citation_count":17,"is_preprint":false},{"pmid":"10826808","id":"PMC_10826808","title":"Bradyrhizobium spp. (TGx) isolates nodulating the new soybean cultivars in Africa are diverse and distinct from bradyrhizobia that nodulate North American soybeans.","date":"2000","source":"International journal of systematic and evolutionary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/10826808","citation_count":16,"is_preprint":false},{"pmid":"29017062","id":"PMC_29017062","title":"Integration of the TGx-28.65 genomic biomarker with the flow cytometry micronucleus test to assess the genotoxicity of disperse orange and 1,2,4-benzenetriol in human TK6 cells.","date":"2017","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/29017062","citation_count":15,"is_preprint":false},{"pmid":"34557502","id":"PMC_34557502","title":"Topical Application of the PI3Kβ-Selective Small Molecule Inhibitor TGX-221 Is an Effective Treatment Option for Experimental Epidermolysis Bullosa Acquisita.","date":"2021","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34557502","citation_count":12,"is_preprint":false},{"pmid":"25644735","id":"PMC_25644735","title":"Novel TGM5 mutations in acral peeling skin syndrome.","date":"2015","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/25644735","citation_count":11,"is_preprint":false},{"pmid":"25890698","id":"PMC_25890698","title":"Exploring the isoform selectivity of TGX-221 related pyrido[1,2-a]pyrimidinone-based Class IA PI 3-kinase inhibitors: synthesis, biological evaluation and molecular modelling.","date":"2015","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25890698","citation_count":10,"is_preprint":false},{"pmid":"36211197","id":"PMC_36211197","title":"Integrated Genotoxicity Testing of three anti-infective drugs using the TGx-DDI transcriptomic biomarker and high-throughput CometChip® assay in TK6 cells.","date":"2022","source":"Frontiers in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/36211197","citation_count":7,"is_preprint":false},{"pmid":"36950431","id":"PMC_36950431","title":"Role of the antineoplastic drug bleomycin based on toxicogenomic-DNA damage inducing (TGx-DDI) genomic biomarkers data: A meta-analysis.","date":"2023","source":"Pakistan journal of medical 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Variety.","date":"2020","source":"Microbiology resource announcements","url":"https://pubmed.ncbi.nlm.nih.gov/32409532","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13616,"output_tokens":917,"usd":0.027301},"stage2":{"model":"claude-opus-4-6","input_tokens":4104,"output_tokens":1241,"usd":0.077317},"total_usd":0.104618,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"TGM5 encodes transglutaminase 5 (TG5), which is strongly expressed in epidermal granular cells and cross-links structural proteins during terminal epidermal differentiation to form the cornified cell envelope; the missense mutation G113C completely abolishes TG5 enzymatic activity in vitro, while T109M does not, demonstrating that TG5 protein cross-linking activity is essential for cell-cell adhesion between the outermost epidermal layers.\",\n      \"method\": \"In vitro biochemical cross-linking assay; 3D structural modeling; homozygosity mapping; mutation analysis in patients with acral peeling skin syndrome\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay with mutagenesis, structural modeling, and disease-linked loss-of-function validation\",\n      \"pmids\": [\"16380904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TGM5 mutations (p.M1T, p.L41P, p.L214CfsX15, p.S604IfsX9, and the recurrent p.G113C) impair TG5 function and alter expression and distribution of epidermal differentiation markers (keratin 1, keratin 10, involucrin, loricrin, and corneodesmosin) in APSS keratinocytes, indicating TG5 is required for normal terminal epidermal differentiation; upregulation of these markers appears to represent a compensatory mechanism for epidermal barrier stabilization.\",\n      \"method\": \"Quantitative real-time PCR, immunoblotting, immunofluorescence analysis of patient keratinocytes and skin; functional transglutaminase activity assay\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (activity assay, qPCR, immunoblot, immunofluorescence) in patient-derived material\",\n      \"pmids\": [\"22622422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Novel TGM5 mutations (c.1001+2_1001+3del, c.1171G>A, c.1498C>T) were confirmed to abolish transglutaminase-5 activity using a functional transglutaminase activity assay, and alternative splicing consequences were demonstrated by RT-PCR, establishing pathogenicity at the molecular level.