Tomt (mercury) is a membrane-associated protein enriched in the Golgi of zebrafish sensory hair cells, with additional reported endoplasmic-reticulum and basolateral membrane localization. It enables selective delivery of Tmc1 and Tmc2b to the stereociliary mechanotransduction complex and is required for hearing and balance. Its catechol O-methyltransferase-family domain supports inferred methyltransferase activity, but the endogenous methyl-acceptor substrate is unresolved. Mouse TOMT active-site-mutant rescue and the failure of zebrafish Comt to substitute show that the hair-cell trafficking role is separable from canonical catecholamine metabolism; they do not establish that native zebrafish Tomt lacks methyltransferase activity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0032502 developmental process | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the developmental annotation as inherited or experimentally curated participation in sensory-cell maturation. Reason: Tomt supplies the functional Tmc-trafficking machinery of sensory hair cells. Normal gross morphology and rapid rescue in mature cells narrow the phenotype to mechanotransduction, but do not exclude contribution to functional differentiation or neuromast development. The developmental IBA is inherited from an actual ancestor, not a label-only transfer. For the older IMP rows, the abstract-only source limits independent reconstruction of the developmental assay, so the curator-established assertion is retained with corroborating target mechanistic evidence rather than rejected because a title or abstract emphasizes another outcome. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000053580 SUPPORTS TRANSFER The live PTHR43836 tree explicitly places A0A193KX02 leaf PTN005185343 beneath this positive ancestor. Target-specific trafficking data do not demonstrate loss of the independently inherited function. Supporting Evidence: PMID:28534737 Tomt is required for trafficking Tmc proteins to the hair bundle file:DANRE/tomt/tomt-A0A193KX02-paint-lineage.json PTN000053580 |
| GO:0016206 catechol O-methyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the inferred methyltransferase function with explicit distinction from the experimentally established trafficking role. Reason: The conserved family/domain and curated phylogenetic or similarity evidence support this molecular function. The actual PAINT tree places A0A193KX02 below the catechol O-methyltransferase IBD at PTN000053580. PMID:28534737 distinguishes non-mammalian conservation from mammalian active-site substitutions: the H183A rescue construct was mouse TOMT, not mutagenized zebrafish Tomt. Rescue establishes dispensability of canonical chemistry for mechanotransduction, not absence of a parallel native enzymatic activity. A retained fold alone would not prove catalysis; the ancestral assertion and comparative biochemical context supply the inference. Physiological substrate and catalytic measurements on native zebrafish Tomt remain unresolved. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000053580 SUPPORTS TRANSFER The live PTHR43836 tree explicitly places A0A193KX02 leaf PTN005185343 beneath this positive ancestor. Target-specific trafficking data do not demonstrate loss of the independently inherited function. Supporting Evidence: PMID:28534737 This DHWK motif is conserved in all vertebrate COMT orthologs and some vertebrate TOMT proteins, most notably those from non-mammalian species. PMID:28534737 To test whether H183 was required for TOMT function, we established a stable transgenic line of fish expressing Mmu.Tomt_H183A-GFP in hair cells. file:DANRE/tomt/tomt-A0A193KX02-paint-lineage.json PTN000053580 |
| GO:0042417 dopamine metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the inherited catecholamine-metabolism annotation; mechanotransduction rescue does not refute a parallel metabolic role. Reason: The target demonstrably descends from the positive PAINT ancestor PTN000053580, with no intervening loss assertion identified. The older review treated failure of COMT to rescue hair-cell mechanotransduction and rescue by mouse TOMT-H183A as proof of metabolic divergence. Those experiments instead separate the trafficking requirement from catecholamine metabolism; they neither assay all native zebrafish Tomt substrates nor demonstrate loss of the ancestral process. Retain the curated inference without claiming that dopamine/catecholamine metabolism causes the auditory phenotype or that a physiological zebrafish substrate has been measured. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000053580 SUPPORTS TRANSFER The live PTHR43836 tree explicitly places A0A193KX02 leaf PTN005185343 beneath this positive ancestor. Target-specific trafficking data do not demonstrate loss of the independently inherited function. Supporting Evidence: file:DANRE/tomt/tomt-A0A193KX02-paint-lineage.json PTN000053580 PMID:28534737 This result suggests that catecholamine metabolism is not the cause of the MET defects. |
