{"gene":"MTM1","run_date":"2026-06-10T02:59:51","timeline":{"discoveries":[{"year":1997,"finding":"MTM1 encodes myotubularin, a protein with a tyrosine phosphatase domain (PTP); missense mutations affecting the predicted PTP domain are expected to inactivate the putative enzymatic activity, and the protein is highly conserved through evolution including yeast and C. elegans orthologs.","method":"Positional cloning, sequence analysis, single-strand conformation polymorphism (SSCP) mutation screening","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — positional cloning plus mutation analysis in 55 patients; enzymatic activity inferred from domain homology, not directly demonstrated in vitro in this paper","pmids":["9305655"],"is_preprint":false},{"year":2003,"finding":"Yeast MTM1 (YGR257c) is a mitochondrial carrier family member required for manganese-dependent activation of SOD2 (superoxide dismutase 2) in the mitochondrial matrix; loss of MTM1 causes SOD2 inactivation that is rescued only by high-dose manganese supplementation, establishing MTM1 as a manganese trafficking factor for mitochondrial SOD2.","method":"Yeast genetic screen (MTM1 deletion), SOD2 activity assays, manganese supplementation rescue experiments, mitochondrial localization studies","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 (genetic screen, enzymatic assay, metal supplementation rescue, localization); rigorous controls in single study","pmids":["12890866"],"is_preprint":false},{"year":2009,"finding":"C. elegans MTM-1 (ortholog of human MTM1) is a negative regulator of apoptotic cell corpse engulfment; its lipid phosphatase activity dephosphorylates PtdIns(3)P on the plasma membrane in engulfing cells, and loss of mtm-1 accelerates cell corpse clearance through the CED-5/CED-12/CED-10 module and requires PI3Ks VPS-34 and PIKI-1.","method":"C. elegans genetics (loss-of-function mutants, RNAi, overexpression), epistasis analysis with engulfment pathway mutants, plasma membrane localization imaging, in vivo PtdIns(3)P level assessment","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic epistasis, multiple engulfment pathway mutants tested, lipid phosphatase activity dependency confirmed, localization experiments; multiple orthogonal approaches in single study","pmids":["19816564"],"is_preprint":false},{"year":2011,"finding":"C. elegans MTM-1 acts upstream of the ced-2/ced-5/ced-12 ternary GEF complex and parallel to mig-2 in regulating apoptotic cell corpse clearance; MTM-1 also promotes phagosome maturation potentially through CED-1 receptor recycling, and the CED-12 PH domain can bind PtdIns(3,5)P2 (a substrate of MTM-1 phosphatase activity), suggesting MTM-1 regulates CED-12 recruitment to the plasma membrane.","method":"C. elegans epistasis analysis, cell corpse quantification, phagosome maturation assays, lipid-binding domain pulldown (CED-12 PH domain binding to PtdIns(3,5)P2)","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistatic ordering with multiple pathway mutants plus biochemical lipid-binding data; two orthogonal methods; replicates and extends PMID:19816564","pmids":["21490059"],"is_preprint":false},{"year":2013,"finding":"Loss of myotubularin (MTM1) in murine muscle leads to activation of the IGF1R/Akt pathway (increased IGF1R and Akt levels), upregulation of atrogenes (ubiquitin-proteasome pathway), increased autophagosomes and autophagy markers (LC3, P62), and abnormal mTOR/FOXO3a phosphorylation; AAV-mediated re-delivery of Mtm1 rescued muscle mass and normalized these pathways, demonstrating MTM1 acts upstream of IGF1R/Akt and downstream on the autophagy/proteasome balance.","method":"Mtm1-null mouse model analysis, immunoblotting, autophagosome counting, AAV-mediated gene rescue, quantification of atrogene expression","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse plus AAV rescue experiment with multiple pathway readouts; loss-of-function and gain-of-function (rescue) orthogonal evidence in same study","pmids":["23695157"],"is_preprint":false},{"year":2013,"finding":"Myotubularin is required for proper function of skeletal muscle during adulthood; conditional adult-specific deletion of Mtm1 via AAV-Cre causes myofiber atrophy, disorganization of mitochondria and nuclei, T-tubule defects, severe muscle weakness, and abnormalities in satellite cell number, autophagy markers, protein synthesis, and neuromuscular junction transmission.","method":"AAV-Cre conditional adult Mtm1 deletion in mouse muscle, histopathology, electron microscopy, muscle force measurement, immunostaining for satellite cells and autophagy/NMJ markers","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional adult-specific KO with multiple orthogonal phenotypic readouts (histology, EM, physiology, molecular markers) in a single rigorous study","pmids":["23390130"],"is_preprint":false},{"year":2018,"finding":"MTM1 forms a complex with UBQLN2 and HSP proteins (MTM1-UBQLN2-HSP complex) that recognizes and guides misfolded intermediate filament proteins desmin and vimentin to the proteasome for degradation prior to aggregate formation, thereby maintaining cytoskeletal integrity in muscle cells.","method":"Co-immunoprecipitation (MTM1-UBQLN2 complex), in vitro and cell-based proteasome degradation assays, loss-of-function studies in muscle cells, electron microscopy of protein aggregates","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP identifying complex, functional assays demonstrating proteasomal degradation, loss-of-function phenotype; multiple orthogonal methods in rigorous study","pmids":["29358706"],"is_preprint":false},{"year":2017,"finding":"The N-terminal domain of MTMR2 (absent in MTM1) is responsible for functional differences between MTM1 and MTMR2; a short MTMR2 isoform lacking this N-terminal extension behaves similarly to MTM1 in yeast complementation and mouse rescue assays, and AAV-mediated expression of MTMR2 isoforms in Mtm1 KO mice ameliorates myopathic phenotype, demonstrating functional redundancy of phosphoinositide phosphatase activity.","method":"Yeast heterologous expression complementation, AAV-mediated gene delivery in Mtm1 KO mice, muscle force measurement, histopathology, domain deletion analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain deletion analysis combined with both yeast complementation and in vivo mouse rescue; multiple orthogonal methods in single study","pmids":["28934386"],"is_preprint":false},{"year":2017,"finding":"In muscles from XLMTM patients, MTM1 mutations cause significant decrease in ryanodine receptor 1 (RyR1) expression, decrease in muscle-specific microRNAs, and up-regulation of histone