{"gene":"CA14","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":1999,"finding":"Human CA14 encodes a 337-amino-acid transmembrane carbonic anhydrase with hydrophobic signal sequence and transmembrane domain at both termini, similar to CA XII. CA14 showed low carbonic anhydrase activity that was sensitive to acetazolamide but not to sulfonamide inhibition, establishing it as a membrane-bound, catalytically active but low-activity CA isozyme.","method":"cDNA cloning, sequence analysis, enzymatic activity assay, Northern blot, RT-PCR","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — enzymatic activity assay and cloning in a single paper; no mutagenesis or structural validation","pmids":["10512682"],"is_preprint":false},{"year":2009,"finding":"CA14 (along with CA4) facilitates AE3-mediated Cl⁻-HCO₃⁻ exchange in hippocampal neurons to regulate intracellular pH. Inhibition of extracellular CA14 with isoform-specific inhibitory antibodies enhanced NH₄⁺-induced cytosolic alkalinization; this effect was abolished when Cl⁻ was removed or anion exchange was blocked by DIDS, and was absent in AE3-knockout neurons.","method":"Inhibitory antibody treatment, pharmacological blockade (benzolamide, DIDS), AE3 knockout mouse neurons, quantitative PCR, single-cell PCR, intracellular pH measurement","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (isoform-specific antibody, genetic KO, pharmacological blockade) in a single rigorous study with clean phenotypic readout","pmids":["19279262"],"is_preprint":false},{"year":2019,"finding":"In melanocytes, MITF activation directly induces CA14 expression. CA14 localizes to the nucleus, where it elevates intracellular pH, which in turn activates the histone acetyltransferase p300/CBP, leading to enhanced H3K27 acetylation at melanocyte differentiation gene loci and amplified MITF-driven gene expression. CRISPR-mediated missense mutation of CA14 in zebrafish produced immature acidic melanocytes with decreased pigmentation.","method":"Cell-based overexpression/knockdown, intracellular pH measurement, CRISPR-mediated zebrafish mutation, histone acetylation assays (H3K27ac ChIP), reporter assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (CRISPR in vivo, pH measurement, ChIP, cell-based functional assays) in one study establishing a nuclear pH-epigenetic mechanism","pmids":["31709752"],"is_preprint":false},{"year":2014,"finding":"CA14 mRNA expression in rat retina is downregulated by low dietary zinc (decreased after 2 and 4 weeks of zinc deficiency) and recovers upon return to normal zinc diet, indicating that CA14 expression is regulated by zinc availability.","method":"RT-PCR on rat retinal RNA from dietary zinc manipulation groups","journal":"Genetics and molecular research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (RT-PCR), single lab, no mechanistic follow-up beyond expression measurement","pmids":["24634117"],"is_preprint":false},{"year":2022,"finding":"Morpholino-based silencing of ca14 in zebrafish larvae reduced melanin content per cell without altering melanocyte number, classifying CA14 as a melanocyte 'differentiator' (affecting melanin synthesis/maturation) rather than a 'specifier' (affecting melanocyte fate/number).","method":"Morpholino knockdown in zebrafish, FACS-based dissection of melanocyte number vs. pigment content, fluorescent transgenic reporter lines","journal":"Journal of visualized experiments","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean loss-of-function with defined cellular phenotype in an in vivo model, single lab, single approach","pmids":["35312674"],"is_preprint":false}],"current_model":"CA14 is a membrane-bound, catalytically active carbonic anhydrase isozyme (low activity, acetazolamide-sensitive) that functions extracellularly to facilitate AE3-mediated Cl⁻-HCO₃⁻ exchange and intracellular pH regulation in hippocampal neurons, and intracellularly in melanocytes where nuclear CA14 raises intracellular pH to activate p300/CBP histone acetyltransferase activity, thereby amplifying MITF-driven H3K27 acetylation and melanocyte differentiation gene expression."},"narrative":{"mechanistic_narrative":"CA14 is a membrane-bound carbonic anhydrase isozyme with low, acetazolamide-sensitive catalytic activity that regulates pH in both extracellular and intracellular compartments to support neuronal pH homeostasis and melanocyte differentiation [PMID:10512682]. At the neuronal cell surface, extracellular CA14 facilitates AE3-mediated Cl⁻–HCO₃⁻ exchange to control intracellular pH in hippocampal neurons; antibody inhibition of CA14 enhances cytosolic alkalinization in a manner dependent on Cl⁻, anion exchange, and AE3, placing CA14 within a CA–anion-exchanger metabolon [PMID:19279262]. In melanocytes, CA14 expression is directly induced by MITF, and nuclear CA14 raises intracellular pH to activate p300/CBP histone acetyltransferase activity, amplifying H3K27 acetylation at melanocyte differentiation loci and reinforcing MITF-driven gene expression [PMID:31709752]. Consistent with this role, loss of CA14 in zebrafish produces acidic, hypopigmented melanocytes with reduced melanin content but