{"gene":"TOMT","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2008,"finding":"LRTOMT has two alternative reading frames encoding two distinct proteins (LRTOMT1 and LRTOMT2); LRTOMT2 is a putative methyltransferase. In primates, LRTOMT arose from fusion of two ancestral genes that remain separate in rodents (Lrrc51 and Tomt).","method":"Protein blot analysis, positional cloning, evolutionary genomic analysis","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein blot detection of two products and evolutionary analysis, single lab, two orthogonal methods but no functional reconstitution of methyltransferase activity","pmids":["18953341"],"is_preprint":false},{"year":2017,"finding":"TOMT is enriched in the Golgi of hair cells and is required for trafficking of Tmc1/2 proteins into the hair bundle; in tomt-deficient zebrafish hair cells, Tmc1/2 are specifically excluded from the hair bundle while other mechanotransduction (MET) complex proteins can still localize there, abolishing mechanotransduction.","method":"Zebrafish tomt mutant model, GFP-tagged Tomt live imaging/confocal localization, mechanotransduction functional assays, immunofluorescence of Tmc1/2 localization","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function zebrafish model with defined cellular phenotype, direct localization imaging with functional consequence, replicated across MET assay and trafficking assay in a single rigorous study","pmids":["28534737"],"is_preprint":false},{"year":2017,"finding":"Mouse TOMT and TMC1 directly interact, as demonstrated in HEK 293 cells, and this interaction is modulated by His183 in TOMT.","method":"Co-immunoprecipitation in HEK 293 cells, site-directed mutagenesis (His183 mutant)","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction shown with mutagenesis, single lab, heterologous expression system","pmids":["28534737"],"is_preprint":false},{"year":2017,"finding":"The role of mTOMT in hair cell mechanotransduction is independent of its methyltransferase enzymatic activity; mCOMT (the canonical catecholamine methyltransferase paralog) cannot substitute for mTOMT function in hair cells.","method":"Knock-in mouse models with methyltransferase-dead mTOMT and mCOMT substitution, auditory/mechanotransduction functional assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — active-site mutagenesis in vivo combined with paralog substitution experiment, loss-of-function with clear functional readout, multiple orthogonal approaches in single study","pmids":["28504928"],"is_preprint":false},{"year":2017,"finding":"mTOMT binds to putative mechanotransduction channel components in cochlear hair cells and is essential for transport of some of these components into the mechanically sensitive stereocilia.","method":"Co-immunoprecipitation, immunofluorescence localization, murine knockout/knockin functional analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP binding plus loss-of-function localization defects with functional MET consequence, replicated independently from zebrafish study (PMID:28534737)","pmids":["28504928"],"is_preprint":false}],"current_model":"TOMT/LRTOMT2 is a Golgi-resident, methyltransferase-homology protein in cochlear and vestibular hair cells that functions — independently of catalytic methyltransferase activity — as a chaperone/trafficking factor that physically interacts with TMC1/2 (via His183) within the secretory pathway and is essential for delivering these mechanotransduction channel subunits to the stereocilia hair bundle, thereby enabling mechanotransduction; loss of TOMT specifically mislocalizes Tmc1/2 while leaving other MET complex components unaffected, causing profound deafness (DFNB63)."},"narrative":{"mechanistic_narrative":"TOMT (LRTOMT2) is a Golgi-enriched, methyltransferase-homology protein in cochlear and vestibular hair cells that functions as a trafficking factor required to deliver the mechanotransduction (MET) channel subunits TMC1/2 into the stereocilia hair bundle, thereby enabling hair-cell mechanotransduction [PMID:28534737, PMID:28504928]. In tomt-deficient hair cells, Tmc1/2 are specifically excluded from the hair bundle while other MET complex proteins still localize correctly, abolishing mechanotransduction [PMID:28534737]. TOMT directly binds TMC1, an interaction modulated by His183, providing a physical basis for its role in channel transport [PMID:28534737, PMID:28504928]. This chaperone/trafficking function is independent of catalytic methyltransferase activity: methyltransferase-dead TOMT retains function in hair cells, and the catecholamine methyltransferase paralog COMT cannot substitute for it [PMID:28504928]. The gene arose in primates from fusion of two ancestral genes (Lrrc51 and Tomt) that remain separate in rodents, with LRTOMT2 corresponding to the methyltransferase-homology product [PMID:18953341].","teleology":[{"year":2008,"claim":"Established the gene's identity and architecture, defining LRTOMT2 as a putative methyltransferase product and clarifying the primate-specific gene fusion underlying the locus.","evidence":"Protein blot analysis, positional cloning, and evolutionary genomic analysis","pmids":["18953341"],"confidence":"Medium","gaps":["No functional reconstitution of methyltransferase activity","No cellular role assigned at this stage"]},{"year":2017,"claim":"Resolved what TOMT does at the cellular level, showing it is Golgi-localized and selectively required to traffic Tmc1/2 into the hair bundle to enable mechanotransduction.","evidence":"Zebrafish tomt mutant with GFP-tagged Tomt live imaging, Tmc1/2 immunofluorescence, and mechanotransduction functional assays","pmids":["28534737"],"confidence":"High","gaps":["Mechanism of cargo selectivity for Tmc1/2 over other MET components unknown","How TOMT exits the Golgi and whether it accompanies cargo not defined"]},{"year":2017,"claim":"Provided a physical basis for the trafficking role by demonstrating a direct