deacetylase-4 (HDAC4); however, at the myotube level MTM1 mutations do not dramatically affect RyR1-mediated calcium homeostasis, indicating these molecular changes are secondary consequences in mature muscle rather than primary defects.","method":"Patient muscle biopsy analysis, patient-derived myotube calcium imaging, immunoblotting for RyR1/HDAC4, microRNA quantification","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient biopsy and cell studies with multiple molecular readouts; single lab, direct patient material but no functional rescue experiment","pmids":["28007904"],"is_preprint":false},{"year":2022,"finding":"Disrupted T-tubular network in MTM1-deficient skeletal muscle fibers is the primary cause of asynchronous and severely impaired SR calcium release; mathematical modeling of T-tubule propagation defects reproduces all features of measured calcium release abnormalities, while Ca2+-induced calcium release from RyRs provides secondary support.","method":"Confocal calcium transient recordings in MTM1-deficient mouse muscle fibers, mathematical modeling of T-tubule depolarization propagation","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct electrophysiology combined with computational modeling; single lab, two complementary methods but no genetic rescue","pmids":["36408764"],"is_preprint":false},{"year":2023,"finding":"Loss of MTM1 in zebrafish causes liver abnormalities including impaired bile flux, structural abnormalities of the bile canaliculus, and improper endosome-mediated trafficking of canalicular transporters; MTM1 localizes to Rab11-positive recycling endosomes in hepatocytes and associates with canalicular transport proteins; hepatocyte-specific re-expression of Mtm1 rescues the cholestatic phenotype; dynasore (a dynamin-2 inhibitor) partially restores bile flow and transporter localization.","method":"Zebrafish mtm1 loss-of-function model, reporter-tagged Mtm1 zebrafish line, co-localization with Rab11 and canalicular transporters, hepatocyte-specific rescue by re-expression, chemical screen with dynasore","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic KO, localization, tissue-specific rescue, chemical rescue) in a single rigorous study with clear functional readouts","pmids":["37490339"],"is_preprint":false},{"year":2023,"finding":"AAV-mediated MTM1 overexpression prevents and reverts BIN1-related centronuclear myopathy in Bin1mck-/- mice; the lipid phosphatase activity of MTM1 is essential for rescue of muscle atrophy and myofiber hypotrophy but dispensable for rescue of myofiber disorganization including organelle mis-position and T-tubule defects; rescue of T-tubule organization correlates with normalization of dysferlin and caveolin levels.","method":"AAV-MTM1 injection (systemic early and intramuscular late) in Bin1mck-/- mouse model, phosphatase-dead MTM1 mutant rescue experiment, histopathology, T-tubule imaging, immunoblotting for dysferlin and caveolin","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — catalytic-dead mutagenesis to dissect phosphatase-dependent vs. -independent rescue, in vivo gene therapy rescue with multiple phenotypic readouts; multiple orthogonal methods","pmids":["37490306"],"is_preprint":false},{"year":2024,"finding":"MTM1 is the main enzyme responsible for producing phosphatidylinositol 5-phosphate (PI5P) in muscle cells; this PI5P fuels PI5P 4-kinase α to generate a functional pool of PI(4,5)P2 that concentrates in podosome-like protrusions (PLPs) containing Tks5, Dynamin-2, and Myomaker, which drive myoblast fusion.","method":"Lipid mass spectrometry in MTM1-depleted myoblasts, PI5P and PI(4,5)P2 quantification, live imaging of PLP formation, co-localization of MTM1 products with PLP markers, myoblast fusion assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — lipidomic quantification establishing MTM1 as PI5P-producing enzyme, functional consequence (PLP formation and myoblast fusion), co-localization; multiple orthogonal methods in single study","pmids":["38805272"],"is_preprint":false},{"year":2025,"finding":"MTM1 dephosphorylates a pool of PI3P on EEA1-positive early endosomes in skeletal muscle cells; loss of MTM1 causes PI3P accumulation on these endosomes and impairs Rab4-positive recycling vesicle biogenesis; depletion of class II PI3-kinase beta (PI3KC2β) in Mtm1-KO cells normalizes PI3P levels on EEA1-positive endosomes and restores Rab4-positive vesicle biogenesis.","method":"Mtm1-KO skeletal muscle cell line, PI3P localization by immunofluorescence on endosomal compartments, Rab4 vesicle biogenesis assay, PI3KC2β depletion rescue experiments","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Strong — cellular KO model with specific endosomal PI3P quantification, vesicle trafficking readout, and rescue by upstream kinase depletion; multiple orthogonal methods","pmids":["39952567"],"is_preprint":false},{"year":2011,"finding":"The human MTM1 p.R69C mutation modeled in mice causes exon 4 skipping in most mRNA transcripts (rather than a simple missense change), leading to premature termination and very low myotubularin protein; residual full-length transcript provides enough myotubularin activity to maintain near-normal PI3P levels and account for a milder phenotype compared to complete KO mice.","method":"Knock-in mouse model, RT-PCR/mRNA analysis, Western blot for myotubularin protein, PI3P level measurement in muscle","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in mouse with molecular characterization of mRNA splicing, protein levels, and lipid substrate levels; multiple orthogonal methods explaining genotype-phenotype correlation","pmids":["22068590"],"is_preprint":false}],"current_model":"MTM1 encodes myotubularin, a phosphoinositide phosphatase that dephosphorylates PI3P and PI(3,5)P2 on early endosomes and the plasma membrane; it produces PI5P to fuel PI(4,5)P2 generation in podosome-like protrusions driving myoblast fusion, controls endosomal Rab4-recycling vesicle biogenesis, forms a complex with UBQLN2 and HSP proteins to guide misfolded intermediate filaments (desmin, vimentin) to the proteasome, regulates the IGF1R/Akt-autophagy/ubiquitin-proteasome balance in muscle, is required for T-tubule integrity and thus excitation-contraction coupling, and in the liver localizes to Rab11-positive recycling endosomes where it supports canalicular transporter trafficking; in C. elegans the ortholog MTM-1 negatively regulates apoptotic cell corpse engulfment by dephosphorylating PI3P upstream of the CED-5/CED-12/CED-10 GEF complex, while the yeast MTM1 ortholog facilitates manganese insertion into the mitochondrial SOD2 enzyme."