normal melanocyte number, defining it as a differentiation effector rather than a fate specifier [PMID:31709752, PMID:35312674].","teleology":[{"year":1999,"claim":"Established that CA14 is a genuine, catalytically active carbonic anhydrase, distinguishing it as a membrane-anchored low-activity isozyme rather than a non-catalytic CA-related protein.","evidence":"cDNA cloning, sequence analysis, and enzymatic activity assay of human CA14","pmids":["10512682"],"confidence":"Medium","gaps":["No mutagenesis or structural confirmation of the catalytic site","Physiological substrate context and tissue function not addressed","Topology of dual-terminal hydrophobic domains inferred from sequence only"]},{"year":2009,"claim":"Defined a physiological function for surface CA14 by showing it couples to the anion exchanger AE3 to regulate neuronal intracellular pH, answering how the low-activity enzyme contributes to bicarbonate transport.","evidence":"Isoform-specific inhibitory antibody, pharmacological blockade (benzolamide, DIDS), and AE3-knockout mouse neurons with intracellular pH measurement","pmids":["19279262"],"confidence":"High","gaps":["Direct physical interaction between CA14 and AE3 not demonstrated","Quantitative contribution of CA14 versus CA4 not separated","Whether catalytic activity per se (vs. scaffolding) drives the effect untested"]},{"year":2019,"claim":"Revealed an unexpected intracellular/nuclear role linking CA14 to chromatin regulation, showing that MITF-induced nuclear CA14 raises pH to activate p300/CBP and amplify melanocyte differentiation gene expression.","evidence":"Cell-based overexpression/knockdown, intracellular pH measurement, H3K27ac ChIP, reporter assays, and CRISPR-mediated zebrafish missense mutation","pmids":["31709752"],"confidence":"High","gaps":["Mechanism of CA14 nuclear targeting unknown for a membrane CA","Direct link between local pH change and p300/CBP activation not biochemically reconstituted","Whether catalytic activity is required for the nuclear effect not isolated"]},{"year":2022,"claim":"Classified CA14's developmental role by separating melanocyte number from pigment content, establishing it as a differentiation effector controlling melanin maturation rather than melanocyte fate.","evidence":"Morpholino knockdown in zebrafish with FACS-based dissection of melanocyte number versus pigment content","pmids":["35312674"],"confidence":"Medium","gaps":["Morpholino approach not corroborated by stable genetic mutant in same study","Molecular link to the nuclear pH/HAT mechanism not directly tested here"]},{"year":2014,"claim":"Showed CA14 expression is responsive to micronutrient availability, with retinal CA14 mRNA reduced by dietary zinc deficiency and recovering upon repletion.","evidence":"RT-PCR on rat retinal RNA from dietary zinc manipulation groups","pmids":["24634117"],"confidence":"Low","gaps":["Single-method expression correlation with no mechanistic follow-up","Whether regulation is direct or secondary to retinal physiology unknown","Functional consequence of altered CA14 levels in retina untested"]},{"year":null,"claim":"It remains unresolved whether CA14's catalytic CO₂/bicarbonate activity, as opposed to a structural/scaffolding role, is the proximate driver of its functions in neuronal pH coupling and nuclear epigenetic regulation.","evidence":"","pmids":[],"confidence":"Low","gaps":["No catalytic-dead mutant rescue experiments reported","No structural model of CA14 in either membrane or nuclear context","Mechanism of dual surface vs. nuclear localization unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[1]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULX7","full_name":"Carbonic anhydrase 14","aliases":["Carbonate dehydratase XIV","Carbonic anhydrase XIV","CA-XIV"],"length_aa":337,"mass_kda":37.7,"function":"Reversible hydration of carbon dioxide","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9ULX7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CA14","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CA14","total_profiled":1310},"omim":[{"mim_id":"604832","title":"CARBONIC ANHYDRASE XIV; CA14","url":"https://www.omim.org/entry/604832"},{"mim_id":"114760","title":"CARBONIC ANHYDRASE IV; CA4","url":"https://www.omim.org/entry/114760"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":43.3},{"tissue":"choroid plexus","ntpm":112.9},{"tissue":"retina","ntpm":36.5},{"tissue":"tongue","ntpm":44.3}],"url":"https://www.proteinatlas.org/search/CA14"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9ULX7","domains":[{"cath_id":"3.10.200.10","chopping":"29-275","consensus_level":"high","plddt":98.1335,"start":29,"end":275},{"cath_id":"1.20.5","chopping":"285-331","consensus_level":"medium","plddt":79.987,"start":285,"end":331}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULX7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULX7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULX7-F1-predicted_aligned_error_v6.png","plddt_mean":90.