TOMT-TMC1 interaction dependent on His183.","evidence":"Co-immunoprecipitation in HEK 293 cells with His183 site-directed mutagenesis","pmids":["28534737"],"confidence":"Medium","gaps":["Heterologous system; not validated in native hair cells","Structural basis of the His183-dependent interface not determined"]},{"year":2017,"claim":"Separated TOMT's hair-cell function from its enzymatic homology, showing the trafficking role is independent of methyltransferase catalysis and not interchangeable with the COMT paralog.","evidence":"Knock-in mice with methyltransferase-dead TOMT and COMT substitution, plus Co-IP and immunofluorescence in cochlear hair cells","pmids":["28504928"],"confidence":"High","gaps":["Whether TOMT retains any enzymatic substrate in vivo is unresolved","Full set of MET components bound by TOMT not defined"]},{"year":null,"claim":"How TOMT achieves selective recognition and Golgi-to-stereocilia delivery of TMC1/2, and whether its methyltransferase fold has any residual biochemical activity, remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the TOMT-TMC1 complex","Mechanism distinguishing Tmc1/2 cargo from other MET proteins unknown","No identified enzymatic substrate"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,4]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,4]}],"complexes":[],"partners":["TMC1","TMC2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WZ04","full_name":"Transmembrane O-methyltransferase","aliases":["Catechol O-methyltransferase 2","Protein LRTOMT2"],"length_aa":291,"mass_kda":32.2,"function":"Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones (By similarity). Required for auditory function (PubMed:18794526). Component of the cochlear hair cell's mechanotransduction (MET) machinery. Involved in the assembly of the asymmetric tip-link MET complex. Required for transportation of TMC1 and TMC2 proteins into the mechanically sensitive stereocilia of the hair cells. The function in MET is independent of the enzymatic activity (By similarity)","subcellular_location":"Cytoplasm; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q8WZ04/entry"},"depmap":{"release":"DepMap","has_data":false,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TOMT"},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TOMT","total_profiled":1310},"omim":[{"mim_id":"612414","title":"LEUCINE-RICH TRANSMEMBRANE O-METHYLTRANSFERASE; LRTOMT","url":"https://www.omim.org/entry/612414"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Not detected","tissue_distribution":"Not detected","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TOMT"},"hgnc":{"alias_symbol":["COMT2"],"prev_symbol":[]},"alphafold":{"accession":"Q8WZ04","domains":[{"cath_id":"3.40.50.150","chopping":"116-288","consensus_level":"high","plddt":97.4943,"start":116,"end":288}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WZ04","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WZ04-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WZ04-F1-predicted_aligned_error_v6.png","plddt_mean":90.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TOMT","jax_strain_url":"https://www.jax.org/strain/search?query=TOMT"},"sequence":{"accession":"Q8WZ04","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WZ04.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WZ04/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WZ04"}},"corpus_meta":[{"pmid":"18953341","id":"PMC_18953341","title":"Mutations of LRTOMT, a fusion gene with alternative reading frames, cause nonsyndromic deafness in humans.","date":"2008","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18953341","citation_count":59,"is_preprint":false},{"pmid":"28534737","id":"PMC_28534737","title":"Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt).","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28534737","citation_count":50,"is_preprint":false},{"pmid":"28504928","id":"PMC_28504928","title":"The murine catecholamine methyltransferase mTOMT is essential for mechanotransduction by cochlear hair cells.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28504928","citation_count":30,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3307,"output_tokens":1217,"usd":0.014088,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7815,"output_tokens":1655,"usd":0.040225,"stage2_stop_reason":"end_turn"},"total_usd":0.054313,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"LRTOMT has two alternative reading frames encoding two distinct proteins (LRTOMT1 and LRTOMT2); LRTOMT2 is a putative methyltransferase. In primates, LRTOMT arose from fusion of two ancestral genes that remain separate in rodents (Lrrc51 and Tomt).\",\n      \"method\": \"Protein blot analysis, positional cloning, evolutionary genomic analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein blot detection of two products and evolutionary analysis, single lab, two orthogonal methods but no functional reconstitution of methyltransferase activity\",\n      \"pmids\": [\"18953341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TOMT is enriched in the Golgi of hair cells and is required for trafficking of Tmc1/2 proteins into the hair bundle; in tomt-deficient zebrafish hair cells, Tmc1/2 are specifically excluded from the hair bundle while other mechanotransduction (MET) complex proteins can still localize there, abolishing mechanotransduction.\",\n      \"method\": \"Zebrafish tomt mutant model, GFP-tagged Tomt live imaging/confocal localization, mechanotransduction functional assays, immunofluorescence of Tmc1/2 localization\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function zebrafish model with defined cellular phenotype, direct localization imaging with functional consequence, replicated across MET assay and trafficking assay in a single rigorous study\",\n      \"pmids\": [\"28534737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mouse TOMT and TMC1 directly interact, as demonstrated in HEK 293 cells, and this interaction is modulated by His183 in TOMT.