},"narrative":{"mechanistic_narrative":"MTM1 encodes myotubularin, a phosphoinositide phosphatase whose loss-of-function mutations cause X-linked myotubular/centronuclear myopathy [PMID:9305655]. Its core catalytic activity dephosphorylates PI3P, including a pool on EEA1-positive early endosomes whose accumulation upon MTM1 loss impairs Rab4-positive recycling-vesicle biogenesis, a defect reversed by depleting the upstream kinase PI3KC2β [PMID:39952567]. Beyond clearing PI3P, MTM1 is the principal enzyme generating PI5P in muscle, feeding PI5P 4-kinase α to build the PI(4,5)P2 pool that concentrates in podosome-like protrusions driving myoblast fusion [PMID:38805272]. These lipid functions underlie MTM1's role in muscle homeostasis: it maintains T-tubule integrity required for synchronous SR calcium release and excitation-contraction coupling [PMID:36408764], sits upstream of the IGF1R/Akt axis to balance autophagy and ubiquitin-proteasome activity [PMID:23695157], and is required to sustain adult myofiber architecture, mitochondrial and nuclear positioning, and neuromuscular function [PMID:23390130]. MTM1 also acts in protein quality control as part of an MTM1-UBQLN2-HSP complex that routes misfolded desmin and vimentin to the proteasome before they aggregate [PMID:29358706]. Catalytic-dissection studies show its lipid phosphatase activity is essential for rescue of muscle atrophy but dispensable for restoring T-tubule organization, indicating distinct phosphatase-dependent and -independent outputs [PMID:37490306]. Orthologs extend this picture: C. elegans MTM-1 negatively regulates apoptotic corpse engulfment by dephosphorylating membrane PI3P upstream of the CED-5/CED-12/CED-10 GEF module [PMID:19816564, PMID:21490059], and the yeast ortholog functions as a mitochondrial manganese-trafficking factor required to activate SOD2 [PMID:12890866]. In vertebrate liver, MTM1 localizes to Rab11-positive recycling endosomes and supports canalicular transporter trafficking and bile flux [PMID:37490339].","teleology":[{"year":1997,"claim":"Identifying MTM1 as the gene mutated in X-linked myotubular myopathy and recognizing its tyrosine phosphatase domain established the founding hypothesis that an enzymatic phosphatase activity underlies the disease.","evidence":"Positional cloning and SSCP mutation screening in patients","pmids":["9305655"],"confidence":"Medium","gaps":["Enzymatic activity inferred from domain homology, not demonstrated in vitro","No lipid substrate identified at this stage"]},{"year":2003,"claim":"The yeast ortholog revealed a mechanistically distinct function as a mitochondrial manganese carrier required for SOD2 activation, showing the MTM1 name covers divergent ortholog roles.","evidence":"Yeast deletion screen, SOD2 activity assays, manganese rescue, mitochondrial localization","pmids":["12890866"],"confidence":"High","gaps":["Relationship to vertebrate phosphoinositide phosphatase function unresolved","Direct manganese-binding by the protein not shown"]},{"year":2009,"claim":"Genetic and lipid-level analysis in C. elegans defined MTM-1 as a PI3P phosphatase that negatively regulates apoptotic corpse engulfment, anchoring the lipid-phosphatase model in a whole-organism pathway.","evidence":"C. elegans genetics, epistasis with engulfment mutants, plasma-membrane PtdIns(3)P imaging","pmids":["19816564"],"confidence":"High","gaps":["Direct in vitro phosphatase kinetics not measured","How phosphatase activity gates engulfment effectors unresolved"]},{"year":2011,"claim":"Epistasis placed MTM-1 upstream of the CED-2/CED-5/CED-12 GEF complex and linked CED-12 PH-domain binding of PtdIns(3,5)P2 to membrane recruitment, providing a substrate-to-effector mechanism for engulfment control.","evidence":"C. elegans epistasis, phagosome maturation assays, CED-12 PH-domain lipid pulldown","pmids":["21490059"],"confidence":"High","gaps":["In vivo demonstration of MTM-1-driven CED-12 recruitment lacking","PtdIns(3,5)P2 vs PI3P substrate preference not quantified"]},{"year":2011,"claim":"A knock-in mouse showed the patient p.R69C allele acts largely by inducing exon 4 skipping with residual full-length protein, explaining a milder phenotype and linking myotubularin level to PI3P homeostasis.","evidence":"Knock-in mouse, mRNA splicing analysis, Western blot, muscle PI3P measurement","pmids":["22068590"],"confidence":"High","gaps":["Generalizability to other missense alleles unknown","Threshold of activity needed for normal muscle not defined"]},{"year":2013,"claim":"Mtm1-null and AAV-rescue studies positioned MTM1 upstream of the IGF1R/Akt axis controlling the autophagy/proteasome balance, connecting the phosphatase to muscle proteostasis signaling.","evidence":"KO mouse, immunoblotting of pathway markers, autophagosome counts, AAV-Mtm1 rescue","pmids":["23695157"],"confidence":"High","gaps":["Mechanism linking phosphoinositide turnover to IGF1R/Akt not defined","Direct phosphatase substrate driving this signaling unknown"]},{"year":2013,"claim":"Adult-specific conditional deletion established that myotubularin is continuously required in mature muscle, producing T-tubule defects, organelle mispositioning, and NMJ abnormalities rather than acting only during development.","evidence":"AAV-Cre conditional deletion, histology, EM, force measurement, marker immunostaining","pmids":["23390130"],"confidence":"High","gaps":["Causal order among the multiple defects unresolved","Cell-autonomous vs systemic contributions not separated"]},{"year":2017,"claim":"Domain-swap and rescue experiments showed phosphoinositide phosphatase activity is the shared functional core, with an MTMR2 N-terminal extension accounting for paralog-specific differences and a short MTMR2 isoform substituting for MTM1.","evidence":"Yeast complementation, AAV MTMR2-isoform rescue in Mtm1 KO mice, domain deletion","pmids":["28934386"],"confidence":"High","gaps":["Molecular function of the MTMR2 N-terminal extension undefined","Endogenous redundancy in humans not addressed"]},{"year":2017,"claim":"Patient muscle and myotube analysis distinguished primary from secondary defects, showing RyR1/HDAC4/microRNA changes are downstream consequences in mature muscle rather than the initiating lesion.","evidence":"Patient biopsy immunoblotting, microRNA quantification, patient myotube calcium imaging","pmids":["28007904"],"confidence":"Medium","gaps":["No rescue experiment to confirm secondary nature","Primary trigger of these changes not identified"]},{"year":2018,"claim":"Discovery of the MTM1-UBQLN2-HSP complex revealed a phosphatase-independent role in cytoskeletal proteostasis, routing misfolded desmin and vimentin to the proteasome