{"gene":"MTMR12","run_date":"2026-06-10T05:19:51","timeline":{"discoveries":[{"year":2001,"finding":"MTMR12 (3-PAP) was cloned and characterized as a catalytically inactive member of the myotubularin gene family; it lacks the consensus HCX5R catalytic motif, yet 3-PAP immunoprecipitates from platelet cytosol hydrolyzed the D3-phosphate from PtdIns(3)P and PtdIns(3,4)P2, indicating that 3-PAP functions as an adapter subunit associated with a catalytically active 65-kDa partner.","method":"cDNA cloning, sequence alignment, immunoprecipitation of endogenous 3-PAP from platelet cytosol with lipid phosphatase activity assay, recombinant protein expression in insect cells confirming catalytic inactivity","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (cloning, sequence analysis, native immunoprecipitation with enzymatic readout, recombinant expression) in a single rigorous study establishing catalytic inactivity and adapter function","pmids":["11504939"],"is_preprint":false},{"year":2003,"finding":"MTMR12 (3-PAP) was identified as the adapter subunit that directly interacts with myotubularin (MTM1), the catalytically active lipid phosphatase subunit. Myotubularin was purified from 3-PAP immunoprecipitates by SDS-PAGE and identified by tandem MS. Reciprocal co-immunoprecipitation confirmed the interaction with both endogenous and recombinant proteins in K562 cells. Co-expression of 3-PAP with myotubularin caused redistribution of myotubularin from the plasma membrane to the cytosol and attenuated the filopodia-formation phenotype induced by myotubularin overexpression alone, demonstrating that MTMR12 regulates myotubularin intracellular localization.","method":"Affinity purification of endogenous complexes, trypsin digest and collision-induced dissociation tandem MS, reciprocal co-immunoprecipitation of endogenous and recombinant proteins in K562 cells, overexpression with fluorescence microscopy for localization phenotype","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP confirmed by MS identification, two orthogonal methods, functional localization consequence demonstrated","pmids":["12847286"],"is_preprint":false},{"year":2013,"finding":"MTMR12 binds directly to myotubularin (MTM1) in skeletal muscle. Knockdown of mtmr12 in zebrafish produced centronuclear myopathy phenotypes (central nucleation, disorganized triads, myofiber hypotrophy, whorled membrane structures) and impaired motor function. Biochemically, loss of MTMR12 reduced myotubularin protein levels in zebrafish and mammalian C2C12 cells, and loss of myotubularin reciprocally reduced MTMR12 levels. XLMTM-causing mutations within the myotubularin interaction domain disrupted binding to MTMR12 in cell culture, and human XLMTM patient myotubes with such mutations showed reduction of both proteins, establishing that MTMR12 is required for mutual stability of the MTM1-MTMR12 complex.","method":"Co-immunoprecipitation in vitro and in vivo, zebrafish mtmr12 morpholino knockdown with histology and motor function assay, Western blotting for protein stability in C2C12 cells and patient myotubes, domain interaction mapping with XLMTM mutants","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, in vivo morphant model, patient-derived cell biochemistry, mutant interaction mapping) across zebrafish, mouse-derived cells, and human tissue","pmids":["23818870"],"is_preprint":false},{"year":2024,"finding":"Specific variants in MTMR12 (an autophagy/phosphoinositide gene) can accelerate or slow the degradation of misfolded α1-antitrypsin variant Z in iPS-derived hepatocyte-like cells, placing MTMR12 in the autophagy pathway that governs proteotoxic clearance in the liver. The pathogenic effect on α1-antitrypsin Z degradation required concurrent variants in both MTMR12 and FAM134A.","method":"iPSC-derived hepatocyte-like cells from affected siblings, pulse-chase/degradation kinetics of α1-antitrypsin variant Z, genomic sequencing with functional variant testing","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, iPSC functional assay establishing pathway placement, but single study with limited replication","pmids":["38557779"],"is_preprint":false}],"current_model":"MTMR12 (3-PAP) is a catalytically inactive pseudophosphatase that functions as an obligate adapter subunit for the active lipid phosphatase myotubularin (MTM1), forming a heteromeric complex in which each partner stabilizes the other's protein levels; MTMR12 also regulates MTM1 intracellular localization (shifting it from plasma membrane to cytosol), and loss of MTMR12 in skeletal muscle causes centronuclear myopathy resembling X-linked myotubular myopathy, while MTMR12 variants additionally modulate autophagic degradation of misfolded proteins in hepatocytes."