{"gene":"TMEM14C","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":2014,"finding":"TMEM14C is an inner mitochondrial membrane protein that functions as an importer of protoporphyrinogen IX into the mitochondrial matrix for heme synthesis. TMEM14C deficiency in mice causes porphyrin accumulation in fetal liver, erythroid maturation arrest, and embryonic lethality due to profound anemia. Rescue with a protoporphyrin IX analog ameliorated the heme synthesis defect, placing TMEM14C function in the terminal steps of the heme synthesis pathway.","method":"Gene expression profiling of differentiating erythroid cells, loss-of-function mouse model (knockout), in vitro erythroid cell culture with porphyrin analog rescue, subcellular fractionation/localization to inner mitochondrial membrane","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (in vivo KO, in vitro rescue, subcellular localization), strong mechanistic conclusion replicated in vivo and in vitro","pmids":["25157825"],"is_preprint":false},{"year":2022,"finding":"Mutant SF3B1 induces missplicing of TMEM14C (and ABCB7) during erythroid differentiation, reducing TMEM14C protein expression via 5' UTR alteration and reduced translation efficiency. Functional rescue of both TMEM14C and ABCB7, but not PPOX, markedly decreased ring sideroblast (RS) formation; combined rescue nearly abolished RS, demonstrating that coordinated missplicing of these mitochondrial transporters sequesters iron in mitochondria to cause RS.","method":"iPSC model of SF3B1-mutant MDS with in vitro erythroid differentiation, RNA-seq for missplicing, western blot for protein expression, polysome profiling for translation efficiency, functional rescue (overexpression of correctly spliced TMEM14C and ABCB7), RS quantification","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 — iPSC disease model with robust RS readout, multiple rescue experiments with orthogonal controls, mechanistic dissection of translation vs. splicing","pmids":["34861039"],"is_preprint":false},{"year":2016,"finding":"In Sf3b1-K700E knock-in mice, the murine orthologues of TMEM14C and ABCB7 were not aberrantly spliced, explaining the absence of ring sideroblasts in the mouse model despite the presence of anemia, and supporting a causal link between TMEM14C missplicing and RS formation in human MDS.","method":"Hematopoietic-specific Sf3b1-K700E knock-in mouse model, global RNA splicing analysis (RNA-seq) of hematopoietic cells","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic model with genome-wide splicing analysis; provides epistatic evidence linking TMEM14C missplicing to RS phenotype by its absence in the mouse","pmids":["27604819"],"is_preprint":false},{"year":2024,"finding":"The SF3B1 E592K variant retains normal RNA splicing of TMEM14C and ABCB7 (unlike canonical SF3B1 hotspot mutations), and this is associated with absence of ring sideroblasts, directly supporting the requirement for TMEM14C missplicing in RS pathogenesis.","method":"RNA splicing analysis of patient samples with SF3B1 E592K vs. canonical mutations, clinical correlation with ring sideroblast phenotype","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 — human patient RNA-seq data with clinical phenotype correlation; mechanistic inference from natural variant, single study","pmids":["38759096"],"is_preprint":false},{"year":2020,"finding":"In Toxoplasma gondii (an apicomplexan parasite), a Tmem14c homolog functions as a putative transporter involved in heme/porphyrin metabolism; its disruption increases susceptibility to dihydroartemisinin, linking Tmem14c-mediated porphyrin transport to artemisinin susceptibility in this organism.","method":"Genome-scale CRISPR screens in Toxoplasma gondii with dihydroartemisinin selection, genetic disruption of Tmem14c","journal":"Nature communications","confidence":"Low","confidence_rationale":"Tier 3 — non-mammalian organism (Toxoplasma); functional context (porphyrin/heme transport) consistent with mammalian TMEM14C but limited direct mechanistic validation","pmids":["32968076"],"is_preprint":false}],"current_model":"TMEM14C is an inner mitochondrial membrane protein that imports protoporphyrinogen IX into the mitochondrial matrix as an essential step in heme synthesis during erythropoiesis; in SF3B1-mutant MDS, aberrant splicing of TMEM14C (together with ABCB7) reduces its protein expression via 5' UTR alteration and impaired translation, causing mitochondrial iron sequestration and ring sideroblast formation."