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CA14","jax_strain_url":"https://www.jax.org/strain/search?query=CA14"},"sequence":{"accession":"Q9ULX7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULX7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULX7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULX7"}},"corpus_meta":[{"pmid":"2851057","id":"PMC_2851057","title":"Distribution 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xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12048675","citation_count":2,"is_preprint":false},{"pmid":"15894934","id":"PMC_15894934","title":"Immunohistochemical Localization of Fas-associated phosphatase-1 (FAP-1) in Alzheimer disease hippocampus.","date":"2005","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/15894934","citation_count":2,"is_preprint":false},{"pmid":"24677295","id":"PMC_24677295","title":"Anterior-posterior cerebral blood volume gradient in human subiculum.","date":"2014","source":"Hippocampus","url":"https://pubmed.ncbi.nlm.nih.gov/24677295","citation_count":2,"is_preprint":false},{"pmid":"35312674","id":"PMC_35312674","title":"Reverse Genetic Approach to Identify Regulators of Pigmentation using Zebrafish.","date":"2022","source":"Journal of visualized experiments : 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CA14 showed low carbonic anhydrase activity that was sensitive to acetazolamide but not to sulfonamide inhibition, establishing it as a membrane-bound, catalytically active but low-activity CA isozyme.\",\n      \"method\": \"cDNA cloning, sequence analysis, enzymatic activity assay, Northern blot, RT-PCR\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — enzymatic activity assay and cloning in a single paper; no mutagenesis or structural validation\",\n      \"pmids\": [\"10512682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CA14 (along with CA4) facilitates AE3-mediated Cl⁻-HCO₃⁻ exchange in hippocampal neurons to regulate intracellular pH. Inhibition of extracellular CA14 with isoform-specific inhibitory antibodies enhanced NH₄⁺-induced cytosolic alkalinization; this effect was abolished when Cl⁻ was removed or anion exchange was blocked by DIDS, and was absent in AE3-knockout neurons.\",\n      \"method\": \"Inhibitory antibody treatment, pharmacological blockade (benzolamide, DIDS), AE3 knockout mouse neurons, quantitative PCR, single-cell PCR, intracellular pH measurement\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (isoform-specific antibody, genetic KO, pharmacological blockade) in a single rigorous study with clean phenotypic readout\",\n      \"pmids\": [\"19279262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In melanocytes, MITF activation directly induces CA14 expression. CA14 localizes to the nucleus, where it elevates intracellular pH, which in turn activates the histone acetyltransferase p300/CBP, leading to enhanced H3K27 acetylation at melanocyte differentiation gene loci and amplified MITF-driven gene expression. CRISPR-mediated missense mutation of CA14 in zebrafish produced immature acidic melanocytes with decreased pigmentation.\",\n      \"method\": \"Cell-based overexpression/knockdown, intracellular pH measurement, CRISPR-mediated zebrafish mutation, histone acetylation assays (H3K27ac ChIP), reporter assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (CRISPR in vivo, pH measurement, ChIP, cell-based functional assays) in one study establishing a nuclear pH-epigenetic mechanism\",\n      \"pmids\": [\"31709752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CA14 mRNA expression in rat retina is downregulated by low dietary zinc (decreased after 2 and 4 weeks of zinc deficiency) and recovers upon return to normal zinc diet, indicating that CA14 expression is regulated by zinc availability.\",\n      \"method\": \"RT-PCR on rat retinal RNA from dietary zinc manipulation groups\",\n      \"journal\": \"Genetics and molecular research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (RT-PCR), single lab, no mechanistic follow-up beyond expression measurement\",\n      \"pmids\": [\"24634117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Morpholino-based silencing of ca14 in zebrafish larvae reduced melanin content per cell without altering melanocyte number, classifying CA14 as a melanocyte 'differentiator' (affecting melanin synthesis/maturation) rather than a 'specifier' (affecting melanocyte fate/number).\",\n      \"method\": \"Morpholino knockdown in zebrafish, FACS-based dissection of melanocyte number vs. pigment content, fluorescent transgenic reporter lines\",\n      \"journal\": \"Journal of visualized experiments\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean loss-of-function with defined cellular phenotype in an in vivo model, single lab, single approach\",\n      \"pmids\": [\"35312674\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CA14 is a membrane-bound, catalytically active carbonic anhydrase isozyme (low activity, acetazolamide-sensitive) that functions extracellularly to facilitate AE3-mediated Cl⁻-HCO₃⁻ exchange and intracellular pH regulation in hippocampal neurons, and intracellularly in melanocytes where nuclear CA14 raises intracellular pH to activate p300/CBP histone acetyltransferase activity, thereby amplifying MITF-driven H3K27 acetylation