{"gene":"SAXO6","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":1992,"finding":"MDM1 protein localizes to novel cytoplasmic spots and punctate arrays distributed throughout the yeast cell cytoplasm; loss of these structures at non-permissive temperature causes defective nuclear and mitochondrial inheritance into developing buds, establishing MDM1 as required for organelle inheritance. Antibodies against MDM1 cross-react with animal cell intermediate filaments, suggesting structural similarity.","method":"Indirect immunofluorescence, gene disruption, temperature-sensitive mutant analysis, antibody cross-reactivity","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotype (organelle inheritance), direct localization by immunofluorescence, single lab","pmids":["1378448"],"is_preprint":false},{"year":2015,"finding":"Yeast Mdm1 (SNX14 ortholog) is an ER-anchored interorganelle tethering protein that localizes to ER-vacuole membrane contact sites (MCSs). It contacts the vacuole surface in trans via its lipid-binding PX domain. Overexpression induces ER-vacuole hypertethering. Truncations analogous to neurological disease-associated SNX14 alleles fail to tether ER and vacuole and perturb sphingolipid metabolism.","method":"Fluorescence-based screen, live-cell imaging, domain truncation/mutagenesis, overexpression hypertethering assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, domain mapping, functional overexpression, mutant analysis), replicated with paralogue Nvj3","pmids":["26283797"],"is_preprint":false},{"year":2015,"finding":"Human MDM1 protein localizes to centrioles of dividing cells and differentiating multiciliated cells, residing in the centriole lumen as shown by 3D-SIM microscopy. MDM1 binds microtubules in vivo and in vitro. Overexpression suppresses centriole duplication; depletion increases granular material representing early centriole intermediates. A repeat motif (also in CCSAP) is required for efficient microtubule binding.","method":"3D-SIM microscopy, overexpression, siRNA depletion, in vitro microtubule-binding assay, domain mutagenesis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro microtubule-binding assay plus mutagenesis, direct localization by super-resolution microscopy, loss- and gain-of-function phenotypes, single lab","pmids":["26337392"],"is_preprint":false},{"year":2019,"finding":"Yeast Mdm1 associates with lipid droplets (LDs) through its hydrophobic N-terminal region, which is sufficient to mark LD budding sites on the ER. Mdm1 binds fatty acids via its Phox-associated (PXA) domain and co-enriches with fatty acyl-CoA ligase Faa1 at LD bud sites. Loss of MDM1 perturbs free fatty acid activation, reduces Dga1-dependent TAG synthesis, elevates cellular fatty acids, perturbs ER morphology, and sensitizes yeast to fatty acid-induced lipotoxicity.","method":"Domain truncation/localization assays, co-enrichment/co-fractionation, lipid metabolite measurements, fatty acid toxicity assay, EM","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (domain mapping, co-enrichment with Faa1, metabolomics, toxicity assay, EM), mechanistic pathway placement established","pmids":["30808705"],"is_preprint":false},{"year":2021,"finding":"Yeast Mdm1 at the nucleus-vacuole junction (NVJ) mediates TORC1 inactivation-induced nucleolar dynamics, including migration of nucleolar proteins to the NVJ and condensation of rDNA away from the NVJ. Mdm1 is required for proper nucleophagic degradation of nucleolar proteins after TORC1 inactivation, but is dispensable for induction of nucleophagic flux itself.","method":"Genetic deletion (mdm1Δ), fluorescence microscopy of nucleolar markers, rapamycin treatment to inactivate TORC1","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KO with defined cellular phenotype (nucleolar dynamics and nucleophagy), single lab, single primary method","pmids":["33740659"],"is_preprint":false},{"year":2022,"finding":"MDM1 protein localizes to the connecting cilium (CC) of photoreceptor cells in the retina. Mdm1-/- mice show mislocalization of opsins in photoreceptor cells, indicating specific intraflagellar transport (IFT) defects; nuclei are entrapped in the outer nuclear layer by retinal pigment epithelial microvilli, leading to apoptosis. Outer segment degeneration begins at postnatal day 7 with complete outer nuclear layer loss by 35 weeks.","method":"Immunofluorescence localization, Mdm1 knockout mouse, electroretinography, histology, opsin mislocalization assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype, direct localization at connecting cilium, multiple readouts (ERG, IFT marker mislocalization, histology), single lab","pmids":["36171205"],"is_preprint":false},{"year":2025,"finding":"MDM1 overexpression in colorectal cancer cells limits YBX1 binding to the TP53 promoter, thereby upregulating p53 expression and promoting apoptosis; MDM1 knockout reduces this effect. This mechanism underlies