{"gene":"SBF1","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2003,"finding":"MTMR5/SBF1 (SBF1) specifically interacts with MTMR2 but not MTM1, via the coiled-coil domain of both proteins; mutations in the coiled-coil domain of either MTMR2 or MTMR5 abrogate this interaction. Through this interaction, MTMR5 increases the enzymatic activity of MTMR2 and dictates its subcellular localization.","method":"Co-immunoprecipitation, mass spectrometry identification, coiled-coil domain mutagenesis, enzymatic activity assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP with mass spectrometry identification, domain mutagenesis abolishing interaction, and in vitro enzymatic activity assay all in one study","pmids":["12668758"],"is_preprint":false},{"year":2001,"finding":"Full-length SBF1 contains PH, GEF homology, and myotubularin homology domains. Forced expression in NIH 3T3 cells inhibits proliferation and alters morphology, requiring intact PH, GEF, and myotubularin homology domains. Deletion of the N-terminal 44 amino acids converts SBF1 from a growth inhibitor to a transforming protein. Oncogenic forms partially localize to the nucleus, whereas endogenous SBF1 is exclusively cytoplasmic.","method":"Overexpression/deletion mutagenesis in NIH 3T3 cells, subcellular fractionation/localization, proliferation and transformation assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple deletion constructs with functional readouts in one lab; no independent replication","pmids":["11686296"],"is_preprint":false},{"year":1998,"finding":"SBF1 was originally discovered by its physical interaction with the SET domain of the proto-oncogene Hrx (MLL). SBF1 lacks phosphatase activity due to conserved amino acid changes in its catalytic pocket. The SET interaction domain of SBF1 is necessary and sufficient for growth stimulation of primary B cell precursors.","method":"Protein interaction assay (SET domain binding), retroviral overexpression in bone marrow cultures, structure/function deletion analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct binding to SET domain shown, deletion analysis in primary cells, single lab","pmids":["9689104"],"is_preprint":false},{"year":2002,"finding":"Sbf1 is a catalytically inactive pseudophosphatase expressed at high levels in seminiferous tubules (Sertoli cells, spermatogonia, pachytene spermatocytes). Mice nullizygous for Sbf1 exhibit male infertility with azoospermia; the spermatogenic defect initiates during the first wave of spermatogenesis at 17 days post-birth at the pachytene-to-haploid spermatid transition, with Sertoli cell vacuolation as the earliest phenotype.","method":"Sbf1 knockout mouse (null allele), histology, immunohistochemistry, expression analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with defined cellular and temporal phenotype, histological characterization, replicated by independent rat study (PMID:27335132)","pmids":["11994405","27335132"],"is_preprint":false},{"year":2022,"finding":"In mouse peripheral nervous system, Mtmr2 is required to maintain wild-type protein levels of Mtmr5 and Mtmr13, suggesting they function in discrete protein complexes. Genetic elimination of both Mtmr5 and Mtmr13 causes perinatal lethality, indicating partial redundancy. Loss of Mtmr5 alone does not cause CMT4B-like myelin outfoldings but results in fewer myelinated axons in adult nerves, likely due to axon radial sorting defects; Mtmr5 levels are highest during radial sorting and drop sharply after postnatal day 7.","method":"Double and single conditional knockout mice, nerve morphology/histology, western blot for protein levels, developmental expression profiling","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with multiple orthogonal methods (protein quantification, histology, developmental time course), distinct from MTMR13 function established by comparative analysis","pmids":["34718573"],"is_preprint":false},{"year":2016,"finding":"A splicing mutation in rat Sbf1 (intron 37 splice site G>A) causes absence of full-length Sbf1 protein in the testis, resulting in azoospermia and male infertility as the sole phenotype, confirming a specific role for Sbf1 in spermatogenesis and corroborating results from the mouse knockout.","method":"Genetic mapping, candidate gene sequencing, western blot (protein absence in mutant testis), histology","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in rat with protein-level confirmation and clear phenotype; replicates mouse finding in an independent organism","pmids":["27335132"],"is_preprint":false},{"year":2025,"finding":"In