| GO:0042424 catecholamine catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the inherited catecholamine-metabolism annotation; mechanotransduction rescue does not refute a parallel metabolic role. Reason: The target demonstrably descends from the positive PAINT ancestor PTN000053580, with no intervening loss assertion identified. The older review treated failure of COMT to rescue hair-cell mechanotransduction and rescue by mouse TOMT-H183A as proof of metabolic divergence. Those experiments instead separate the trafficking requirement from catecholamine metabolism; they neither assay all native zebrafish Tomt substrates nor demonstrate loss of the ancestral process. Retain the curated inference without claiming that dopamine/catecholamine metabolism causes the auditory phenotype or that a physiological zebrafish substrate has been measured. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000053580 SUPPORTS TRANSFER The live PTHR43836 tree explicitly places A0A193KX02 leaf PTN005185343 beneath this positive ancestor. Target-specific trafficking data do not demonstrate loss of the independently inherited function. Supporting Evidence: file:DANRE/tomt/tomt-A0A193KX02-paint-lineage.json PTN000053580 PMID:28534737 This result suggests that catecholamine metabolism is not the cause of the MET defects. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | ACCEPT | Summary: endoplasmic reticulum (GO:0005783) is supported for tomt. Reason: Retain the reported minor location alongside Golgi enrichment. The primary target imaging explicitly describes possible lower-level ER/basolateral Tomt-GFP; the relative enrichment and cautious wording are recorded rather than interpreted as exclusion of these compartments. Supporting Evidence: file:DANRE/tomt/tomt-uniprot.txt Required for transportation of TMC1 and TMC2 proteins into the mechanically sensitive stereocilia PMID:28534737 Tomt-GFP may be present at lower levels in the endoplasmic reticulum and the basolateral membrane in addition to the Golgi apparatus file:DANRE/tomt/tomt-deep-research-falcon.md TOMT is localized to the ER/secretory pathway and is required for **TMC1 transport into stereocilia** |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | ACCEPT | Summary: Golgi apparatus (GO:0005794) is supported for tomt. Reason: Functional Tomt-GFP is enriched in and partly colocalizes with a Golgi marker in zebrafish hair cells, directly supporting this major secretory-pathway location. Supporting Evidence: file:DANRE/tomt/tomt-uniprot.txt Required for transportation of TMC1 and TMC2 proteins into the mechanically sensitive stereocilia PMID:28534737 Tomt-GFP and Mgat1a_1-110-mKate2 are partially co-localized in hair cells file:DANRE/tomt/tomt-deep-research-falcon.md GFP-tagged Tomt is enriched in the Golgi and excluded from stereociliary bundles |
| GO:0008171 O-methyltransferase activity | IEA GO_REF:0000002 | ACCEPT | Summary: Retain the inferred methyltransferase function with explicit distinction from the experimentally established trafficking role. Reason: The conserved family/domain and curated phylogenetic or similarity evidence support this molecular function. The actual PAINT tree places A0A193KX02 below the catechol O-methyltransferase IBD at PTN000053580. PMID:28534737 distinguishes non-mammalian conservation from mammalian active-site substitutions: the H183A rescue construct was mouse TOMT, not mutagenized zebrafish Tomt. Rescue establishes dispensability of canonical chemistry for mechanotransduction, not absence of a parallel native enzymatic activity. A retained fold alone would not prove catalysis; the ancestral assertion and comparative biochemical context supply the inference. Physiological substrate and catalytic measurements on native zebrafish Tomt remain unresolved. Supporting Evidence: PMID:28534737 This DHWK motif is conserved in all vertebrate COMT orthologs and some vertebrate TOMT proteins, most notably those from non-mammalian species. PMID:28534737 To test whether H183 was required for TOMT function, we established a stable transgenic line of fish expressing Mmu.Tomt_H183A-GFP in hair cells. file:DANRE/tomt/tomt-A0A193KX02-paint-lineage.json PTN000053580 |