and melanocyte differentiation gene expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CA14 is a membrane-bound carbonic anhydrase isozyme with low, acetazolamide-sensitive catalytic activity that regulates pH in both extracellular and intracellular compartments to support neuronal pH homeostasis and melanocyte differentiation [#0]. At the neuronal cell surface, extracellular CA14 facilitates AE3-mediated Cl\\u207b\\u2013HCO\\u2083\\u207b exchange to control intracellular pH in hippocampal neurons; antibody inhibition of CA14 enhances cytosolic alkalinization in a manner dependent on Cl\\u207b, anion exchange, and AE3, placing CA14 within a CA\\u2013anion-exchanger metabolon [#1]. In melanocytes, CA14 expression is directly induced by MITF, and nuclear CA14 raises intracellular pH to activate p300/CBP histone acetyltransferase activity, amplifying H3K27 acetylation at melanocyte differentiation loci and reinforcing MITF-driven gene expression [#2]. Consistent with this role, loss of CA14 in zebrafish produces acidic, hypopigmented melanocytes with reduced melanin content but normal melanocyte number, defining it as a differentiation effector rather than a fate specifier [#2, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that CA14 is a genuine, catalytically active carbonic anhydrase, distinguishing it as a membrane-anchored low-activity isozyme rather than a non-catalytic CA-related protein.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and enzymatic activity assay of human CA14\",\n      \"pmids\": [\"10512682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No mutagenesis or structural confirmation of the catalytic site\",\n        \"Physiological substrate context and tissue function not addressed\",\n        \"Topology of dual-terminal hydrophobic domains inferred from sequence only\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined a physiological function for surface CA14 by showing it couples to the anion exchanger AE3 to regulate neuronal intracellular pH, answering how the low-activity enzyme contributes to bicarbonate transport.\",\n      \"evidence\": \"Isoform-specific inhibitory antibody, pharmacological blockade (benzolamide, DIDS), and AE3-knockout mouse neurons with intracellular pH measurement\",\n      \"pmids\": [\"19279262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct physical interaction between CA14 and AE3 not demonstrated\",\n        \"Quantitative contribution of CA14 versus CA4 not separated\",\n        \"Whether catalytic activity per se (vs. scaffolding) drives the effect untested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed an unexpected intracellular/nuclear role linking CA14 to chromatin regulation, showing that MITF-induced nuclear CA14 raises pH to activate p300/CBP and amplify melanocyte differentiation gene expression.\",\n      \"evidence\": \"Cell-based overexpression/knockdown, intracellular pH measurement, H3K27ac ChIP, reporter assays, and CRISPR-mediated zebrafish missense mutation\",\n      \"pmids\": [\"31709752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of CA14 nuclear targeting unknown for a membrane CA\",\n        \"Direct link between local pH change and p300/CBP activation not biochemically reconstituted\",\n        \"Whether catalytic activity is required for the nuclear effect not isolated\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Classified CA14's developmental role by separating melanocyte number from pigment content, establishing it as a differentiation effector controlling melanin maturation rather than melanocyte fate.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish with FACS-based dissection of melanocyte number versus pigment content\",\n      \"pmids\": [\"35312674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Morpholino approach not corroborated by stable genetic mutant in same study\",\n        \"Molecular link to the nuclear pH/HAT mechanism not directly tested here\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed CA14 expression is responsive to micronutrient availability, with retinal CA14 mRNA reduced by dietary zinc deficiency and recovering upon repletion.\",\n      \"evidence\": \"RT-PCR on rat retinal RNA from dietary zinc manipulation groups\",\n      \"pmids\": [\"24634117\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single-method expression correlation with no mechanistic follow-up\",\n        \"Whether regulation is direct or secondary to retinal physiology unknown\",\n        \"Functional consequence of altered CA14 levels in retina untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether CA14's catalytic CO\\u2082/bicarbonate activity, as opposed to a structural/scaffolding role, is the proximate driver of its functions in neuronal pH coupling and nuclear epigenetic regulation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No catalytic-dead mutant rescue experiments reported\",\n        \"No structural model of CA14 in either membrane or nuclear context\",\n        \"Mechanism of dual surface vs. nuclear localization unexplained\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":4,"faith_pct":75.0}}