CMT4B3 patient-derived fibroblasts with compound heterozygous MTMR5/SBF1 mutations, basal macroautophagy is normal but fails to upregulate in response to mitochondrial stress or protein aggregates. Conversely, mitophagy via the PINK1-PRKN pathway is strongly activated, revealing an uncoupling between macroautophagy and mitophagy caused by MTMR5/SBF1 dysfunction.","method":"LC3B/SQSTM1 flux assay, PINK1/PRKN recruitment assay, mitophagosome/autolysosome quantification, Proteostat aggregate staining in patient fibroblasts","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple orthogonal autophagy assays in patient-derived cells, single lab, no genetic rescue","pmids":["40998285"],"is_preprint":false},{"year":2019,"finding":"A novel homozygous frameshift deletion in SBF1 exon 40 results in markedly reduced MTMR5 protein levels in patient fibroblasts, establishing that loss-of-function SBF1 mutations cause sensory-motor axonal neuropathy with necklace fibres on muscle biopsy.","method":"Whole-exome sequencing, cDNA analysis, western blot of patient fibroblasts","journal":"Journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — protein-level confirmation of loss of function in patient-derived cells, single family","pmids":["32444983"],"is_preprint":false}],"current_model":"SBF1 (MTMR5) is a catalytically inactive pseudophosphatase of the myotubularin family that functions as a regulatory subunit: it physically interacts with the active phosphatase MTMR2 via coiled-coil domains, enhancing MTMR2's enzymatic activity toward phosphoinositide substrates and dictating its subcellular localization; SBF1 also binds SET domains of epigenetic regulators such as MLL/Hrx, modulating growth signaling in B cell progenitors; its N-terminal GEF homology domain suppresses transforming activity and sequesters the protein to the cytoplasm; in vivo, SBF1 is essential for spermatogenesis (pachytene-to-spermatid transition) and for axon radial sorting in peripheral nerves, with loss-of-function mutations causing CMT4B3 neuropathy and, in cellular models, an uncoupling of selective mitophagy from macroautophagy."},"narrative":{"mechanistic_narrative":"SBF1 (MTMR5) is a catalytically inactive pseudophosphatase of the myotubularin family that functions as a regulatory partner of active phosphoinositide phosphatases and a multidomain signaling protein governing tissue-specific differentiation programs [PMID:12668758, PMID:11994405, PMID:27335132]. It interacts specifically with the active phosphatase MTMR2 — but not MTM1 — through reciprocal coiled-coil domains, and this interaction increases MTMR2 enzymatic activity and dictates its subcellular localization [PMID:12668758]. SBF1 lost catalytic activity through conserved substitutions in its phosphatase pocket, and was first identified through binding the SET domain of the proto-oncogene Hrx/MLL, a SET-interaction module sufficient to stimulate growth of primary B cell precursors [PMID:9689104]. The full-length protein carries PH, GEF homology, and myotubularin homology domains, all required for its growth-inhibitory activity; removal of the N-terminal 44 residues converts it into a transforming protein and permits partial nuclear localization, whereas the endogenous protein is cytoplasmic [PMID:11686296]. In vivo, SBF1 is essential for spermatogenesis: loss of function in mouse and rat produces azoospermia and male infertility, with the defect initiating at the pachytene-to-haploid spermatid transition [PMID:11994405, PMID:27335132]. In peripheral nerve, SBF1 acts during myelination in a manner partly redundant with MTMR13, with its loss reducing the number of myelinated axons through radial sorting defects [PMID:34718573], and loss-of-function mutations in patients cause sensory-motor axonal neuropathy (CMT4B3) with necklace fibres [PMID:32444983]. Patient fibroblasts reveal an uncoupling of selective mitophagy from macroautophagy upon SBF1 dysfunction [PMID:40998285].","teleology":[{"year":1998,"claim":"Established SBF1's molecular identity as a catalytically dead myotubularin-family protein and linked it to chromatin/oncogene signaling by showing it binds the SET domain of MLL/Hrx.","evidence":"SET-domain binding assay and retroviral overexpression/deletion analysis in primary B cell precursors","pmids":["9689104"],"confidence":"Medium","gaps":["Mechanism by which SET binding stimulates B cell precursor growth unresolved","Single lab, no in vivo validation of the MLL interaction","Did not define the phosphoinositide-related role of the