increased sensitivity to chemoradiation upon MDM1 overexpression.","method":"Colony formation assay, RNA sequencing, chromatin/promoter binding assay (YBX1-TP53 promoter interaction), MDM1 knockout and overexpression in cell lines, xenograft model","journal":"Cancer biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — mechanistic pathway defined (YBX1-TP53 promoter), multiple cellular assays, but single lab and abstract-level detail on chromatin binding method","pmids":["40200809"],"is_preprint":false},{"year":2026,"finding":"SAXO6 (MDM1) co-localizes with distinct ciliary microtubules in immotile cilia of rod and cone photoreceptors and motile cilia of lung epithelial cells, as shown by ultrastructure expansion microscopy and immuno-gold transmission electron microscopy. Cross-linking mass spectrometry identified a direct interaction between SAXO6 and α-tubulin, classifying SAXO6 as a microtubule inner protein (MIP). Bi-allelic null variants in SAXO6 cause late-onset recessive retinal dystrophy in humans.","method":"Iterative ultrastructure expansion microscopy, immuno-gold transmission electron microscopy, cross-linking mass spectrometry, human genetics (bi-allelic null variants)","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cross-linking MS establishes direct α-tubulin interaction, orthogonal structural imaging (expansion microscopy + immuno-gold TEM) confirms MIP localization, human loss-of-function variants validate in vivo role","pmids":["41742423"],"is_preprint":false}],"current_model":"SAXO6/MDM1 encodes a microtubule inner protein (MIP) that directly binds α-tubulin and localizes within the ciliary axoneme of photoreceptor connecting cilia and lung motile cilia; in its yeast ortholog role it functions as an ER-anchored interorganelle tether at ER-vacuole membrane contact sites via its PX domain, regulates lipid droplet biogenesis by binding fatty acids and scaffolding fatty acyl-CoA activation, and mediates TORC1-dependent nucleolar dynamics and nucleophagy, while in mammalian dividing cells it localizes to the centriole lumen, binds microtubules through a repeat motif, and acts as a negative regulator of centriole duplication."},"narrative":{"mechanistic_narrative":"SAXO6/MDM1 is a microtubule-associated protein whose mammalian and yeast lineages reveal a dual role in ciliary microtubule architecture and ER-organelle membrane biology [PMID:26337392, PMID:41742423, PMID:26283797]. In mammalian photoreceptors and lung epithelium, SAXO6 co-localizes with ciliary microtubules in both immotile and motile cilia and binds α-tubulin directly, classifying it as a microtubule inner protein (MIP); bi-allelic null variants cause late-onset recessive retinal dystrophy in humans [PMID:41742423]. Consistent with a ciliary role, MDM1 localizes to the photoreceptor connecting cilium, where its loss in mice causes opsin mislocalization, intraflagellar transport defects, and progressive outer-segment degeneration [PMID:36171205]. In dividing cells, MDM1 resides in the centriole lumen, binds microtubules in vitro through a repeat motif shared with CCSAP, and negatively regulates centriole duplication [PMID:26337392]. The yeast ortholog functions in ER membrane biology as an ER-anchored interorganelle tether that contacts the vacuole in trans through its lipid-binding PX domain [PMID:26283797], marks lipid-droplet budding sites and scaffolds fatty-acid activation with the acyl-CoA ligase Faa1 via its PXA domain [PMID:30808705], and mediates TORC1-inactivation-induced nucleolar dynamics and nucleophagy at the nucleus-vacuole junction [PMID:33740659]. In colorectal cancer cells, MDM1 overexpression limits YBX1 binding to the TP53 promoter, upregulating p53 and promoting apoptosis [PMID:40200809].","teleology":[{"year":1992,"claim":"Established that MDM1 is required for organelle inheritance, the first functional assignment for the gene.","evidence":"Indirect immunofluorescence and temperature-sensitive mutant analysis in yeast","pmids":["1378448"],"confidence":"Medium","gaps":["Molecular basis of inheritance defect not defined","Cytoplasmic 'spots/arrays' not assigned to a specific organelle or complex","Intermediate-filament cross-reactivity not mechanistically explained"]},{"year":2015,"claim":"Resolved yeast Mdm1 as an ER-anchored tether at ER-vacuole contact sites, defining a membrane contact site function and linking it to SNX14 disease alleles.","evidence":"Fluorescence screen, live-cell imaging, PX-domain truncation/mutagenesis and overexpression hypertethering in yeast","pmids":["26283797"],"confidence":"High","gaps":["In trans vacuolar lipid ligand not identified","Relationship between tethering and the earlier organelle-inheritance phenotype unresolved"]},{"year":2015,"claim":"Identified mammalian MDM1 as a centriole-lumen microtubule-binding protein that restrains centriole duplication, establishing a microtubule-cytoskeletal role distinct from the yeast membrane