\",\n      \"method\": \"Co-immunoprecipitation in HEK 293 cells, site-directed mutagenesis (His183 mutant)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction shown with mutagenesis, single lab, heterologous expression system\",\n      \"pmids\": [\"28534737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The role of mTOMT in hair cell mechanotransduction is independent of its methyltransferase enzymatic activity; mCOMT (the canonical catecholamine methyltransferase paralog) cannot substitute for mTOMT function in hair cells.\",\n      \"method\": \"Knock-in mouse models with methyltransferase-dead mTOMT and mCOMT substitution, auditory/mechanotransduction functional assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — active-site mutagenesis in vivo combined with paralog substitution experiment, loss-of-function with clear functional readout, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"28504928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"mTOMT binds to putative mechanotransduction channel components in cochlear hair cells and is essential for transport of some of these components into the mechanically sensitive stereocilia.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization, murine knockout/knockin functional analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP binding plus loss-of-function localization defects with functional MET consequence, replicated independently from zebrafish study (PMID:28534737)\",\n      \"pmids\": [\"28504928\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TOMT/LRTOMT2 is a Golgi-resident, methyltransferase-homology protein in cochlear and vestibular hair cells that functions — independently of catalytic methyltransferase activity — as a chaperone/trafficking factor that physically interacts with TMC1/2 (via His183) within the secretory pathway and is essential for delivering these mechanotransduction channel subunits to the stereocilia hair bundle, thereby enabling mechanotransduction; loss of TOMT specifically mislocalizes Tmc1/2 while leaving other MET complex components unaffected, causing profound deafness (DFNB63).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TOMT (LRTOMT2) is a Golgi-enriched, methyltransferase-homology protein in cochlear and vestibular hair cells that functions as a trafficking factor required to deliver the mechanotransduction (MET) channel subunits TMC1/2 into the stereocilia hair bundle, thereby enabling hair-cell mechanotransduction [#1, #4]. In tomt-deficient hair cells, Tmc1/2 are specifically excluded from the hair bundle while other MET complex proteins still localize correctly, abolishing mechanotransduction [#1]. TOMT directly binds TMC1, an interaction modulated by His183, providing a physical basis for its role in channel transport [#2, #4]. This chaperone/trafficking function is independent of catalytic methyltransferase activity: methyltransferase-dead TOMT retains function in hair cells, and the catecholamine methyltransferase paralog COMT cannot substitute for it [#3]. The gene arose in primates from fusion of two ancestral genes (Lrrc51 and Tomt) that remain separate in rodents, with LRTOMT2 corresponding to the methyltransferase-homology product [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established the gene's identity and architecture, defining LRTOMT2 as a putative methyltransferase product and clarifying the primate-specific gene fusion underlying the locus.\",\n      \"evidence\": \"Protein blot analysis, positional cloning, and evolutionary genomic analysis\",\n      \"pmids\": [\"18953341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional reconstitution of methyltransferase activity\", \"No cellular role assigned at this stage\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved what TOMT does at the cellular level, showing it is Golgi-localized and selectively required to traffic Tmc1/2 into the hair bundle to enable mechanotransduction.\",\n      \"evidence\": \"Zebrafish tomt mutant with GFP-tagged Tomt live imaging, Tmc1/2 immunofluorescence, and mechanotransduction functional assays\",\n      \"pmids\": [\"28534737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of cargo selectivity for Tmc1/2 over other MET components unknown\", \"How TOMT exits the Golgi and whether it accompanies cargo not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided a physical basis for the trafficking role by demonstrating a direct TOMT-TMC1 interaction dependent on His183.\",\n      \"evidence\": \"Co-immunoprecipitation in HEK 293 cells with His183 site-directed mutagenesis\",\n      \"pmids\": [\"28534737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Heterologous system; not validated in native hair cells\", \"Structural basis of the His183-dependent interface not determined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Separated TOMT's hair-cell function from its enzymatic homology, showing the trafficking role is independent of methyltransferase catalysis and not interchangeable with the COMT paralog.\",\n      \"evidence\": \"Knock-in mice with methyltransferase-dead TOMT and COMT substitution, plus Co-IP and immunofluorescence in cochlear hair cells\",\n      \"pmids\": [\"28504928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TOMT retains any enzymatic substrate in vivo is unresolved\", \"Full set of MET components bound by TOMT not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TOMT achieves selective recognition and Golgi-to-stereocilia delivery of TMC1/2, and whether its methyltransferase fold has any residual biochemical activity, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the TOMT-TMC1 complex\", \"Mechanism distinguishing Tmc1/2 cargo from other MET proteins unknown\", \"No identified enzymatic substrate\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TMC1\", \"TMC2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}