pseudophosphatase domain"]},{"year":2001,"claim":"Defined the domain architecture and revealed an N-terminal autoinhibitory element that suppresses transformation and enforces cytoplasmic localization.","evidence":"Overexpression and deletion mutagenesis in NIH 3T3 cells with proliferation, transformation, and fractionation readouts","pmids":["11686296"],"confidence":"Medium","gaps":["Physiological relevance of the transforming activity unestablished","No independent replication","Endogenous regulators of the N-terminal switch unknown"]},{"year":2002,"claim":"Demonstrated an essential, non-redundant in vivo role in spermatogenesis through a clean genetic knockout, placing the defect at a specific developmental transition.","evidence":"Sbf1 null mouse with histology, immunohistochemistry, and expression analysis","pmids":["11994405","27335132"],"confidence":"High","gaps":["Molecular substrate/pathway driving the pachytene-to-spermatid block not defined","Whether Sertoli cell vacuolation is primary or secondary unresolved"]},{"year":2003,"claim":"Showed SBF1 is a regulatory subunit of an active phosphatase, explaining how a catalytically dead protein influences phosphoinositide metabolism.","evidence":"Reciprocal Co-IP with MS identification, coiled-coil domain mutagenesis, and in vitro enzymatic activity assay","pmids":["12668758"],"confidence":"High","gaps":["Phosphoinositide species and cellular compartments controlled by the MTMR5-MTMR2 complex in vivo not mapped","Structural basis of activity enhancement undetermined"]},{"year":2016,"claim":"Confirmed the spermatogenesis requirement in an independent organism via a natural loss-of-function allele, strengthening the causal link.","evidence":"Genetic mapping, candidate sequencing, and protein-absence western blot in rat testis","pmids":["27335132"],"confidence":"Medium","gaps":["Does not extend the mechanism beyond the mouse phenotype","Cellular target of the spermatogenic defect not addressed"]},{"year":2019,"claim":"Established SBF1 loss-of-function as a cause of human sensory-motor axonal neuropathy, connecting the gene to peripheral nerve disease.","evidence":"Whole-exome sequencing, cDNA analysis, and western blot of patient fibroblasts (single family)","pmids":["32444983"],"confidence":"Medium","gaps":["Single family limits genotype-phenotype generalization","Cellular mechanism of axonal degeneration not addressed"]},{"year":2022,"claim":"Dissected SBF1's peripheral nerve function from its paralog MTMR13, revealing partial redundancy and a specific role in axon radial sorting.","evidence":"Single and double conditional knockout mice with nerve histology, protein quantification, and developmental expression profiling","pmids":["34718573"],"confidence":"High","gaps":["Molecular basis of the radial sorting defect undefined","How MTMR2 stabilizes Mtmr5/Mtmr13 mechanistically unclear"]},{"year":2025,"claim":"Linked SBF1 dysfunction to a selective autophagy defect, showing macroautophagy and PINK1-PRKN mitophagy become uncoupled.","evidence":"LC3B/SQSTM1 flux, PINK1/PRKN recruitment, and aggregate staining in CMT4B3 patient fibroblasts (single lab, no genetic rescue)","pmids":["40998285"],"confidence":"Medium","gaps":["No genetic rescue to confirm causality","Mechanistic link between SBF1 phosphoinositide regulation and autophagy uncoupling not established","Relevance to the in vivo neuropathy phenotype untested"]},{"year":null,"claim":"How SBF1's phosphoinositide-regulatory role (via MTMR2) mechanistically connects to its disparate phenotypes — spermatogenesis, radial sorting, and autophagy uncoupling — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying substrate or pathway tying the molecular and organismal phenotypes together","Role of the MLL/SET interaction in nerve or testis biology unexplored","No structural model of the MTMR5-MTMR2 complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,4]}],"complexes":[],"partners":["MTMR2","MLL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95248","full_name":"Myotubularin-related protein 5","aliases":["Inactive phosphatidylinositol 3-phosphatase 5","SET-binding factor 1","Sbf1"],"length_aa":1868,"mass_kda":208.4,"function":"Acts as an adapter for the phosphatase MTMR2 to regulate MTMR2 catalytic activity and subcellular location (PubMed:12668758). Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form (PubMed:20937701). May function as a guanine nucleotide exchange factor (GEF) activating RAB28 (PubMed:20937701). Acts as a suppressor of autophagy in neurons (PubMed:35580604). Together with its binding partner, the phosphatase MTMR2, plays a role in dephosphorylation of phosphoinositides critical for autophagy initiation and autophagosome maturation (PubMed:35580604). Plays a role in positively regulating late-stage radial sorting of large caliber axons, a process leading to myelination by Schwann cells, possibly via regulating endosomal trafficking (By similarity). Inhibits myoblast differentiation in vitro and induces oncogenic transformation in fibroblasts (PubMed:9537414)","subcellular_location":"Cytoplasm; Cytoplasm, perinuclear region; Cell projection, neuron projection","url":"https://www.uniprot.org/uniprotkb/O95248/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SBF1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CTTN","stoichiometry":0.2},{"gene":"MTMR1","stoichiometry":0.2},{"gene":"MTMR2","stoichiometry":0.2},{"gene":"PTGES3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SBF1","total_profiled":1310},"omim":[{"mim_id":"615284","title":"CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4B3; CMT4B3","url":"https://www.omim.org/entry/615284"},{"mim_id":"607697","title":"SET-BINDING FACTOR 2; SBF2","url":"https://www.omim.org/entry/607697"},{"mim_id":"606501","title":"MYOTUBULARIN-RELATED PROTEIN 12; MTMR12","url":"https://www.omim.org/entry/606501"},{"mim_id":"606260","title":"MYOTUBULARIN-RELATED PROTEIN 9; MTMR9","url":"https://www.omim.org/entry/606260"},{"mim_id":"604563","title":"CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4B2; CMT4B2","url":"https://www.omim.org/entry/604563"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SBF1"},"hgnc":{"alias_symbol":["MTMR5","DENND7A"],"prev_symbol":[]},"alphafold":{"accession":"O95248","domains":[{"cath_id":"3.30.450.200","chopping":"3-91_127-201_490-527","consensus_level":"high","plddt":79.2505,"start":3,"end":527},{"cath_id":"3.40.50.11500","chopping":"212-344_361-481","consensus_level":"medium","plddt":87.8149,"start":212,"end":481},{"cath_id":"-","chopping":"563-671","consensus_level":"medium","plddt":84.4617,"start":563,"end":671},{"cath_id":"2.30.29.30","chopping":"897-1030","consensus_level":"medium","plddt":82.7113,"start":897,"end":1030},{"cath_id":"-","chopping":"1364-1416_1425-1540_1551-1594","consensus_level":"medium","plddt":89.45,"start":1364,"end":1594},{"cath_id":"2.30.29.30","chopping":"1764-1868","consensus_level":"medium","plddt":85.5765,"start":1764,"end":1868}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95248","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95248-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95248-F1-predicted_aligned_error_v6.png","plddt_mean":73.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SBF1","jax_strain_url":"https://www.jax.org/strain/search?query=SBF1"},"sequence":{"accession":"O95248","fasta_url":"https://rest.uniprot.org/uniprotkb/O95248.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95248/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95248"}},"corpus_meta":[{"pmid":"12687498","id":"PMC_12687498","title":"Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma.","date":"2003","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12687498","citation_count":232,"is_preprint":false},{"pmid":"12668758","id":"PMC_12668758","title":"Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase.","date":"2003","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12668758","citation_count":121,"is_preprint":false},{"pmid":"1893099","id":"PMC_1893099","title":"Silencer region of a chalcone synthase promoter contains multiple binding sites for a factor, SBF-1, closely related to GT-1.","date":"1991","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/1893099","citation_count":81,"is_preprint":false},{"pmid":"11994405","id":"PMC_11994405","title":"Male infertility, impaired spermatogenesis, and azoospermia in mice deficient for the pseudophosphatase Sbf1.","date":"2002","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/11994405","citation_count":61,"is_preprint":false},{"pmid":"23749797","id":"PMC_23749797","title":"SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3.","date":"2013","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/23749797","citation_count":56,"is_preprint":false},{"pmid":"25522275","id":"PMC_25522275","title":"SBF-1 exerts strong anticervical cancer effect through inducing endoplasmic reticulum stress-associated cell death via targeting sarco/endoplasmic reticulum Ca(2+)-ATPase 2.","date":"2014","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/25522275","citation_count":35,"is_preprint":false},{"pmid":"11686296","id":"PMC_11686296","title":"Pseudo-phosphatase Sbf1 contains an N-terminal GEF homology domain that modulates its growth regulatory properties.","date":"2001","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/11686296","citation_count":29,"is_preprint":false},{"pmid":"9689104","id":"PMC_9689104","title":"Growth stimulation of primary B cell precursors by the anti-phosphatase Sbf1.