function.","evidence":"3D-SIM microscopy, in vitro microtubule-binding assay, repeat-motif mutagenesis, siRNA depletion and overexpression in mammalian cells","pmids":["26337392"],"confidence":"High","gaps":["Mechanism by which MDM1 suppresses duplication not defined","Centriolar recruitment partners unknown"]},{"year":2019,"claim":"Placed yeast Mdm1 in lipid-droplet biogenesis, showing it marks LD bud sites and couples to fatty-acid activation via its PXA domain.","evidence":"Domain mapping, co-enrichment with Faa1, lipid metabolomics, fatty-acid toxicity assay and EM in yeast","pmids":["30808705"],"confidence":"High","gaps":["Direct enzymatic role versus scaffolding not separated","Conservation of LD function in mammalian MDM1 not tested"]},{"year":2021,"claim":"Connected Mdm1 to TORC1-dependent nucleolar remodeling and selective nucleophagy at the nucleus-vacuole junction.","evidence":"mdm1Δ deletion, fluorescence microscopy of nucleolar markers, rapamycin-induced TORC1 inactivation in yeast","pmids":["33740659"],"confidence":"Medium","gaps":["Single primary method","Molecular link between NVJ tethering and nucleolar protein migration unresolved"]},{"year":2022,"claim":"Demonstrated MDM1 function at the photoreceptor connecting cilium, tying its loss to IFT defects and retinal degeneration in vivo.","evidence":"Immunofluorescence, Mdm1 knockout mouse, electroretinography, opsin mislocalization and histology","pmids":["36171205"],"confidence":"Medium","gaps":["Direct molecular role within the cilium not yet defined at this stage","Whether opsin mislocalization is a primary IFT defect or secondary not separated"]},{"year":2025,"claim":"Defined a transcriptional axis whereby MDM1 modulates p53 via YBX1, linking it to apoptosis and chemoradiation sensitivity in cancer.","evidence":"Promoter-binding assay, RNA-seq, MDM1 knockout/overexpression and xenografts in colorectal cancer cells","pmids":["40200809"],"confidence":"Medium","gaps":["Mechanism of how a microtubule/ER protein influences YBX1-promoter occupancy unclear","Subcellular site of this activity not localized"]},{"year":2026,"claim":"Resolved SAXO6 as a microtubule inner protein binding α-tubulin directly within ciliary axonemes and established human disease causation.","evidence":"Ultrastructure expansion microscopy, immuno-gold TEM, cross-linking mass spectrometry, bi-allelic null human variants","pmids":["41742423"],"confidence":"High","gaps":["Structural model of α-tubulin contact not determined","Reconciliation of MIP role with yeast membrane functions not addressed"]},{"year":null,"claim":"How the divergent activities — ciliary MIP/microtubule binding versus ER-vacuole tethering and lipid-droplet biogenesis — relate within a single conserved protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model unifying microtubule-binding and lipid/PX-domain functions","No demonstration of which functions are conserved between yeast and mammalian orthologs","Mechanism connecting cytoskeletal localization to the p53/YBX1 transcriptional effect unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[5,7]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[2]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[3]}],"pathway":[],"complexes":[],"partners":["TUBA1A","FAA1","YBX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"MDM1","url":"https://depmap.org/portal/gene/MDM1","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SAXO6","total_profiled":1310},"omim":[{"mim_id":"613813","title":"STABILIZER OF AXONEMAL MICROTUBULES 6; SAXO6","url":"https://www.omim.org/entry/613813"}],"hpa":{"profiled":true,"resolved_as":"MDM1","reliability":"Approved","locations":[{"location":"Centriolar satellite","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MDM1"},"hgnc":{"alias_symbol":[],"prev_symbol":["MDM1"]},"alphafold":{},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SAXO6","jax_strain_url":"https://www.jax.org/strain/search?query=SAXO6"},"sequence":{}},"corpus_meta":[{"pmid":"26283797","id":"PMC_26283797","title":"Mdm1/Snx13 is a novel ER-endolysosomal interorganelle tethering protein.","date":"2015","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26283797","citation_count":124,"is_preprint":false},{"pmid":"30808705","id":"PMC_30808705","title":"Mdm1 maintains endoplasmic reticulum homeostasis by spatially regulating lipid droplet biogenesis.","date":"2019","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30808705","citation_count":90,"is_preprint":false},{"pmid":"1378448","id":"PMC_1378448","title":"Nuclear and mitochondrial inheritance in yeast depends on novel cytoplasmic structures defined by the MDM1 protein.","date":"1992","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1378448","citation_count":85,"is_preprint":false},{"pmid":"18805803","id":"PMC_18805803","title":"Age-related retinal degeneration (arrd2) in a novel mouse model due to a nonsense mutation in the Mdm1 gene.