},"narrative":{"mechanistic_narrative":"MTMR12 (3-PAP) is a catalytically inactive member of the myotubularin family that functions as an obligate adapter subunit for the active lipid phosphatase myotubularin (MTM1) [PMID:11504939, PMID:12847286]. It lacks the consensus HCX5R catalytic motif, yet endogenous 3-PAP immunoprecipitates carry D3-phosphatase activity against PtdIns(3)P and PtdIns(3,4)P2, reflecting the activity of its associated 65-kDa active partner rather than its own catalysis [PMID:11504939]. MTMR12 binds MTM1 directly, and complex formation redistributes myotubularin from the plasma membrane to the cytosol, attenuating myotubularin-driven filopodia formation — establishing MTMR12 as a regulator of myotubularin localization [PMID:12847286]. In skeletal muscle the two proteins are mutually stabilizing: loss of MTMR12 lowers MTM1 levels and vice versa, and XLMTM-causing mutations in the myotubularin interaction domain disrupt binding and reduce both proteins [PMID:23818870]. Consistent with a role in the myopathy axis, mtmr12 knockdown in zebrafish produces centronuclear myopathy with central nucleation, disorganized triads, and impaired motor function [PMID:23818870]. Separately, MTMR12 variants act within the autophagy pathway governing clearance of misfolded α1-antitrypsin variant Z in hepatocytes, where pathogenic acceleration of degradation required concurrent variants in both MTMR12 and FAM134A [PMID:38557779].","teleology":[{"year":2001,"claim":"Established that MTMR12, despite belonging to the myotubularin phosphatase family, is itself catalytically dead and instead serves as an adapter for an active lipid phosphatase — reframing it from enzyme to regulatory subunit.","evidence":"cDNA cloning and sequence alignment showing loss of the HCX5R motif, native immunoprecipitation from platelet cytosol with PtdIns(3)P/PtdIns(3,4)P2 phosphatase readout, and recombinant expression confirming inactivity","pmids":["11504939"],"confidence":"High","gaps":["Identity of the active 65-kDa partner not yet defined in this study","Cellular and physiological role of the adapter function unaddressed"]},{"year":2003,"claim":"Identified myotubularin (MTM1) as the direct catalytic partner of MTMR12 and showed the adapter controls where the active phosphatase acts, answering what MTMR12 binds and what its binding does.","evidence":"Affinity purification of endogenous complexes with tandem MS identification, reciprocal Co-IP of endogenous and recombinant proteins in K562 cells, and overexpression microscopy showing plasma-membrane-to-cytosol redistribution of myotubularin and loss of filopodia phenotype","pmids":["12847286"],"confidence":"High","gaps":["Physiological tissue context of the complex not established","Structural basis of the interaction not resolved"]},{"year":2013,"claim":"Demonstrated that the MTM1-MTMR12 complex is mutually stabilizing and physiologically required in muscle, linking MTMR12 loss to centronuclear myopathy and connecting it mechanistically to XLMTM mutations.","evidence":"Co-IP in vitro and in vivo, zebrafish mtmr12 morpholino knockdown with histology and motor assays, Western blotting for reciprocal protein stability in C2C12 cells and patient myotubes, and interaction mapping with XLMTM mutants","pmids":["23818870"],"confidence":"High","gaps":["Morpholino-based knockdown not corroborated by a stable genetic null","Mechanism by which the complex prevents central nucleation and triad disorganization unresolved"]},{"year":2024,"claim":"Placed MTMR12 in the autophagy pathway controlling proteotoxic clearance in liver, expanding its role beyond the muscle MTM1 axis to hepatic misfolded-protein degradation.","evidence":"iPSC-derived hepatocyte-like cells from affected siblings with pulse-chase degradation kinetics of α1-antitrypsin variant Z and functional variant testing showing a requirement for concurrent MTMR12 and FAM134A variants","pmids":["38557779"],"confidence":"Medium","gaps":["Single-lab study with limited replication","Direct molecular link between MTMR12 and the autophagy/FAM134A machinery not established","Whether the hepatic role involves the MTM1 partnership unknown"]},{"year":null,"claim":"How MTMR12 mechanistically connects its myotubularin-adapter function to autophagic clearance, and the structural basis of complex assembly, remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the MTM1-MTMR12 complex","Mechanism bridging phosphoinositide regulation and autophagy not defined","Direct partner status of FAM134A relative to MTMR12 unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3]}],"complexes":["MTM1-MTMR12 