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9689104","citation_count":28,"is_preprint":false},{"pmid":"22525724","id":"PMC_22525724","title":"SBF-1, a synthetic steroidal glycoside, inhibits melanoma growth and metastasis through blocking interaction between PDK1 and AKT3.","date":"2012","source":"Biochemical 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involvement.","date":"2016","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/28005197","citation_count":12,"is_preprint":false},{"pmid":"34718573","id":"PMC_34718573","title":"Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination.","date":"2022","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34718573","citation_count":10,"is_preprint":false},{"pmid":"36104480","id":"PMC_36104480","title":"A (GCC) repeat in SBF1 reveals a novel biological phenomenon in human and links to late onset neurocognitive disorder.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36104480","citation_count":10,"is_preprint":false},{"pmid":"34118926","id":"PMC_34118926","title":"Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction.","date":"2021","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/34118926","citation_count":8,"is_preprint":false},{"pmid":"33411211","id":"PMC_33411211","title":"Selective targeting of the androgen receptor-DNA binding domain by the novel antiandrogen SBF-1 and inhibition of the growth of prostate cancer cells.","date":"2021","source":"Investigational new drugs","url":"https://pubmed.ncbi.nlm.nih.gov/33411211","citation_count":8,"is_preprint":false},{"pmid":"30415825","id":"PMC_30415825","title":"SBF-1 preferentially inhibits growth of highly malignant human liposarcoma cells.","date":"2018","source":"Journal of pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30415825","citation_count":8,"is_preprint":false},{"pmid":"24817947","id":"PMC_24817947","title":"DNA microarray reveals ZNF195 and SBF1 are potential biomarkers for gemcitabine sensitivity in head and neck squamous cell carcinoma cell lines.","date":"2014","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24817947","citation_count":7,"is_preprint":false},{"pmid":"32444983","id":"PMC_32444983","title":"A novel frameshift deletion in autosomal recessive SBF1-related syndromic neuropathy with necklace fibres.","date":"2020","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/32444983","citation_count":7,"is_preprint":false},{"pmid":"31197600","id":"PMC_31197600","title":"Discovery of SBF1 as an allosteric inhibitor targeting the PIF-pocket of 3-phosphoinositide-dependent protein kinase-1.","date":"2019","source":"Journal of molecular modeling","url":"https://pubmed.ncbi.nlm.nih.gov/31197600","citation_count":4,"is_preprint":false},{"pmid":"27335132","id":"PMC_27335132","title":"Splicing mutation in Sbf1 causes nonsyndromic male infertility in the rat.","date":"2016","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/27335132","citation_count":4,"is_preprint":false},{"pmid":"36272304","id":"PMC_36272304","title":"Generation and characterization of CSSi016-A (9938) human pluripotent stem cell line carrying two biallelic variants in MTMR5/SBF1 gene resulting in a case of severe CMT4B3.","date":"2022","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/36272304","citation_count":4,"is_preprint":false},{"pmid":"40066109","id":"PMC_40066109","title":"Characterization of a novel zebrafish model of MTMR5-associated Charcot-Marie-Tooth disease type 4B3.","date":"2025","source":"Brain communications","url":"https://pubmed.ncbi.nlm.nih.gov/40066109","citation_count":2,"is_preprint":false},{"pmid":"40998285","id":"PMC_40998285","title":"Selective mitophagy activation and protein aggregate accumulation in MTMR5/SBF1-deficient fibroblasts.","date":"2025","source":"Life 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communications","url":"https://pubmed.ncbi.nlm.nih.gov/41317708","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16323,"output_tokens":2285,"usd":0.041622,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9307,"output_tokens":2866,"usd":0.059092,"stage2_stop_reason":"end_turn"},"total_usd":0.100714,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"MTMR5/SBF1 (SBF1) specifically interacts with MTMR2 but not MTM1, via the coiled-coil domain of both proteins; mutations in the coiled-coil domain of either MTMR2 or MTMR5 abrogate this interaction. Through this interaction, MTMR5 increases the enzymatic activity of MTMR2 and dictates its subcellular localization.