before aggregation.","evidence":"Reciprocal Co-IP, proteasome degradation assays, loss-of-function in muscle cells, EM of aggregates","pmids":["29358706"],"confidence":"High","gaps":["Stoichiometry and assembly of the complex undefined","Whether substrate recognition requires MTM1 lipid binding unknown"]},{"year":2022,"claim":"Calcium-transient recording with modeling identified the disrupted T-tubular network as the primary cause of impaired SR calcium release, ranking T-tubule structure above RyR-level changes in the EC-coupling defect.","evidence":"Confocal calcium recordings in MTM1-deficient fibers, mathematical modeling of T-tubule propagation","pmids":["36408764"],"confidence":"Medium","gaps":["No genetic rescue confirming causality","Lipid mechanism linking MTM1 loss to T-tubule disruption not shown here"]},{"year":2023,"claim":"A zebrafish model extended MTM1 function to liver, showing it acts on Rab11 recycling endosomes to traffic canalicular transporters and maintain bile flux, with dynamin-2 inhibition partially correcting the defect.","evidence":"Zebrafish KO, Rab11/transporter co-localization, hepatocyte-specific rescue, dynasore chemical rescue","pmids":["37490339"],"confidence":"High","gaps":["Direct lipid substrate at canalicular endosomes not measured","Relevance to human hepatic phenotypes not established"]},{"year":2023,"claim":"Catalytic-dead rescue in a BIN1-CNM model dissected phosphatase-dependent (atrophy/hypotrophy) from phosphatase-independent (T-tubule and organelle organization) outputs of MTM1, and linked T-tubule rescue to dysferlin/caveolin normalization.","evidence":"AAV-MTM1 and phosphatase-dead mutant rescue in Bin1mck-/- mice, histology, T-tubule imaging, immunoblotting","pmids":["37490306"],"confidence":"High","gaps":["Identity of the phosphatase-independent activity unresolved","How MTM1 cross-corrects a BIN1 defect mechanistically unclear"]},{"year":2024,"claim":"Lipidomics established MTM1 as the principal PI5P-producing enzyme in muscle, feeding PIP4Kα-generated PI(4,5)P2 into podosome-like protrusions that drive myoblast fusion, defining a synthetic rather than purely degradative lipid output.","evidence":"Lipid mass spectrometry in depleted myoblasts, PLP live imaging, fusion assays","pmids":["38805272"],"confidence":"High","gaps":["In vivo contribution of this pathway to muscle regeneration not shown","Direct enzymatic route from MTM1 substrate to PI5P not fully traced"]},{"year":2025,"claim":"Endosomal mapping showed MTM1 dephosphorylates PI3P on EEA1-positive early endosomes to enable Rab4 recycling-vesicle biogenesis, with PI3KC2β identified as the opposing kinase whose depletion rescues the defect.","evidence":"Mtm1-KO muscle cells, compartment-specific PI3P imaging, Rab4 vesicle assay, PI3KC2β depletion rescue","pmids":["39952567"],"confidence":"High","gaps":["Cargo identity of Rab4 vesicles in muscle undefined","Link between endosomal recycling defect and myopathy phenotype not established"]},{"year":null,"claim":"How MTM1's distinct molecular activities — PI3P turnover, PI5P synthesis, and UBQLN2-mediated proteostasis — are coordinated and which is the proximal driver of human myopathy remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified mechanism linking lipid and proteostasis functions","Tissue-specific substrate map incomplete","Structural basis of substrate selection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2,12,13]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3,12,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[13,10]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,12]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[13,10]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[9,5]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[10]}],"complexes":["MTM1-UBQLN2-HSP complex"],"partners":["UBQLN2","PI3KC2Β"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13496","full_name":"Myotubularin","aliases":["Phosphatidylinositol-3,5-bisphosphate 3-phosphatase","Phosphatidylinositol-3-phosphate phosphatase"],"length_aa":603,"mass_kda":69.9,"function":"Lipid phosphatase which dephosphorylates phosphatidylinositol 3-monophosphate (PI3P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) (PubMed:10900271, PubMed:11001925, PubMed:12646134, PubMed:14722070). Has also been shown to dephosphorylate phosphotyrosine- and phosphoserine-containing peptides (PubMed:9537414). Negatively regulates EGFR degradation through regulation of EGFR trafficking from the late endosome to the lysosome (PubMed:14722070). Plays a role in vacuolar formation and morphology. Regulates desmin intermediate filament assembly and architecture (PubMed:21135508). Plays a role in mitochondrial morphology and positioning (PubMed:21135508). Required for skeletal muscle maintenance but not for myogenesis (PubMed:21135508). In skeletal muscles, stabilizes MTMR12 protein levels (PubMed:23818870)","subcellular_location":"Cytoplasm; Cell membrane; Cell projection, filopodium; Cell projection, ruffle; Late endosome; Cytoplasm, myofibril, sarcomere","url":"https://www.uniprot.org/uniprotkb/Q13496/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MTM1","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/MTM1","total_profiled":1310},"omim":[{"mim_id":"619967","title":"CONGENITAL MYOPATHY 11; CMYO11","url":"https://www.omim.org/entry/619967"},{"mim_id":"615950","title":"SPEG COMPLEX LOCUS; SPEG","url":"https://www.omim.org/entry/615950"},{"mim_id":"611089","title":"MYOTUBULARIN-RELATED PROTEIN 14; MTMR14","url":"https://www.omim.org/entry/611089"},{"mim_id":"610820","title":"SOLUTE CARRIER FAMILY 25, MEMBER 39; SLC25A39","url":"https://www.omim.org/entry/610820"},{"mim_id":"610467","title":"3-@HYDROXYACYL-CoA DEHYDRATASE 1; HACD1","url":"https://www.omim.org/entry/610467"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MTM1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q13496","domains":[{"cath_id":"2.30.29.30","chopping":"42-141","consensus_level":"high","plddt":92.105,"start":42,"end":141},{"cath_id":"-","chopping":"168-539","consensus_level":"high","plddt":97.4094,"start":168,"end":539}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13496","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13496-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13496-F1-predicted_aligned_error_v6.png","plddt_mean":89.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MTM1","jax_strain_url":"https://www.jax.org/strain/search?query=MTM1"},"sequence":{"accession":"Q13496","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13496.