complex"],"partners":["MTM1","FAM134A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9C0I1","full_name":"Myotubularin-related protein 12","aliases":["Inactive phosphatidylinositol 3-phosphatase 12","Phosphatidylinositol 3 phosphate 3-phosphatase adapter subunit","3-PAP","3-phosphatase adapter protein"],"length_aa":747,"mass_kda":86.1,"function":"Acts as an adapter for the myotubularin-related phosphatases (PubMed:11504939, PubMed:12847286, PubMed:23818870). Regulates phosphatase MTM1 protein stability and possibly its intracellular location (PubMed:23818870). By stabilizing MTM1 protein levels, required for skeletal muscle maintenance but not for myogenesis (By similarity)","subcellular_location":"Cytoplasm; Sarcoplasmic reticulum; Cytoplasm, myofibril, sarcomere","url":"https://www.uniprot.org/uniprotkb/Q9C0I1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MTMR12","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MTMR2","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/MTMR12","total_profiled":1310},"omim":[{"mim_id":"606501","title":"MYOTUBULARIN-RELATED PROTEIN 12; MTMR12","url":"https://www.omim.org/entry/606501"}],"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/MTMR12"},"hgnc":{"alias_symbol":["3-PAP","FLJ20476","KIAA1682","3PAP"],"prev_symbol":["PIP3AP"]},"alphafold":{"accession":"Q9C0I1","domains":[{"cath_id":"2.30.29.30","chopping":"50-174","consensus_level":"high","plddt":86.0619,"start":50,"end":174},{"cath_id":"-","chopping":"207-502_516-534","consensus_level":"high","plddt":93.4036,"start":207,"end":534}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C0I1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C0I1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C0I1-F1-predicted_aligned_error_v6.png","plddt_mean":77.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MTMR12","jax_strain_url":"https://www.jax.org/strain/search?query=MTMR12"},"sequence":{"accession":"Q9C0I1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9C0I1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9C0I1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C0I1"}},"corpus_meta":[{"pmid":"14505699","id":"PMC_14505699","title":"Prophenoloxidase-activating 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breaks generated by oxidative damage.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11278717","citation_count":29,"is_preprint":false},{"pmid":"23818870","id":"PMC_23818870","title":"Loss of catalytically inactive lipid phosphatase myotubularin-related protein 12 impairs myotubularin stability and promotes centronuclear myopathy in zebrafish.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23818870","citation_count":27,"is_preprint":false},{"pmid":"17912428","id":"PMC_17912428","title":"Expression profiling of fecal colonocytes for RNA-based screening of colorectal cancer.","date":"2007","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17912428","citation_count":23,"is_preprint":false},{"pmid":"7882330","id":"PMC_7882330","title":"In vitro and in vivo cytotoxicity of an anti-osteosarcoma immunotoxin containing pokeweed antiviral protein.","date":"1995","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/7882330","citation_count":22,"is_preprint":false},{"pmid":"22223344","id":"PMC_22223344","title":"Geranyl derivative of phloroacetophenone induces cancer cell-specific apoptosis through Bax-mediated mitochondrial pathway in MCF-7 human breast cancer cells.","date":"2012","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/22223344","citation_count":22,"is_preprint":false},{"pmid":"6953924","id":"PMC_6953924","title":"Prostate-specific acid phosphatase versus acid phosphatase in monitoring patients with prostate cancer.","date":"1982","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/6953924","citation_count":19,"is_preprint":false},{"pmid":"17916451","id":"PMC_17916451","title":"Effect of salt on the activity of Streptomyces prolyl aminopeptidase.","date":"2007","source":"Biochimica et biophysica 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Varying Electronic Form, C-C Coupling, and Receptor Feature.","date":"2023","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37163348","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14324,"output_tokens":1563,"usd":0.033209,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8270,"output_tokens":2186,"usd":0.048,"stage2_stop_reason":"end_turn"},"total_usd":0.081209,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"MTMR12 (3-PAP) was cloned and characterized as a catalytically inactive member of the myotubularin gene family; it lacks the consensus HCX5R catalytic motif, yet 3-PAP immunoprecipitates from platelet cytosol hydrolyzed the D3-phosphate from PtdIns(3)P and PtdIns(3,4)P2, indicating that 3-PAP functions as an adapter subunit associated with a catalytically active 65-kDa partner.