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry identification, coiled-coil domain mutagenesis, enzymatic activity assay\",\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 — reciprocal Co-IP with mass spectrometry identification, domain mutagenesis abolishing interaction, and in vitro enzymatic activity assay all in one study\",\n      \"pmids\": [\"12668758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Full-length SBF1 contains PH, GEF homology, and myotubularin homology domains. Forced expression in NIH 3T3 cells inhibits proliferation and alters morphology, requiring intact PH, GEF, and myotubularin homology domains. Deletion of the N-terminal 44 amino acids converts SBF1 from a growth inhibitor to a transforming protein. Oncogenic forms partially localize to the nucleus, whereas endogenous SBF1 is exclusively cytoplasmic.\",\n      \"method\": \"Overexpression/deletion mutagenesis in NIH 3T3 cells, subcellular fractionation/localization, proliferation and transformation assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple deletion constructs with functional readouts in one lab; no independent replication\",\n      \"pmids\": [\"11686296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SBF1 was originally discovered by its physical interaction with the SET domain of the proto-oncogene Hrx (MLL). SBF1 lacks phosphatase activity due to conserved amino acid changes in its catalytic pocket. The SET interaction domain of SBF1 is necessary and sufficient for growth stimulation of primary B cell precursors.\",\n      \"method\": \"Protein interaction assay (SET domain binding), retroviral overexpression in bone marrow cultures, structure/function deletion analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct binding to SET domain shown, deletion analysis in primary cells, single lab\",\n      \"pmids\": [\"9689104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Sbf1 is a catalytically inactive pseudophosphatase expressed at high levels in seminiferous tubules (Sertoli cells, spermatogonia, pachytene spermatocytes). Mice nullizygous for Sbf1 exhibit male infertility with azoospermia; the spermatogenic defect initiates during the first wave of spermatogenesis at 17 days post-birth at the pachytene-to-haploid spermatid transition, with Sertoli cell vacuolation as the earliest phenotype.\",\n      \"method\": \"Sbf1 knockout mouse (null allele), histology, immunohistochemistry, expression analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with defined cellular and temporal phenotype, histological characterization, replicated by independent rat study (PMID:27335132)\",\n      \"pmids\": [\"11994405\", \"27335132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In mouse peripheral nervous system, Mtmr2 is required to maintain wild-type protein levels of Mtmr5 and Mtmr13, suggesting they function in discrete protein complexes. Genetic elimination of both Mtmr5 and Mtmr13 causes perinatal lethality, indicating partial redundancy. Loss of Mtmr5 alone does not cause CMT4B-like myelin outfoldings but results in fewer myelinated axons in adult nerves, likely due to axon radial sorting defects; Mtmr5 levels are highest during radial sorting and drop sharply after postnatal day 7.\",\n      \"method\": \"Double and single conditional knockout mice, nerve morphology/histology, western blot for protein levels, developmental expression profiling\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with multiple orthogonal methods (protein quantification, histology, developmental time course), distinct from MTMR13 function established by comparative analysis\",\n      \"pmids\": [\"34718573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A splicing mutation in rat Sbf1 (intron 37 splice site G>A) causes absence of full-length Sbf1 protein in the testis, resulting in azoospermia and male infertility as the sole phenotype, confirming a specific role for Sbf1 in spermatogenesis and corroborating results from the mouse knockout.