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13496/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13496"}},"corpus_meta":[{"pmid":"10790201","id":"PMC_10790201","title":"MTM1 mutations in X-linked myotubular myopathy.","date":"2000","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/10790201","citation_count":161,"is_preprint":false},{"pmid":"12890866","id":"PMC_12890866","title":"Manganese activation of superoxide dismutase 2 in Saccharomyces cerevisiae requires MTM1, a member of the mitochondrial carrier family.","date":"2003","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12890866","citation_count":115,"is_preprint":false},{"pmid":"9305655","id":"PMC_9305655","title":"Mutations in the MTM1 gene implicated in X-linked myotubular myopathy. ENMC International Consortium on Myotubular Myopathy. European Neuro-Muscular Center.","date":"1997","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9305655","citation_count":107,"is_preprint":false},{"pmid":"20682747","id":"PMC_20682747","title":"MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20682747","citation_count":100,"is_preprint":false},{"pmid":"19084976","id":"PMC_19084976","title":"\"Necklace\" fibers, a new histological marker of late-onset MTM1-related centronuclear myopathy.","date":"2008","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/19084976","citation_count":94,"is_preprint":false},{"pmid":"7726166","id":"PMC_7726166","title":"Myotubular myopathy in a girl with a deletion at Xq27-q28 and unbalanced X inactivation assigns the MTM1 gene to a 600-kb region.","date":"1995","source":"American 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domain (PTP); missense mutations affecting the predicted PTP domain are expected to inactivate the putative enzymatic activity, and the protein is highly conserved through evolution including yeast and C. elegans orthologs.\",\n      \"method\": \"Positional cloning, sequence analysis, single-strand conformation polymorphism (SSCP) mutation screening\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — positional cloning plus mutation analysis in 55 patients; enzymatic activity inferred from domain homology, not directly demonstrated in vitro in this paper\",\n      \"pmids\": [\"9305655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Yeast MTM1 (YGR257c) is a mitochondrial carrier family member required for manganese-dependent activation of SOD2 (superoxide dismutase 2) in the mitochondrial matrix; loss of MTM1 causes SOD2 inactivation that is rescued only by high-dose manganese supplementation, establishing MTM1 as a manganese trafficking factor for mitochondrial SOD2.\",\n      \"method\": \"Yeast genetic screen (MTM1 deletion), SOD2 activity assays, manganese supplementation rescue experiments, mitochondrial localization studies\",\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 (genetic screen, enzymatic assay, metal supplementation rescue, localization); rigorous controls in single study\",\n      \"pmids\": [\"12890866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"C. elegans MTM-1 (ortholog of human MTM1) is a negative regulator of apoptotic cell corpse engulfment; its lipid phosphatase activity dephosphorylates PtdIns(3)P on the plasma membrane in engulfing cells, and loss of mtm-1 accelerates cell corpse clearance through the CED-5/CED-12/CED-10 module and requires PI3Ks VPS-34 and PIKI-1.\",\n      \"method\": \"C. elegans genetics (loss-of-function mutants, RNAi, overexpression), epistasis analysis with engulfment pathway mutants, plasma membrane localization imaging, in vivo PtdIns(3)P level assessment\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic epistasis, multiple engulfment pathway mutants tested, lipid phosphatase activity dependency confirmed, localization experiments; multiple orthogonal approaches in single study\",\n      \"pmids\": [\"19816564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"C. elegans MTM-1 acts upstream of the ced-2/ced-5/ced-12 ternary GEF complex and parallel to mig-2 in regulating apoptotic cell corpse clearance; MTM-1 also promotes phagosome maturation potentially through CED-1 receptor recycling, and the CED-12 PH domain can bind PtdIns(3,5)P2 (a substrate of MTM-1 phosphatase activity), suggesting MTM-1 regulates CED-12 recruitment to the plasma membrane.\",\n      \"method\": \"C. elegans epistasis analysis, cell corpse quantification, phagosome maturation assays, lipid-binding domain pulldown (CED-12 PH domain binding to PtdIns(3,5)P2)\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistatic ordering with multiple pathway mutants plus biochemical lipid-binding data; two orthogonal methods; replicates and extends PMID:19816564\",\n      \"pmids\": [\"21490059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss of myotubularin (MTM1) in murine muscle leads to activation of the IGF1R/Akt pathway (increased IGF1R and Akt levels), upregulation of atrogenes (ubiquitin-proteasome pathway), increased autophagosomes and autophagy markers (LC3, P62), and abnormal mTOR/FOXO3a phosphorylation; AAV-mediated re-delivery of Mtm1 rescued muscle mass and normalized these pathways, demonstrating MTM1 acts upstream of IGF1R/Akt and downstream on the autophagy/proteasome balance.\",\n      \"method\": \"Mtm1-null mouse model analysis, immunoblotting, autophagosome counting, AAV-mediated gene rescue, quantification of atrogene expression\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse plus AAV rescue experiment with multiple pathway readouts; loss-of-function and gain-of-function (rescue) orthogonal evidence in same study\",\n      \"pmids\": [\"23695157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Myotubularin is required for proper function of skeletal muscle during adulthood; conditional adult-specific deletion of Mtm1 via AAV-Cre causes myofiber atrophy, disorganization of mitochondria and nuclei, T-tubule defects, severe muscle weakness, and abnormalities in satellite cell number, autophagy markers, protein synthesis, and neuromuscular junction transmission.\",\n      \"method\": \"AAV-Cre conditional adult Mtm1 deletion in mouse muscle, histopathology, electron microscopy, muscle force measurement, immunostaining for satellite cells and autophagy/NMJ markers\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional adult-specific KO with multiple orthogonal phenotypic readouts (histology, EM, physiology, molecular markers) in a single rigorous study\",\n      \"pmids\": [\"23390130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MTM1 forms a complex with UBQLN2 and HSP proteins (MTM1-UBQLN2-HSP complex) that recognizes and guides misfolded intermediate filament proteins desmin and vimentin to the proteasome for degradation prior to aggregate formation, thereby maintaining cytoskeletal integrity in muscle cells.