},"narrative":{"teleology":[{"year":2014,"claim":"The fundamental question of what transports protoporphyrinogen IX into the mitochondrial matrix was answered: TMEM14C was identified as this importer, establishing its essential role in terminal heme synthesis and erythropoiesis.","evidence":"Loss-of-function mouse model, subcellular fractionation to inner mitochondrial membrane, and porphyrin analog rescue in erythroid cells","pmids":["25157825"],"confidence":"High","gaps":["No direct transport assay with reconstituted TMEM14C in liposomes","Structural basis of substrate recognition for protoporphyrinogen IX unknown","Whether TMEM14C transports additional porphyrin intermediates not tested"]},{"year":2016,"claim":"The absence of TMEM14C missplicing in Sf3b1-K700E knock-in mice—which lack ring sideroblasts despite anemia—provided epistatic evidence that aberrant TMEM14C splicing is specifically required for ring sideroblast formation in SF3B1-mutant disease.","evidence":"Hematopoietic-specific Sf3b1-K700E knock-in mouse with genome-wide RNA-seq splicing analysis","pmids":["27604819"],"confidence":"Medium","gaps":["Indirect evidence from species difference rather than direct manipulation of TMEM14C splicing","Does not distinguish contribution of TMEM14C missplicing from ABCB7 missplicing individually"]},{"year":2020,"claim":"Conservation of TMEM14C function in porphyrin/heme metabolism was extended to apicomplexan parasites, where disruption of a Tmem14c homolog in Toxoplasma gondii increased artemisinin susceptibility.","evidence":"Genome-scale CRISPR screen in Toxoplasma gondii with dihydroartemisinin selection","pmids":["32968076"],"confidence":"Low","gaps":["Non-mammalian system with limited direct mechanistic validation of transport activity","No biochemical demonstration of substrate specificity in Toxoplasma","Relevance to mammalian TMEM14C mechanism not directly tested"]},{"year":2022,"claim":"The mechanism by which SF3B1 mutations cause ring sideroblasts was resolved: mutant SF3B1 missplices TMEM14C to alter its 5′ UTR, reducing protein via impaired translation; combined rescue of TMEM14C and ABCB7 nearly abolished ring sideroblast formation, proving coordinated loss of these transporters drives mitochondrial iron sequestration.","evidence":"SF3B1-mutant iPSC-derived erythroid differentiation model with RNA-seq, polysome profiling, western blot, and functional rescue experiments","pmids":["34861039"],"confidence":"High","gaps":["Quantitative contribution of TMEM14C versus ABCB7 missplicing individually to RS formation not fully delineated","Whether additional SF3B1 missplicing targets contribute to the MDS phenotype beyond RS"]},{"year":2024,"claim":"Natural variant analysis confirmed the specificity of the TMEM14C missplicing–RS link: the SF3B1 E592K variant retains normal TMEM14C splicing and lacks ring sideroblasts, distinguishing it from canonical hotspot mutations.","evidence":"RNA splicing analysis and clinical phenotype correlation in patient samples with SF3B1 E592K versus canonical mutations","pmids":["38759096"],"confidence":"Medium","gaps":["Single-study observation without functional validation of E592K in an experimental model","Mechanism by which E592K spares TMEM14C splicing while other hotspot mutations do not is unexplained"]},{"year":null,"claim":"The structural basis of TMEM14C-mediated protoporphyrinogen IX transport and the precise mechanism by which specific SF3B1 mutations selectively target TMEM14C splicing remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of TMEM14C or reconstituted transport assay exists","Mechanism of selective branch-point usage by different SF3B1 mutations at the TMEM14C locus unknown","Whether TMEM14C has additional substrates or interacting partners in the heme synthesis machinery is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,3]}],"complexes":[],"partners":["ABCB7"],"other_free_text":[]},"mechanistic_narrative":"TMEM14C is an inner mitochondrial membrane protein that functions as the importer of protoporphyrinogen IX into the mitochondrial matrix, constituting an essential step in the terminal heme biosynthesis pathway [PMID:25157825]. TMEM14C deficiency in mice causes porphyrin accumulation, erythroid maturation arrest, and embryonic lethality from severe anemia, a phenotype partially rescued by a protoporphyrin IX analog [PMID:25157825]. In SF3B1-mutant myelodysplastic syndromes, hotspot mutations induce aberrant splicing of TMEM14C that alters its 5′ UTR and reduces protein expression through impaired translation; combined functional rescue of TMEM14C and ABCB7 nearly abolishes ring sideroblast formation, establishing coordinated missplicing of these mitochondrial transporters as the mechanism of mitochondrial iron sequestration in this disease [PMID:34861039, PMID:38759096]."},"prefetch_data":{"uniprot":{"accession":"Q9P0S9","full_name":"Transmembrane protein 14C","aliases":[],"length_aa":112,"mass_kda":11.6,"function":"Required for normal heme biosynthesis","subcellular_location":"Mitochondrion membrane","url":"https://www.uniprot.org/uniprotkb/Q9P0S9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM14C","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/TMEM14C","total_profiled":1310},"omim":[{"mim_id":"615318","title":"TRANSMEMBRANE PROTEIN 14C; TMEM14C","url":"https://www.omim.org/entry/615318"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM14C"},"hgnc":{"alias_symbol":["HSPC194","bA421M1.6","NET26"],"prev_symbol":["C6orf53"]},"alphafold":{"accession":"Q9P0S9","domains":[{"cath_id":"-","chopping":"6-57","consensus_level":"medium","plddt":66.2012,"start":6,"end":57}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0S9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0S9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0S9-F1-predicted_aligned_error_v6.png","plddt_mean":62.