| GO:0016206 catechol O-methyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Retain the inferred methyltransferase function with explicit distinction from the experimentally established trafficking role. Reason: The conserved family/domain and curated phylogenetic or similarity evidence support this molecular function. The actual PAINT tree places A0A193KX02 below the catechol O-methyltransferase IBD at PTN000053580. PMID:28534737 distinguishes non-mammalian conservation from mammalian active-site substitutions: the H183A rescue construct was mouse TOMT, not mutagenized zebrafish Tomt. Rescue establishes dispensability of canonical chemistry for mechanotransduction, not absence of a parallel native enzymatic activity. A retained fold alone would not prove catalysis; the ancestral assertion and comparative biochemical context supply the inference. Physiological substrate and catalytic measurements on native zebrafish Tomt remain unresolved. Supporting Evidence: PMID:28534737 This DHWK motif is conserved in all vertebrate COMT orthologs and some vertebrate TOMT proteins, most notably those from non-mammalian species. PMID:28534737 To test whether H183 was required for TOMT function, we established a stable transgenic line of fish expressing Mmu.Tomt_H183A-GFP in hair cells. file:DANRE/tomt/tomt-A0A193KX02-paint-lineage.json PTN000053580 |
| GO:0016323 basolateral plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: basolateral plasma membrane (GO:0016323) is supported for tomt. Reason: Retain the reported minor location alongside Golgi enrichment. The primary target imaging explicitly describes possible lower-level ER/basolateral Tomt-GFP; the relative enrichment and cautious wording are recorded rather than interpreted as exclusion of these compartments. Supporting Evidence: file:DANRE/tomt/tomt-uniprot.txt Required for transportation of TMC1 and TMC2 proteins into the mechanically sensitive stereocilia PMID:28534737 Tomt-GFP may be present at lower levels in the endoplasmic reticulum and the basolateral membrane in addition to the Golgi apparatus file:DANRE/tomt/tomt-deep-research-falcon.md functions primarily in the **secretory pathway (Golgi/ER)** to enable **trafficking and bundle targeting of Tmc1/Tmc2 (MET channel subunits)** |
| GO:0016206 catechol O-methyltransferase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Retain the inferred methyltransferase function with explicit distinction from the experimentally established trafficking role. Reason: The conserved family/domain and curated phylogenetic or similarity evidence support this molecular function. The actual PAINT tree places A0A193KX02 below the catechol O-methyltransferase IBD at PTN000053580. PMID:28534737 distinguishes non-mammalian conservation from mammalian active-site substitutions: the H183A rescue construct was mouse TOMT, not mutagenized zebrafish Tomt. Rescue establishes dispensability of canonical chemistry for mechanotransduction, not absence of a parallel native enzymatic activity. A retained fold alone would not prove catalysis; the ancestral assertion and comparative biochemical context supply the inference. Physiological substrate and catalytic measurements on native zebrafish Tomt remain unresolved. Supporting Evidence: PMID:28534737 This DHWK motif is conserved in all vertebrate COMT orthologs and some vertebrate TOMT proteins, most notably those from non-mammalian species. PMID:28534737 To test whether H183 was required for TOMT function, we established a stable transgenic line of fish expressing Mmu.Tomt_H183A-GFP in hair cells. file:DANRE/tomt/tomt-A0A193KX02-paint-lineage.json PTN000053580 |
| GO:0005783 endoplasmic reticulum | IDA PMID:28534737 Integration of Tmc1/2 into the mechanotransduction complex i... | ACCEPT | Summary: endoplasmic reticulum (GO:0005783) is supported for tomt. Reason: Retain the reported minor location alongside Golgi enrichment. The primary target imaging explicitly describes possible lower-level ER/basolateral Tomt-GFP; the relative enrichment and cautious wording are recorded rather than interpreted as exclusion of these compartments. Supporting Evidence: PMID:28534737 Tomt-GFP may be present at lower levels in the endoplasmic reticulum and the basolateral membrane in addition to the Golgi apparatus file:DANRE/tomt/tomt-deep-research-falcon.md TOMT is localized to the ER/secretory pathway and is required for **TMC1 transport into stereocilia** |