\",\n      \"method\": \"Co-immunoprecipitation (MTM1-UBQLN2 complex), in vitro and cell-based proteasome degradation assays, loss-of-function studies in muscle cells, electron microscopy of protein aggregates\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP identifying complex, functional assays demonstrating proteasomal degradation, loss-of-function phenotype; multiple orthogonal methods in rigorous study\",\n      \"pmids\": [\"29358706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The N-terminal domain of MTMR2 (absent in MTM1) is responsible for functional differences between MTM1 and MTMR2; a short MTMR2 isoform lacking this N-terminal extension behaves similarly to MTM1 in yeast complementation and mouse rescue assays, and AAV-mediated expression of MTMR2 isoforms in Mtm1 KO mice ameliorates myopathic phenotype, demonstrating functional redundancy of phosphoinositide phosphatase activity.\",\n      \"method\": \"Yeast heterologous expression complementation, AAV-mediated gene delivery in Mtm1 KO mice, muscle force measurement, histopathology, domain deletion analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain deletion analysis combined with both yeast complementation and in vivo mouse rescue; multiple orthogonal methods in single study\",\n      \"pmids\": [\"28934386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In muscles from XLMTM patients, MTM1 mutations cause significant decrease in ryanodine receptor 1 (RyR1) expression, decrease in muscle-specific microRNAs, and up-regulation of histone deacetylase-4 (HDAC4); however, at the myotube level MTM1 mutations do not dramatically affect RyR1-mediated calcium homeostasis, indicating these molecular changes are secondary consequences in mature muscle rather than primary defects.\",\n      \"method\": \"Patient muscle biopsy analysis, patient-derived myotube calcium imaging, immunoblotting for RyR1/HDAC4, microRNA quantification\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient biopsy and cell studies with multiple molecular readouts; single lab, direct patient material but no functional rescue experiment\",\n      \"pmids\": [\"28007904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Disrupted T-tubular network in MTM1-deficient skeletal muscle fibers is the primary cause of asynchronous and severely impaired SR calcium release; mathematical modeling of T-tubule propagation defects reproduces all features of measured calcium release abnormalities, while Ca2+-induced calcium release from RyRs provides secondary support.\",\n      \"method\": \"Confocal calcium transient recordings in MTM1-deficient mouse muscle fibers, mathematical modeling of T-tubule depolarization propagation\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct electrophysiology combined with computational modeling; single lab, two complementary methods but no genetic rescue\",\n      \"pmids\": [\"36408764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of MTM1 in zebrafish causes liver abnormalities including impaired bile flux, structural abnormalities of the bile canaliculus, and improper endosome-mediated trafficking of canalicular transporters; MTM1 localizes to Rab11-positive recycling endosomes in hepatocytes and associates with canalicular transport proteins; hepatocyte-specific re-expression of Mtm1 rescues the cholestatic phenotype; dynasore (a dynamin-2 inhibitor) partially restores bile flow and transporter localization.\",\n      \"method\": \"Zebrafish mtm1 loss-of-function model, reporter-tagged Mtm1 zebrafish line, co-localization with Rab11 and canalicular transporters, hepatocyte-specific rescue by re-expression, chemical screen with dynasore\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic KO, localization, tissue-specific rescue, chemical rescue) in a single rigorous study with clear functional readouts\",\n      \"pmids\": [\"37490339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AAV-mediated MTM1 overexpression prevents and reverts BIN1-related centronuclear myopathy in Bin1mck-/- mice; the lipid phosphatase activity of MTM1 is essential for rescue of muscle atrophy and myofiber hypotrophy but dispensable for rescue of myofiber disorganization including organelle mis-position and T-tubule defects; rescue of T-tubule organization correlates with normalization of dysferlin and caveolin levels.\",\n      \"method\": \"AAV-MTM1 injection (systemic early and intramuscular late) in Bin1mck-/- mouse model, phosphatase-dead MTM1 mutant rescue experiment, histopathology, T-tubule imaging, immunoblotting for dysferlin and caveolin\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — catalytic-dead mutagenesis to dissect phosphatase-dependent vs. -independent rescue, in vivo gene therapy rescue with multiple phenotypic readouts; multiple orthogonal methods\",\n      \"pmids\": [\"37490306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MTM1 is the main enzyme responsible for producing phosphatidylinositol 5-phosphate (PI5P) in muscle cells; this PI5P fuels PI5P 4-kinase α to generate a functional pool of PI(4,5)P2 that concentrates in podosome-like protrusions (PLPs) containing Tks5, Dynamin-2, and Myomaker, which drive myoblast fusion.\",\n      \"method\": \"Lipid mass spectrometry in MTM1-depleted myoblasts, PI5P and PI(4,5)P2 quantification, live imaging of PLP formation, co-localization of MTM1 products with PLP markers, myoblast fusion assays\",\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 — lipidomic quantification establishing MTM1 as PI5P-producing enzyme, functional consequence (PLP formation and myoblast fusion), co-localization; multiple orthogonal methods in single study\",\n      \"pmids\": [\"38805272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MTM1 dephosphorylates a pool of PI3P on EEA1-positive early endosomes in skeletal muscle cells; loss of MTM1 causes PI3P accumulation on these endosomes and impairs Rab4-positive recycling vesicle biogenesis; depletion of class II PI3-kinase beta (PI3KC2β) in Mtm1-KO cells normalizes PI3P levels on EEA1-positive endosomes and restores Rab4-positive vesicle biogenesis.