\",\n      \"method\": \"cDNA cloning, sequence alignment, immunoprecipitation of endogenous 3-PAP from platelet cytosol with lipid phosphatase activity assay, recombinant protein expression in insect cells confirming catalytic inactivity\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (cloning, sequence analysis, native immunoprecipitation with enzymatic readout, recombinant expression) in a single rigorous study establishing catalytic inactivity and adapter function\",\n      \"pmids\": [\"11504939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MTMR12 (3-PAP) was identified as the adapter subunit that directly interacts with myotubularin (MTM1), the catalytically active lipid phosphatase subunit. Myotubularin was purified from 3-PAP immunoprecipitates by SDS-PAGE and identified by tandem MS. Reciprocal co-immunoprecipitation confirmed the interaction with both endogenous and recombinant proteins in K562 cells. Co-expression of 3-PAP with myotubularin caused redistribution of myotubularin from the plasma membrane to the cytosol and attenuated the filopodia-formation phenotype induced by myotubularin overexpression alone, demonstrating that MTMR12 regulates myotubularin intracellular localization.\",\n      \"method\": \"Affinity purification of endogenous complexes, trypsin digest and collision-induced dissociation tandem MS, reciprocal co-immunoprecipitation of endogenous and recombinant proteins in K562 cells, overexpression with fluorescence microscopy for localization phenotype\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP confirmed by MS identification, two orthogonal methods, functional localization consequence demonstrated\",\n      \"pmids\": [\"12847286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MTMR12 binds directly to myotubularin (MTM1) in skeletal muscle. Knockdown of mtmr12 in zebrafish produced centronuclear myopathy phenotypes (central nucleation, disorganized triads, myofiber hypotrophy, whorled membrane structures) and impaired motor function. Biochemically, loss of MTMR12 reduced myotubularin protein levels in zebrafish and mammalian C2C12 cells, and loss of myotubularin reciprocally reduced MTMR12 levels. XLMTM-causing mutations within the myotubularin interaction domain disrupted binding to MTMR12 in cell culture, and human XLMTM patient myotubes with such mutations showed reduction of both proteins, establishing that MTMR12 is required for mutual stability of the MTM1-MTMR12 complex.\",\n      \"method\": \"Co-immunoprecipitation in vitro and in vivo, zebrafish mtmr12 morpholino knockdown with histology and motor function assay, Western blotting for protein stability in C2C12 cells and patient myotubes, domain interaction mapping with XLMTM mutants\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, in vivo morphant model, patient-derived cell biochemistry, mutant interaction mapping) across zebrafish, mouse-derived cells, and human tissue\",\n      \"pmids\": [\"23818870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Specific variants in MTMR12 (an autophagy/phosphoinositide gene) can accelerate or slow the degradation of misfolded α1-antitrypsin variant Z in iPS-derived hepatocyte-like cells, placing MTMR12 in the autophagy pathway that governs proteotoxic clearance in the liver. The pathogenic effect on α1-antitrypsin Z degradation required concurrent variants in both MTMR12 and FAM134A.\",\n      \"method\": \"iPSC-derived hepatocyte-like cells from affected siblings, pulse-chase/degradation kinetics of α1-antitrypsin variant Z, genomic sequencing with functional variant testing\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, iPSC functional assay establishing pathway placement, but single study with limited replication\",\n      \"pmids\": [\"38557779\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MTMR12 (3-PAP) is a catalytically inactive pseudophosphatase that functions as an obligate adapter subunit for the active lipid phosphatase myotubularin (MTM1), forming a heteromeric complex in which each partner stabilizes the other's protein levels; MTMR12 also regulates MTM1 intracellular localization (shifting it from plasma membrane to cytosol), and loss of MTMR12 in skeletal muscle causes centronuclear myopathy resembling X-linked myotubular myopathy, while MTMR12 variants additionally modulate autophagic degradation of misfolded proteins in hepatocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MTMR12 (3-PAP) is a catalytically inactive member of the myotubularin family that functions as an obligate adapter subunit