| GO:0005794 Golgi apparatus | IDA PMID:28534737 Integration of Tmc1/2 into the mechanotransduction complex i... | ACCEPT | Summary: Golgi apparatus (GO:0005794) is supported for tomt. Reason: Functional Tomt-GFP is enriched in and partly colocalizes with a Golgi marker in zebrafish hair cells, directly supporting this major secretory-pathway location. Supporting Evidence: PMID:28534737 Tomt-GFP and Mgat1a_1-110-mKate2 are partially co-localized in hair cells file:DANRE/tomt/tomt-deep-research-falcon.md A functional Tomt-GFP fusion is reported to be **enriched in the Golgi** of zebrafish hair cells and excluded from the stereocilia bundle |
| GO:0016323 basolateral plasma membrane | IDA PMID:28534737 Integration of Tmc1/2 into the mechanotransduction complex i... | ACCEPT | Summary: basolateral plasma membrane (GO:0016323) is supported for tomt. Reason: Retain the reported minor location alongside Golgi enrichment. The primary target imaging explicitly describes possible lower-level ER/basolateral Tomt-GFP; the relative enrichment and cautious wording are recorded rather than interpreted as exclusion of these compartments. Supporting Evidence: PMID:28534737 Tomt-GFP may be present at lower levels in the endoplasmic reticulum and the basolateral membrane in addition to the Golgi apparatus file:DANRE/tomt/tomt-deep-research-falcon.md functions primarily in the **secretory pathway (Golgi/ER)** to enable **trafficking and bundle targeting of Tmc1/Tmc2 (MET channel subunits)** |
| GO:0031223 auditory behavior | IMP PMID:28534737 Integration of Tmc1/2 into the mechanotransduction complex i... | ACCEPT | Summary: Auditory behavior is an established consequence of Tomt-dependent sensory transduction. Reason: Loss and hair-cell-specific rescue connect Tomt to auditory responses. The organism-level scope does not make this genuine sensory function non-core merely because trafficking is the immediate molecular step. Supporting Evidence: PMID:28534737 non-transgenic mercury mutants exhibited a startle response to 2% of stimuli, confirming that Tomt-deficient zebrafish are deaf file:DANRE/tomt/tomt-deep-research-falcon.md mutants show auditory and vestibular phenotypes consistent with loss of sensory hair-cell function |
| GO:0042424 catecholamine catabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: Retain the inherited catecholamine-metabolism annotation; mechanotransduction rescue does not refute a parallel metabolic role. Reason: The target demonstrably descends from the positive PAINT ancestor PTN000053580, with no intervening loss assertion identified. The older review treated failure of COMT to rescue hair-cell mechanotransduction and rescue by mouse TOMT-H183A as proof of metabolic divergence. Those experiments instead separate the trafficking requirement from catecholamine metabolism; they neither assay all native zebrafish Tomt substrates nor demonstrate loss of the ancestral process. Retain the curated inference without claiming that dopamine/catecholamine metabolism causes the auditory phenotype or that a physiological zebrafish substrate has been measured. Supporting Evidence: file:DANRE/tomt/tomt-A0A193KX02-paint-lineage.json PTN000053580 PMID:28534737 This result suggests that catecholamine metabolism is not the cause of the MET defects. |
| GO:0060122 inner ear receptor cell stereocilium organization | IMP PMID:28534737 Integration of Tmc1/2 into the mechanotransduction complex i... | ACCEPT | Summary: inner ear receptor cell stereocilium organization (GO:0060122) is supported for tomt. Reason: Tomt-dependent delivery of Tmc1/Tmc2b establishes functional organization of the stereociliary complex; the paper also describes mild bundle morphology defects. Participation is supported beyond a generic loss-of-hearing phenotype. Supporting Evidence: PMID:28534737 GFP-tagged Tmc1 and Tmc2b fail to localize to the hair bundle in mercury mutants file:DANRE/tomt/tomt-deep-research-falcon.md Tmc1-GFP** and **Tmc2b-GFP** are absent from bundles and remain in the cell body |