\",\n      \"method\": \"Mtm1-KO skeletal muscle cell line, PI3P localization by immunofluorescence on endosomal compartments, Rab4 vesicle biogenesis assay, PI3KC2β depletion rescue experiments\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cellular KO model with specific endosomal PI3P quantification, vesicle trafficking readout, and rescue by upstream kinase depletion; multiple orthogonal methods\",\n      \"pmids\": [\"39952567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The human MTM1 p.R69C mutation modeled in mice causes exon 4 skipping in most mRNA transcripts (rather than a simple missense change), leading to premature termination and very low myotubularin protein; residual full-length transcript provides enough myotubularin activity to maintain near-normal PI3P levels and account for a milder phenotype compared to complete KO mice.\",\n      \"method\": \"Knock-in mouse model, RT-PCR/mRNA analysis, Western blot for myotubularin protein, PI3P level measurement in muscle\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in mouse with molecular characterization of mRNA splicing, protein levels, and lipid substrate levels; multiple orthogonal methods explaining genotype-phenotype correlation\",\n      \"pmids\": [\"22068590\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MTM1 encodes myotubularin, a phosphoinositide phosphatase that dephosphorylates PI3P and PI(3,5)P2 on early endosomes and the plasma membrane; it produces PI5P to fuel PI(4,5)P2 generation in podosome-like protrusions driving myoblast fusion, controls endosomal Rab4-recycling vesicle biogenesis, forms a complex with UBQLN2 and HSP proteins to guide misfolded intermediate filaments (desmin, vimentin) to the proteasome, regulates the IGF1R/Akt-autophagy/ubiquitin-proteasome balance in muscle, is required for T-tubule integrity and thus excitation-contraction coupling, and in the liver localizes to Rab11-positive recycling endosomes where it supports canalicular transporter trafficking; in C. elegans the ortholog MTM-1 negatively regulates apoptotic cell corpse engulfment by dephosphorylating PI3P upstream of the CED-5/CED-12/CED-10 GEF complex, while the yeast MTM1 ortholog facilitates manganese insertion into the mitochondrial SOD2 enzyme.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MTM1 encodes myotubularin, a phosphoinositide phosphatase whose loss-of-function mutations cause X-linked myotubular/centronuclear myopathy [#0]. Its core catalytic activity dephosphorylates PI3P, including a pool on EEA1-positive early endosomes whose accumulation upon MTM1 loss impairs Rab4-positive recycling-vesicle biogenesis, a defect reversed by depleting the upstream kinase PI3KC2\\u03b2 [#13]. Beyond clearing PI3P, MTM1 is the principal enzyme generating PI5P in muscle, feeding PI5P 4-kinase \\u03b1 to build the PI(4,5)P2 pool that concentrates in podosome-like protrusions driving myoblast fusion [#12]. These lipid functions underlie MTM1's role in muscle homeostasis: it maintains T-tubule integrity required for synchronous SR calcium release and excitation-contraction coupling [#9], sits upstream of the IGF1R/Akt axis to balance autophagy and ubiquitin-proteasome activity [#4], and is required to sustain adult myofiber architecture, mitochondrial and nuclear positioning, and neuromuscular function [#5]. MTM1 also acts in protein quality control as part of an MTM1-UBQLN2-HSP complex that routes misfolded desmin and vimentin to the proteasome before they aggregate [#6]. Catalytic-dissection studies show its lipid phosphatase activity is essential for rescue of muscle atrophy but dispensable for restoring T-tubule organization, indicating distinct phosphatase-dependent and -independent outputs [#11]. Orthologs extend this picture: C. elegans MTM-1 negatively regulates apoptotic corpse engulfment by dephosphorylating membrane PI3P upstream of the CED-5/CED-12/CED-10 GEF module [#2, #3], and the yeast ortholog functions as a mitochondrial manganese-trafficking factor required to activate SOD2 [#1]. In vertebrate liver, MTM1 localizes to Rab11-positive recycling endosomes and supports canalicular transporter trafficking and bile flux [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Identifying MTM1 as the gene mutated in X-linked myotubular myopathy and recognizing its tyrosine phosphatase domain established the founding hypothesis that an enzymatic phosphatase activity underlies the disease.\",\n      \"evidence\": \"Positional cloning and SSCP mutation screening in patients\",\n      \"pmids\": [\"9305655\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzymatic activity inferred from domain homology, not demonstrated in vitro\", \"No lipid substrate identified at this stage\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The yeast ortholog revealed a mechanistically distinct function as a mitochondrial manganese carrier required for SOD2 activation, showing the MTM1 name covers divergent ortholog roles.\",\n      \"evidence\": \"Yeast deletion screen, SOD2 activity assays, manganese rescue, mitochondrial localization\",\n      \"pmids\": [\"12890866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship to vertebrate phosphoinositide phosphatase function unresolved\", \"Direct manganese-binding by the protein not shown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic and lipid-level analysis in C. elegans defined MTM-1 as a PI3P phosphatase that negatively regulates apoptotic corpse engulfment, anchoring the lipid-phosphatase model in a whole-organism pathway.\",\n      \"evidence\": \"C. elegans genetics, epistasis with engulfment mutants, plasma-membrane PtdIns(3)P imaging\",\n      \"pmids\": [\"19816564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct in vitro phosphatase kinetics not measured\", \"How phosphatase activity gates engulfment effectors unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Epistasis placed MTM-1 upstream of the CED-2/CED-5/CED-12 GEF complex and linked CED-12 PH-domain binding of PtdIns(3,5)P2 to membrane recruitment, providing a substrate-to-effector mechanism for engulfment control.\",\n      \"evidence\": \"C. elegans epistasis, phagosome maturation assays, CED-12 PH-domain lipid pulldown\",\n      \"pmids\": [\"21490059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo demonstration of MTM-1-driven CED-12 recruitment lacking\", \"PtdIns(3,5)P2 vs PI3P substrate preference not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"A knock-in mouse showed the patient p.R69C allele acts largely by inducing exon 4 skipping with residual full-length protein, explaining a milder phenotype and linking myotubularin level to PI3P homeostasis.\",\n      \"evidence\": \"Knock-in mouse, mRNA splicing analysis, Western blot, muscle PI3P measurement\",\n      \"pmids\": [\"22068590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability to other missense alleles unknown\", \"Threshold of activity needed for normal muscle not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mtm1-null and AAV-rescue studies positioned MTM1 upstream of the IGF1R/Akt axis controlling the autophagy/proteasome balance, connecting the phosphatase to muscle proteostasis signaling.