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM14C","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM14C"},"sequence":{"accession":"Q9P0S9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P0S9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P0S9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0S9"}},"corpus_meta":[{"pmid":"34172893","id":"PMC_34172893","title":"Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms.","date":"2021","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/34172893","citation_count":151,"is_preprint":false},{"pmid":"25424858","id":"PMC_25424858","title":"SF3B1 mutations constitute a novel therapeutic target in breast cancer.","date":"2014","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25424858","citation_count":145,"is_preprint":false},{"pmid":"27604819","id":"PMC_27604819","title":"Hemopoietic-specific Sf3b1-K700E knock-in mice display the splicing defect seen in human MDS but develop anemia without ring sideroblasts.","date":"2016","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/27604819","citation_count":110,"is_preprint":false},{"pmid":"34861039","id":"PMC_34861039","title":"Coordinated missplicing of TMEM14C and ABCB7 causes ring sideroblast formation in SF3B1-mutant myelodysplastic syndrome.","date":"2022","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/34861039","citation_count":74,"is_preprint":false},{"pmid":"25157825","id":"PMC_25157825","title":"TMEM14C is required for erythroid mitochondrial heme metabolism.","date":"2014","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/25157825","citation_count":59,"is_preprint":false},{"pmid":"32968076","id":"PMC_32968076","title":"Genetic screens reveal a central role for heme metabolism in artemisinin susceptibility.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32968076","citation_count":50,"is_preprint":false},{"pmid":"31795200","id":"PMC_31795200","title":"Regulation of Oncogenic Targets by miR-99a-3p (Passenger Strand of miR-99a-Duplex) in Head and Neck Squamous Cell Carcinoma.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31795200","citation_count":36,"is_preprint":false},{"pmid":"32079689","id":"PMC_32079689","title":"Differential RNA splicing as a potentially important driver mechanism in multiple myeloma.","date":"2021","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/32079689","citation_count":30,"is_preprint":false},{"pmid":"25572802","id":"PMC_25572802","title":"A co-culture genome-wide RNAi screen with mammary epithelial cells reveals transmembrane signals required for growth and differentiation.","date":"2015","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/25572802","citation_count":20,"is_preprint":false},{"pmid":"15987602","id":"PMC_15987602","title":"Identification of eight genes that are potentially involved in tamoxifen sensitivity in breast cancer cells.","date":"2005","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/15987602","citation_count":16,"is_preprint":false},{"pmid":"38759096","id":"PMC_38759096","title":"The E592K variant of SF3B1 creates unique RNA missplicing and associates with high-risk MDS without ring sideroblasts.","date":"2024","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/38759096","citation_count":8,"is_preprint":false},{"pmid":"36937665","id":"PMC_36937665","title":"A conjoint analysis of bulk RNA-seq and single-nucleus RNA-seq for revealing the role of ferroptosis and iron metabolism in ALS.","date":"2023","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36937665","citation_count":8,"is_preprint":false},{"pmid":"35635507","id":"PMC_35635507","title":"Understanding Myoblast Differentiation Pathways When Cultured on Electroactive Scaffolds through Proteomic Analysis.","date":"2022","source":"ACS applied materials & interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/35635507","citation_count":8,"is_preprint":false},{"pmid":"37090662","id":"PMC_37090662","title":"The E592K variant of SF3B1 creates unique RNA missplicing and associates with high-risk MDS without ring sideroblasts.","date":"2023","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/37090662","citation_count":1,"is_preprint":false},{"pmid":"41163575","id":"PMC_41163575","title":"TGFβ-activated kinase-1 knockdown in hematopoietic stem-progenitor cells causes PANoptosis and myelodysplastic syndrome-like disease in mice.","date":"2025","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/41163575","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9315,"output_tokens":1429,"usd":0.02469},"stage2":{"model":"claude-opus-4-6","input_tokens":4651,"output_tokens":1664,"usd":0.097282},"total_usd":0.121972,"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\": 2014,\n      \"finding\": \"TMEM14C is an inner mitochondrial membrane protein that functions as an importer of protoporphyrinogen IX into the mitochondrial matrix for heme synthesis. TMEM14C deficiency in mice causes porphyrin accumulation in fetal liver, erythroid maturation arrest, and embryonic lethality due to profound anemia. Rescue with a protoporphyrin IX analog ameliorated the heme synthesis defect, placing TMEM14C function in the terminal steps of the heme synthesis pathway.