\",\n      \"method\": \"Genetic mapping, candidate gene sequencing, western blot (protein absence in mutant testis), histology\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in rat with protein-level confirmation and clear phenotype; replicates mouse finding in an independent organism\",\n      \"pmids\": [\"27335132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In CMT4B3 patient-derived fibroblasts with compound heterozygous MTMR5/SBF1 mutations, basal macroautophagy is normal but fails to upregulate in response to mitochondrial stress or protein aggregates. Conversely, mitophagy via the PINK1-PRKN pathway is strongly activated, revealing an uncoupling between macroautophagy and mitophagy caused by MTMR5/SBF1 dysfunction.\",\n      \"method\": \"LC3B/SQSTM1 flux assay, PINK1/PRKN recruitment assay, mitophagosome/autolysosome quantification, Proteostat aggregate staining in patient fibroblasts\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple orthogonal autophagy assays in patient-derived cells, single lab, no genetic rescue\",\n      \"pmids\": [\"40998285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A novel homozygous frameshift deletion in SBF1 exon 40 results in markedly reduced MTMR5 protein levels in patient fibroblasts, establishing that loss-of-function SBF1 mutations cause sensory-motor axonal neuropathy with necklace fibres on muscle biopsy.\",\n      \"method\": \"Whole-exome sequencing, cDNA analysis, western blot of patient fibroblasts\",\n      \"journal\": \"Journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — protein-level confirmation of loss of function in patient-derived cells, single family\",\n      \"pmids\": [\"32444983\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SBF1 (MTMR5) is a catalytically inactive pseudophosphatase of the myotubularin family that functions as a regulatory subunit: it physically interacts with the active phosphatase MTMR2 via coiled-coil domains, enhancing MTMR2's enzymatic activity toward phosphoinositide substrates and dictating its subcellular localization; SBF1 also binds SET domains of epigenetic regulators such as MLL/Hrx, modulating growth signaling in B cell progenitors; its N-terminal GEF homology domain suppresses transforming activity and sequesters the protein to the cytoplasm; in vivo, SBF1 is essential for spermatogenesis (pachytene-to-spermatid transition) and for axon radial sorting in peripheral nerves, with loss-of-function mutations causing CMT4B3 neuropathy and, in cellular models, an uncoupling of selective mitophagy from macroautophagy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SBF1 (MTMR5) is a catalytically inactive pseudophosphatase of the myotubularin family that functions as a regulatory partner of active phosphoinositide phosphatases and a multidomain signaling protein governing tissue-specific differentiation programs [#0, #3]. It interacts specifically with the active phosphatase MTMR2 — but not MTM1 — through reciprocal coiled-coil domains, and this interaction increases MTMR2 enzymatic activity and dictates its subcellular localization [#0]. SBF1 lost catalytic activity through conserved substitutions in its phosphatase pocket, and was first identified through binding the SET domain of the proto-oncogene Hrx/MLL, a SET-interaction module sufficient to stimulate growth of primary B cell precursors [#2]. The full-length protein carries PH, GEF homology, and myotubularin homology domains, all required for its growth-inhibitory activity; removal of the N-terminal 44 residues converts it into a transforming protein and permits partial nuclear localization, whereas the endogenous protein is cytoplasmic [#1]. In vivo, SBF1 is essential for spermatogenesis: loss of function in mouse and rat produces azoospermia and male infertility, with the defect initiating at the pachytene-to-haploid spermatid transition [#3, #5]. In peripheral nerve, SBF1 acts during myelination in a manner partly redundant with MTMR13, with its loss reducing the number of myelinated axons through radial sorting defects [#4], and loss-of-function mutations in patients cause sensory-motor axonal neuropathy (CMT4B3) with necklace fibres [#7]. Patient fibroblasts reveal an uncoupling of selective mitophagy from macroautophagy upon SBF1 dysfunction [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established SBF1's molecular identity as a catalytically dead myotubularin-family protein and linked it to chromatin/oncogene signaling by showing it binds the SET domain of MLL/Hrx.