\",\n      \"evidence\": \"KO mouse, immunoblotting of pathway markers, autophagosome counts, AAV-Mtm1 rescue\",\n      \"pmids\": [\"23695157\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking phosphoinositide turnover to IGF1R/Akt not defined\", \"Direct phosphatase substrate driving this signaling unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Adult-specific conditional deletion established that myotubularin is continuously required in mature muscle, producing T-tubule defects, organelle mispositioning, and NMJ abnormalities rather than acting only during development.\",\n      \"evidence\": \"AAV-Cre conditional deletion, histology, EM, force measurement, marker immunostaining\",\n      \"pmids\": [\"23390130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal order among the multiple defects unresolved\", \"Cell-autonomous vs systemic contributions not separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Domain-swap and rescue experiments showed phosphoinositide phosphatase activity is the shared functional core, with an MTMR2 N-terminal extension accounting for paralog-specific differences and a short MTMR2 isoform substituting for MTM1.\",\n      \"evidence\": \"Yeast complementation, AAV MTMR2-isoform rescue in Mtm1 KO mice, domain deletion\",\n      \"pmids\": [\"28934386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular function of the MTMR2 N-terminal extension undefined\", \"Endogenous redundancy in humans not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Patient muscle and myotube analysis distinguished primary from secondary defects, showing RyR1/HDAC4/microRNA changes are downstream consequences in mature muscle rather than the initiating lesion.\",\n      \"evidence\": \"Patient biopsy immunoblotting, microRNA quantification, patient myotube calcium imaging\",\n      \"pmids\": [\"28007904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No rescue experiment to confirm secondary nature\", \"Primary trigger of these changes not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery of the MTM1-UBQLN2-HSP complex revealed a phosphatase-independent role in cytoskeletal proteostasis, routing misfolded desmin and vimentin to the proteasome before aggregation.\",\n      \"evidence\": \"Reciprocal Co-IP, proteasome degradation assays, loss-of-function in muscle cells, EM of aggregates\",\n      \"pmids\": [\"29358706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly of the complex undefined\", \"Whether substrate recognition requires MTM1 lipid binding unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Calcium-transient recording with modeling identified the disrupted T-tubular network as the primary cause of impaired SR calcium release, ranking T-tubule structure above RyR-level changes in the EC-coupling defect.\",\n      \"evidence\": \"Confocal calcium recordings in MTM1-deficient fibers, mathematical modeling of T-tubule propagation\",\n      \"pmids\": [\"36408764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genetic rescue confirming causality\", \"Lipid mechanism linking MTM1 loss to T-tubule disruption not shown here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A zebrafish model extended MTM1 function to liver, showing it acts on Rab11 recycling endosomes to traffic canalicular transporters and maintain bile flux, with dynamin-2 inhibition partially correcting the defect.\",\n      \"evidence\": \"Zebrafish KO, Rab11/transporter co-localization, hepatocyte-specific rescue, dynasore chemical rescue\",\n      \"pmids\": [\"37490339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct lipid substrate at canalicular endosomes not measured\", \"Relevance to human hepatic phenotypes not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Catalytic-dead rescue in a BIN1-CNM model dissected phosphatase-dependent (atrophy/hypotrophy) from phosphatase-independent (T-tubule and organelle organization) outputs of MTM1, and linked T-tubule rescue to dysferlin/caveolin normalization.\",\n      \"evidence\": \"AAV-MTM1 and phosphatase-dead mutant rescue in Bin1mck-/- mice, histology, T-tubule imaging, immunoblotting\",\n      \"pmids\": [\"37490306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the phosphatase-independent activity unresolved\", \"How MTM1 cross-corrects a BIN1 defect mechanistically unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Lipidomics established MTM1 as the principal PI5P-producing enzyme in muscle, feeding PIP4K\\u03b1-generated PI(4,5)P2 into podosome-like protrusions that drive myoblast fusion, defining a synthetic rather than purely degradative lipid output.\",\n      \"evidence\": \"Lipid mass spectrometry in depleted myoblasts, PLP live imaging, fusion assays\",\n      \"pmids\": [\"38805272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution of this pathway to muscle regeneration not shown\", \"Direct enzymatic route from MTM1 substrate to PI5P not fully traced\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Endosomal mapping showed MTM1 dephosphorylates PI3P on EEA1-positive early endosomes to enable Rab4 recycling-vesicle biogenesis, with PI3KC2\\u03b2 identified as the opposing kinase whose depletion rescues the defect.\",\n      \"evidence\": \"Mtm1-KO muscle cells, compartment-specific PI3P imaging, Rab4 vesicle assay, PI3KC2\\u03b2 depletion rescue\",\n      \"pmids\": [\"39952567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo identity of Rab4 vesicles in muscle undefined\", \"Link between endosomal recycling defect and myopathy phenotype not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MTM1's distinct molecular activities — PI3P turnover, PI5P synthesis, and UBQLN2-mediated proteostasis — are coordinated and which is the proximal driver of human myopathy remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified mechanism linking lipid and proteostasis functions\", \"Tissue-specific substrate map incomplete\", \"Structural basis of substrate selection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2, 12, 13]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3, 12, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [13, 10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 12]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [13, 10]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [9, 5]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\"MTM1-UBQLN2-HSP complex\"],\n    \"partners\": [\"UBQLN2\", \"PI3KC2\\u03b2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}