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18805803","citation_count":25,"is_preprint":false},{"pmid":"12612829","id":"PMC_12612829","title":"MDM-1 and MDM-2: two mutator-derived MITE families in rice.","date":"2003","source":"Journal of molecular evolution","url":"https://pubmed.ncbi.nlm.nih.gov/12612829","citation_count":25,"is_preprint":false},{"pmid":"31681433","id":"PMC_31681433","title":"Exome Sequencing in BRCA1- and BRCA2-Negative Greek Families Identifies MDM1 and NBEAL1 as Candidate Risk Genes for Hereditary Breast Cancer.","date":"2019","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31681433","citation_count":21,"is_preprint":false},{"pmid":"26337392","id":"PMC_26337392","title":"MDM1 is a microtubule-binding protein that negatively regulates centriole duplication.","date":"2015","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/26337392","citation_count":20,"is_preprint":false},{"pmid":"30781002","id":"PMC_30781002","title":"The Mdm1 Locus and Maize Resistance to Maize dwarf mosaic virus.","date":"2007","source":"Plant disease","url":"https://pubmed.ncbi.nlm.nih.gov/30781002","citation_count":18,"is_preprint":false},{"pmid":"24173923","id":"PMC_24173923","title":"Co-segregation of the maize dwarf mosaic virus resistance gene, Mdm1, with the nucleolus organizer region in maize.","date":"1995","source":"TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/24173923","citation_count":18,"is_preprint":false},{"pmid":"37122692","id":"PMC_37122692","title":"Melittin derived peptide-drug conjugate, M-DM1, inhibits tumor progression and induces effector cell infiltration in melanoma by targeting M2 tumor-associated macrophages.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37122692","citation_count":16,"is_preprint":false},{"pmid":"7849395","id":"PMC_7849395","title":"Ifg, Gli, Mdm1, Mdm2, and Mdm3: candidate genes for the mouse pg locus.","date":"1994","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/7849395","citation_count":8,"is_preprint":false},{"pmid":"33740659","id":"PMC_33740659","title":"Sorting nexin Mdm1/SNX14 regulates nucleolar dynamics at the NVJ after TORC1 inactivation.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/33740659","citation_count":7,"is_preprint":false},{"pmid":"27658201","id":"PMC_27658201","title":"Molecular Evolution of MDM1, a \"Duplication-Resistant\" Gene in Vertebrates.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27658201","citation_count":6,"is_preprint":false},{"pmid":"10712011","id":"PMC_10712011","title":"Close linkage of Mdm-1, a gene amplified and overexpressed in a transformed 3T3 cell line, with gamma interferon (Ifg) on chromosome 10 of the mouse.","date":"1992","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/10712011","citation_count":6,"is_preprint":false},{"pmid":"38868186","id":"PMC_38868186","title":"De novo TLK1 and MDM1 mutations in a patient with a neurodevelopmental disorder and immunodeficiency.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38868186","citation_count":4,"is_preprint":false},{"pmid":"36171205","id":"PMC_36171205","title":"Mdm1 ablation results in retinal degeneration by specific intraflagellar transport defects of photoreceptor cells.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36171205","citation_count":3,"is_preprint":false},{"pmid":"40200809","id":"PMC_40200809","title":"MDM1 overexpression promotes p53 expression and cell apoptosis to enhance therapeutic sensitivity to chemoradiotherapy in patients with colorectal cancer.","date":"2025","source":"Cancer biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40200809","citation_count":2,"is_preprint":false},{"pmid":"41742423","id":"PMC_41742423","title":"Loss-of-function variants in SAXO6, encoding a microtubule inner protein of photoreceptor cilia, cause a late-onset retinal dystrophy.","date":"2026","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41742423","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10371,"output_tokens":2361,"usd":0.033264,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9508,"output_tokens":2895,"usd":0.059957,"stage2_stop_reason":"end_turn"},"total_usd":0.093221,"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\": 1992,\n      \"finding\": \"MDM1 protein localizes to novel cytoplasmic spots and punctate arrays distributed throughout the yeast cell cytoplasm; loss of these structures at non-permissive temperature causes defective nuclear and mitochondrial inheritance into developing buds, establishing MDM1 as required for organelle inheritance. Antibodies against MDM1 cross-react with animal cell intermediate filaments, suggesting structural similarity.