\",\n      \"evidence\": \"SET-domain binding assay and retroviral overexpression/deletion analysis in primary B cell precursors\",\n      \"pmids\": [\"9689104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SET binding stimulates B cell precursor growth unresolved\", \"Single lab, no in vivo validation of the MLL interaction\", \"Did not define the phosphoinositide-related role of the pseudophosphatase domain\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the domain architecture and revealed an N-terminal autoinhibitory element that suppresses transformation and enforces cytoplasmic localization.\",\n      \"evidence\": \"Overexpression and deletion mutagenesis in NIH 3T3 cells with proliferation, transformation, and fractionation readouts\",\n      \"pmids\": [\"11686296\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of the transforming activity unestablished\", \"No independent replication\", \"Endogenous regulators of the N-terminal switch unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated an essential, non-redundant in vivo role in spermatogenesis through a clean genetic knockout, placing the defect at a specific developmental transition.\",\n      \"evidence\": \"Sbf1 null mouse with histology, immunohistochemistry, and expression analysis\",\n      \"pmids\": [\"11994405\", \"27335132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular substrate/pathway driving the pachytene-to-spermatid block not defined\", \"Whether Sertoli cell vacuolation is primary or secondary unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed SBF1 is a regulatory subunit of an active phosphatase, explaining how a catalytically dead protein influences phosphoinositide metabolism.\",\n      \"evidence\": \"Reciprocal Co-IP with MS identification, coiled-coil domain mutagenesis, and in vitro enzymatic activity assay\",\n      \"pmids\": [\"12668758\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphoinositide species and cellular compartments controlled by the MTMR5-MTMR2 complex in vivo not mapped\", \"Structural basis of activity enhancement undetermined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmed the spermatogenesis requirement in an independent organism via a natural loss-of-function allele, strengthening the causal link.\",\n      \"evidence\": \"Genetic mapping, candidate sequencing, and protein-absence western blot in rat testis\",\n      \"pmids\": [\"27335132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not extend the mechanism beyond the mouse phenotype\", \"Cellular target of the spermatogenic defect not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established SBF1 loss-of-function as a cause of human sensory-motor axonal neuropathy, connecting the gene to peripheral nerve disease.\",\n      \"evidence\": \"Whole-exome sequencing, cDNA analysis, and western blot of patient fibroblasts (single family)\",\n      \"pmids\": [\"32444983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family limits genotype-phenotype generalization\", \"Cellular mechanism of axonal degeneration not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Dissected SBF1's peripheral nerve function from its paralog MTMR13, revealing partial redundancy and a specific role in axon radial sorting.\",\n      \"evidence\": \"Single and double conditional knockout mice with nerve histology, protein quantification, and developmental expression profiling\",\n      \"pmids\": [\"34718573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the radial sorting defect undefined\", \"How MTMR2 stabilizes Mtmr5/Mtmr13 mechanistically unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked SBF1 dysfunction to a selective autophagy defect, showing macroautophagy and PINK1-PRKN mitophagy become uncoupled.\",\n      \"evidence\": \"LC3B/SQSTM1 flux, PINK1/PRKN recruitment, and aggregate staining in CMT4B3 patient fibroblasts (single lab, no genetic rescue)\",\n      \"pmids\": [\"40998285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genetic rescue to confirm causality\", \"Mechanistic link between SBF1 phosphoinositide regulation and autophagy uncoupling not established\", \"Relevance to the in vivo neuropathy phenotype untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SBF1's phosphoinositide-regulatory role (via MTMR2) mechanistically connects to its disparate phenotypes — spermatogenesis, radial sorting, and autophagy uncoupling — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying substrate or pathway tying the molecular and organismal phenotypes together\", \"Role of the MLL/SET interaction in nerve or testis biology unexplored\", \"No structural model of the MTMR5-MTMR2 complex\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MTMR2\", \"MLL\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}