\",\n      \"method\": \"Gene expression profiling of differentiating erythroid cells, loss-of-function mouse model (knockout), in vitro erythroid cell culture with porphyrin analog rescue, subcellular fractionation/localization to inner mitochondrial membrane\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (in vivo KO, in vitro rescue, subcellular localization), strong mechanistic conclusion replicated in vivo and in vitro\",\n      \"pmids\": [\"25157825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Mutant SF3B1 induces missplicing of TMEM14C (and ABCB7) during erythroid differentiation, reducing TMEM14C protein expression via 5' UTR alteration and reduced translation efficiency. Functional rescue of both TMEM14C and ABCB7, but not PPOX, markedly decreased ring sideroblast (RS) formation; combined rescue nearly abolished RS, demonstrating that coordinated missplicing of these mitochondrial transporters sequesters iron in mitochondria to cause RS.\",\n      \"method\": \"iPSC model of SF3B1-mutant MDS with in vitro erythroid differentiation, RNA-seq for missplicing, western blot for protein expression, polysome profiling for translation efficiency, functional rescue (overexpression of correctly spliced TMEM14C and ABCB7), RS quantification\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — iPSC disease model with robust RS readout, multiple rescue experiments with orthogonal controls, mechanistic dissection of translation vs. splicing\",\n      \"pmids\": [\"34861039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Sf3b1-K700E knock-in mice, the murine orthologues of TMEM14C and ABCB7 were not aberrantly spliced, explaining the absence of ring sideroblasts in the mouse model despite the presence of anemia, and supporting a causal link between TMEM14C missplicing and RS formation in human MDS.\",\n      \"method\": \"Hematopoietic-specific Sf3b1-K700E knock-in mouse model, global RNA splicing analysis (RNA-seq) of hematopoietic cells\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with genome-wide splicing analysis; provides epistatic evidence linking TMEM14C missplicing to RS phenotype by its absence in the mouse\",\n      \"pmids\": [\"27604819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The SF3B1 E592K variant retains normal RNA splicing of TMEM14C and ABCB7 (unlike canonical SF3B1 hotspot mutations), and this is associated with absence of ring sideroblasts, directly supporting the requirement for TMEM14C missplicing in RS pathogenesis.\",\n      \"method\": \"RNA splicing analysis of patient samples with SF3B1 E592K vs. canonical mutations, clinical correlation with ring sideroblast phenotype\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human patient RNA-seq data with clinical phenotype correlation; mechanistic inference from natural variant, single study\",\n      \"pmids\": [\"38759096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Toxoplasma gondii (an apicomplexan parasite), a Tmem14c homolog functions as a putative transporter involved in heme/porphyrin metabolism; its disruption increases susceptibility to dihydroartemisinin, linking Tmem14c-mediated porphyrin transport to artemisinin susceptibility in this organism.\",\n      \"method\": \"Genome-scale CRISPR screens in Toxoplasma gondii with dihydroartemisinin selection, genetic disruption of Tmem14c\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — non-mammalian organism (Toxoplasma); functional context (porphyrin/heme transport) consistent with mammalian TMEM14C but limited direct mechanistic validation\",\n      \"pmids\": [\"32968076\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM14C is an inner mitochondrial membrane protein that imports protoporphyrinogen IX into the mitochondrial matrix as an essential step in heme synthesis during erythropoiesis; in SF3B1-mutant MDS, aberrant splicing of TMEM14C (together with ABCB7) reduces its protein expression via 5' UTR alteration and impaired translation, causing mitochondrial iron sequestration and ring sideroblast formation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TMEM14C is an inner mitochondrial membrane protein that functions as the importer of protoporphyrinogen IX into the mitochondrial matrix, constituting an essential step in the terminal heme biosynthesis pathway [PMID:25157825]. TMEM14C deficiency in mice causes porphyrin accumulation, erythroid maturation arrest, and embryonic lethality from severe anemia, a phenotype partially rescued by a protoporphyrin IX analog [PMID:25157825]. In SF3B1-mutant myelodysplastic syndromes, hotspot mutations induce aberrant splicing of TMEM14C that alters its 5′ UTR and reduces protein expression through impaired translation; combined functional rescue of TMEM14C and ABCB7 nearly abolishes ring sideroblast formation, establishing coordinated missplicing of these mitochondrial transporters as the mechanism of mitochondrial iron sequestration in this disease [PMID:34861039, PMID:38759096].