\",\n      \"method\": \"Transglutaminase activity assay; reverse-transcribed PCR for alternative splicing; in silico prediction tools\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional activity assay combined with RT-PCR, single study\",\n      \"pmids\": [\"25644735\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TGM5 encodes transglutaminase 5 (TG5), an enzyme expressed in epidermal granular cells that cross-links structural proteins (including keratins, involucrin, loricrin, and corneodesmosin) to form the cornified cell envelope during terminal epidermal differentiation; loss of TG5 catalytic activity—caused by mutations such as G113C that lie close to the catalytic domain—disrupts protein cross-linking and cell-cell adhesion between the stratum granulosum and stratum corneum, leading to acral peeling skin syndrome.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TGM5 encodes transglutaminase 5 (TG5), a calcium-dependent enzyme strongly expressed in epidermal granular cells that catalyzes protein cross-linking of structural substrates—including keratins 1 and 10, involucrin, loricrin, and corneodesmosin—during terminal differentiation to form the cornified cell envelope [PMID:16380904, PMID:22622422]. Loss-of-function mutations in TGM5, such as the recurrent G113C missense change that completely abolishes enzymatic activity in vitro, cause acral peeling skin syndrome (APSS) by disrupting cell–cell adhesion between the stratum granulosum and stratum corneum [PMID:16380904, PMID:25644735]. In APSS keratinocytes, compensatory upregulation of cornified envelope components occurs in response to TG5 deficiency, indicating a feedback mechanism for epidermal barrier stabilization [PMID:22622422].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"The central question of whether TG5 enzymatic cross-linking activity is essential for epidermal cohesion was answered: the G113C mutation abolishes TG5 activity in vitro, establishing a direct causal link between TGM5 loss-of-function and acral peeling skin syndrome.\",\n      \"evidence\": \"In vitro biochemical cross-linking assay, 3D structural modeling, and homozygosity mapping in APSS families\",\n      \"pmids\": [\"16380904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No in vivo animal model to confirm epidermal barrier defect is cell-autonomous\",\n        \"Structural basis of catalytic inactivation by G113C not resolved at atomic resolution\",\n        \"Relative contribution of TG5 versus other transglutaminases (TG1, TG3) to cornified envelope formation not delineated\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The downstream consequences of TG5 deficiency in patient skin were characterized: multiple TGM5 mutations alter the expression and distribution of key differentiation markers (K1, K10, involucrin, loricrin, corneodesmosin), revealing compensatory upregulation that partially stabilizes the barrier.\",\n      \"evidence\": \"qPCR, immunoblotting, immunofluorescence, and transglutaminase activity assay in APSS patient keratinocytes and skin biopsies\",\n      \"pmids\": [\"22622422\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether compensatory upregulation is transcriptionally driven or reflects post-translational stabilization is unclear\",\n        \"Which specific cross-linked products are missing in TG5-deficient cornified envelopes has not been mapped\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The allelic spectrum of pathogenic TGM5 variants was expanded with splice-site and missense mutations confirmed to abolish TG5 activity, reinforcing that catalytic loss is the unifying pathogenic mechanism.\",\n      \"evidence\": \"Transglutaminase activity assay and RT-PCR for aberrant splicing in patient samples\",\n      \"pmids\": [\"25644735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study; independent replication of specific splice-site consequences not yet reported\",\n        \"Quantitative relationship between residual TG5 activity and disease severity not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The specific cross-linked protein products generated by TG5 in vivo, the structural determinants of substrate selectivity, and the functional interplay with TG1 and TG3 in cornified envelope assembly remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal structure or cryo-EM structure of TG5 available\",\n        \"No Tgm5-knockout mouse model reported\",\n        \"Genotype–phenotype correlation across the full mutation spectrum is incomplete\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0140096\",\n        \"supporting_discovery_ids\": [0, 1, 2]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005829\",\n        \"supporting_discovery_ids\": [1]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1266738\",\n        \"supporting_discovery_ids\": [0, 1]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"KRT1\",\n      \"KRT10\",\n      \"IVL\",\n      \"LOR\",\n      \"CDSN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}