| GO:0006897 endocytosis | IMP PMID:10526320 Defective calmodulin-dependent rapid apical endocytosis in z... | UNDECIDED | Summary: The endocytosis interpretation requires separation of vesicle uptake from dye permeation through MET channels. Reason: PMID:10526320 interpreted reduced rapid FM1-43 loading in mercury mutants as defective apical endocytosis. Only its abstract is cached. Subsequent primary work demonstrates FM1-43 permeation through hair-cell mechanotransducer channels, and PMID:28534737 directly establishes the target-specific MET defect and uses FM dyes as channel-function readouts. Thus reduced labeling does not itself establish reduced vesicle internalization. This is a concrete assay-interpretation conflict, not proof that Tomt cannot participate in endocytosis; retain UNDECIDED pending full-text assessment of independent endocytic evidence in the original experiments. Supporting Evidence: PMID:10526320 rapid apical endocytosis in zebrafish lateral line sensory hair cells is calcium and calmodulin dependent PMID:11549711 FM1-43 behaves as a permeant blocker of the mechanotransducer channel. PMID:28534737 Tomt-deficient hair cells have no evoked MET current and do not label with MET channel permeant FM dyes |
| GO:0035315 hair cell differentiation | IMP PMID:10526320 Defective calmodulin-dependent rapid apical endocytosis in z... | ACCEPT | Summary: Retain the developmental annotation as inherited or experimentally curated participation in sensory-cell maturation. Reason: Tomt supplies the functional Tmc-trafficking machinery of sensory hair cells. Normal gross morphology and rapid rescue in mature cells narrow the phenotype to mechanotransduction, but do not exclude contribution to functional differentiation or neuromast development. The developmental IBA is inherited from an actual ancestor, not a label-only transfer. For the older IMP rows, the abstract-only source limits independent reconstruction of the developmental assay, so the curator-established assertion is retained with corroborating target mechanistic evidence rather than rejected because a title or abstract emphasizes another outcome. Supporting Evidence: PMID:28534737 Tomt is required for trafficking Tmc proteins to the hair bundle file:DANRE/tomt/tomt-A0A193KX02-paint-lineage.json PTN000053580 |
| GO:0048884 neuromast development | IMP PMID:9491988 Genetic analysis of vertebrate sensory hair cell mechanosens... | ACCEPT | Summary: Retain the developmental annotation as inherited or experimentally curated participation in sensory-cell maturation. Reason: Tomt supplies the functional Tmc-trafficking machinery of sensory hair cells. Normal gross morphology and rapid rescue in mature cells narrow the phenotype to mechanotransduction, but do not exclude contribution to functional differentiation or neuromast development. The developmental IBA is inherited from an actual ancestor, not a label-only transfer. For the older IMP rows, the abstract-only source limits independent reconstruction of the developmental assay, so the curator-established assertion is retained with corroborating target mechanistic evidence rather than rejected because a title or abstract emphasizes another outcome. Supporting Evidence: PMID:28534737 Tomt is required for trafficking Tmc proteins to the hair bundle file:DANRE/tomt/tomt-A0A193KX02-paint-lineage.json PTN000053580 |
| GO:0050974 detection of mechanical stimulus involved in sensory perception | IMP PMID:9491988 Genetic analysis of vertebrate sensory hair cell mechanosens... | ACCEPT | Summary: detection of mechanical stimulus involved in sensory perception (GO:0050974) is supported for tomt. Reason: The mercury mutant has defective microphonic responses and sensory behavior; later Tomt identification, absent MET currents, and target-specific rescue confirm participation in mechanosensory detection. Supporting Evidence: PMID:9491988 orbiter, mercury, and gemini larvae have normal hair cell morphology and yet do not respond to acoustic-vibrational stimuli file:DANRE/tomt/tomt-deep-research-falcon.md essential for hair-cell mechano-electrical transduction (MET) |
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Download this section (compressed HTML)Q: What is the physiological methyl-acceptor substrate of Tomt in hair cells, if any, and is methyl transfer required for Tmc trafficking?
Q: Does Tomt act as a dedicated TMC chaperone in the secretory pathway, or does it more broadly assist folding/trafficking of other MET-complex membrane proteins?
Q: Does PMID:10526320 show a Tomt/mercury endocytic defect independently of rapid FM1-43 entry through mechanotransducer channels?
Experiment: Test direct zebrafish Tomt-Tmc interaction and native Tomt active-site variants while independently measuring methyl transfer and Tmc delivery. Distinguish these experiments from the published mouse TOMT-H183A rescue of zebrafish mutants.
Experiment: Perform unbiased biochemical screening (e.g., SAM-dependent methylation assays / proteomics) on Tomt-associated secretory-pathway clients to identify any endogenous methyl-acceptor substrate.
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