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"The fundamental question of what transports protoporphyrinogen IX into the mitochondrial matrix was answered: TMEM14C was identified as this importer, establishing its essential role in terminal heme synthesis and erythropoiesis.\",\n      \"evidence\": \"Loss-of-function mouse model, subcellular fractionation to inner mitochondrial membrane, and porphyrin analog rescue in erythroid cells\",\n      \"pmids\": [\"25157825\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No direct transport assay with reconstituted TMEM14C in liposomes\",\n        \"Structural basis of substrate recognition for protoporphyrinogen IX unknown\",\n        \"Whether TMEM14C transports additional porphyrin intermediates not tested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The absence of TMEM14C missplicing in Sf3b1-K700E knock-in mice—which lack ring sideroblasts despite anemia—provided epistatic evidence that aberrant TMEM14C splicing is specifically required for ring sideroblast formation in SF3B1-mutant disease.\",\n      \"evidence\": \"Hematopoietic-specific Sf3b1-K700E knock-in mouse with genome-wide RNA-seq splicing analysis\",\n      \"pmids\": [\"27604819\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Indirect evidence from species difference rather than direct manipulation of TMEM14C splicing\",\n        \"Does not distinguish contribution of TMEM14C missplicing from ABCB7 missplicing individually\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Conservation of TMEM14C function in porphyrin/heme metabolism was extended to apicomplexan parasites, where disruption of a Tmem14c homolog in Toxoplasma gondii increased artemisinin susceptibility.\",\n      \"evidence\": \"Genome-scale CRISPR screen in Toxoplasma gondii with dihydroartemisinin selection\",\n      \"pmids\": [\"32968076\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Non-mammalian system with limited direct mechanistic validation of transport activity\",\n        \"No biochemical demonstration of substrate specificity in Toxoplasma\",\n        \"Relevance to mammalian TMEM14C mechanism not directly tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The mechanism by which SF3B1 mutations cause ring sideroblasts was resolved: mutant SF3B1 missplices TMEM14C to alter its 5′ UTR, reducing protein via impaired translation; combined rescue of TMEM14C and ABCB7 nearly abolished ring sideroblast formation, proving coordinated loss of these transporters drives mitochondrial iron sequestration.\",\n      \"evidence\": \"SF3B1-mutant iPSC-derived erythroid differentiation model with RNA-seq, polysome profiling, western blot, and functional rescue experiments\",\n      \"pmids\": [\"34861039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Quantitative contribution of TMEM14C versus ABCB7 missplicing individually to RS formation not fully delineated\",\n        \"Whether additional SF3B1 missplicing targets contribute to the MDS phenotype beyond RS\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Natural variant analysis confirmed the specificity of the TMEM14C missplicing–RS link: the SF3B1 E592K variant retains normal TMEM14C splicing and lacks ring sideroblasts, distinguishing it from canonical hotspot mutations.\",\n      \"evidence\": \"RNA splicing analysis and clinical phenotype correlation in patient samples with SF3B1 E592K versus canonical mutations\",\n      \"pmids\": [\"38759096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-study observation without functional validation of E592K in an experimental model\",\n        \"Mechanism by which E592K spares TMEM14C splicing while other hotspot mutations do not is unexplained\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of TMEM14C-mediated protoporphyrinogen IX transport and the precise mechanism by which specific SF3B1 mutations selectively target TMEM14C splicing remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of TMEM14C or reconstituted transport assay exists\",\n        \"Mechanism of selective branch-point usage by different SF3B1 mutations at the TMEM14C locus unknown\",\n        \"Whether TMEM14C has additional substrates or interacting partners in the heme synthesis machinery is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ABCB7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}