for the active lipid phosphatase myotubularin (MTM1) [#0, #1]. It lacks the consensus HCX5R catalytic motif, yet endogenous 3-PAP immunoprecipitates carry D3-phosphatase activity against PtdIns(3)P and PtdIns(3,4)P2, reflecting the activity of its associated 65-kDa active partner rather than its own catalysis [#0]. MTMR12 binds MTM1 directly, and complex formation redistributes myotubularin from the plasma membrane to the cytosol, attenuating myotubularin-driven filopodia formation — establishing MTMR12 as a regulator of myotubularin localization [#1]. In skeletal muscle the two proteins are mutually stabilizing: loss of MTMR12 lowers MTM1 levels and vice versa, and XLMTM-causing mutations in the myotubularin interaction domain disrupt binding and reduce both proteins [#2]. Consistent with a role in the myopathy axis, mtmr12 knockdown in zebrafish produces centronuclear myopathy with central nucleation, disorganized triads, and impaired motor function [#2]. Separately, MTMR12 variants act within the autophagy pathway governing clearance of misfolded α1-antitrypsin variant Z in hepatocytes, where pathogenic acceleration of degradation required concurrent variants in both MTMR12 and FAM134A [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that MTMR12, despite belonging to the myotubularin phosphatase family, is itself catalytically dead and instead serves as an adapter for an active lipid phosphatase — reframing it from enzyme to regulatory subunit.\",\n      \"evidence\": \"cDNA cloning and sequence alignment showing loss of the HCX5R motif, native immunoprecipitation from platelet cytosol with PtdIns(3)P/PtdIns(3,4)P2 phosphatase readout, and recombinant expression confirming inactivity\",\n      \"pmids\": [\"11504939\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the active 65-kDa partner not yet defined in this study\", \"Cellular and physiological role of the adapter function unaddressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified myotubularin (MTM1) as the direct catalytic partner of MTMR12 and showed the adapter controls where the active phosphatase acts, answering what MTMR12 binds and what its binding does.\",\n      \"evidence\": \"Affinity purification of endogenous complexes with tandem MS identification, reciprocal Co-IP of endogenous and recombinant proteins in K562 cells, and overexpression microscopy showing plasma-membrane-to-cytosol redistribution of myotubularin and loss of filopodia phenotype\",\n      \"pmids\": [\"12847286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological tissue context of the complex not established\", \"Structural basis of the interaction not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that the MTM1-MTMR12 complex is mutually stabilizing and physiologically required in muscle, linking MTMR12 loss to centronuclear myopathy and connecting it mechanistically to XLMTM mutations.\",\n      \"evidence\": \"Co-IP in vitro and in vivo, zebrafish mtmr12 morpholino knockdown with histology and motor assays, Western blotting for reciprocal protein stability in C2C12 cells and patient myotubes, and interaction mapping with XLMTM mutants\",\n      \"pmids\": [\"23818870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Morpholino-based knockdown not corroborated by a stable genetic null\", \"Mechanism by which the complex prevents central nucleation and triad disorganization unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed MTMR12 in the autophagy pathway controlling proteotoxic clearance in liver, expanding its role beyond the muscle MTM1 axis to hepatic misfolded-protein degradation.\",\n      \"evidence\": \"iPSC-derived hepatocyte-like cells from affected siblings with pulse-chase degradation kinetics of α1-antitrypsin variant Z and functional variant testing showing a requirement for concurrent MTMR12 and FAM134A variants\",\n      \"pmids\": [\"38557779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study with limited replication\", \"Direct molecular link between MTMR12 and the autophagy/FAM134A machinery not established\", \"Whether the hepatic role involves the MTM1 partnership unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MTMR12 mechanistically connects its myotubularin-adapter function to autophagic clearance, and the structural basis of complex assembly, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the MTM1-MTMR12 complex\", \"Mechanism bridging phosphoinositide regulation and autophagy not defined\", \"Direct partner status of FAM134A relative to MTMR12 unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"MTM1-MTMR12 complex\"],\n    \"partners\": [\"MTM1\", \"FAM134A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}