\",\n      \"method\": \"Indirect immunofluorescence, gene disruption, temperature-sensitive mutant analysis, antibody cross-reactivity\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotype (organelle inheritance), direct localization by immunofluorescence, single lab\",\n      \"pmids\": [\"1378448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Yeast Mdm1 (SNX14 ortholog) is an ER-anchored interorganelle tethering protein that localizes to ER-vacuole membrane contact sites (MCSs). It contacts the vacuole surface in trans via its lipid-binding PX domain. Overexpression induces ER-vacuole hypertethering. Truncations analogous to neurological disease-associated SNX14 alleles fail to tether ER and vacuole and perturb sphingolipid metabolism.\",\n      \"method\": \"Fluorescence-based screen, live-cell imaging, domain truncation/mutagenesis, overexpression hypertethering assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, domain mapping, functional overexpression, mutant analysis), replicated with paralogue Nvj3\",\n      \"pmids\": [\"26283797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Human MDM1 protein localizes to centrioles of dividing cells and differentiating multiciliated cells, residing in the centriole lumen as shown by 3D-SIM microscopy. MDM1 binds microtubules in vivo and in vitro. Overexpression suppresses centriole duplication; depletion increases granular material representing early centriole intermediates. A repeat motif (also in CCSAP) is required for efficient microtubule binding.\",\n      \"method\": \"3D-SIM microscopy, overexpression, siRNA depletion, in vitro microtubule-binding assay, domain mutagenesis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro microtubule-binding assay plus mutagenesis, direct localization by super-resolution microscopy, loss- and gain-of-function phenotypes, single lab\",\n      \"pmids\": [\"26337392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Yeast Mdm1 associates with lipid droplets (LDs) through its hydrophobic N-terminal region, which is sufficient to mark LD budding sites on the ER. Mdm1 binds fatty acids via its Phox-associated (PXA) domain and co-enriches with fatty acyl-CoA ligase Faa1 at LD bud sites. Loss of MDM1 perturbs free fatty acid activation, reduces Dga1-dependent TAG synthesis, elevates cellular fatty acids, perturbs ER morphology, and sensitizes yeast to fatty acid-induced lipotoxicity.\",\n      \"method\": \"Domain truncation/localization assays, co-enrichment/co-fractionation, lipid metabolite measurements, fatty acid toxicity assay, EM\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (domain mapping, co-enrichment with Faa1, metabolomics, toxicity assay, EM), mechanistic pathway placement established\",\n      \"pmids\": [\"30808705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Yeast Mdm1 at the nucleus-vacuole junction (NVJ) mediates TORC1 inactivation-induced nucleolar dynamics, including migration of nucleolar proteins to the NVJ and condensation of rDNA away from the NVJ. Mdm1 is required for proper nucleophagic degradation of nucleolar proteins after TORC1 inactivation, but is dispensable for induction of nucleophagic flux itself.\",\n      \"method\": \"Genetic deletion (mdm1Δ), fluorescence microscopy of nucleolar markers, rapamycin treatment to inactivate TORC1\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KO with defined cellular phenotype (nucleolar dynamics and nucleophagy), single lab, single primary method\",\n      \"pmids\": [\"33740659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MDM1 protein localizes to the connecting cilium (CC) of photoreceptor cells in the retina. Mdm1-/- mice show mislocalization of opsins in photoreceptor cells, indicating specific intraflagellar transport (IFT) defects; nuclei are entrapped in the outer nuclear layer by retinal pigment epithelial microvilli, leading to apoptosis. Outer segment degeneration begins at postnatal day 7 with complete outer nuclear layer loss by 35 weeks.\",\n      \"method\": \"Immunofluorescence localization, Mdm1 knockout mouse, electroretinography, histology, opsin mislocalization assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype, direct localization at connecting cilium, multiple readouts (ERG, IFT marker mislocalization, histology), single lab\",\n      \"pmids\": [\"36171205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MDM1 overexpression in colorectal cancer cells limits YBX1 binding to the TP53 promoter, thereby upregulating p53 expression and promoting apoptosis; MDM1 knockout reduces this effect. This mechanism underlies increased sensitivity to chemoradiation upon MDM1 overexpression.\",\n      \"method\": \"Colony formation assay, RNA sequencing, chromatin/promoter binding assay (YBX1-TP53 promoter interaction), MDM1 knockout and overexpression in cell lines, xenograft model\",\n      \"journal\": \"Cancer biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mechanistic pathway defined (YBX1-TP53 promoter), multiple cellular assays, but single lab and abstract-level detail on chromatin binding method\",\n      \"pmids\": [\"40200809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SAXO6 (MDM1) co-localizes with distinct ciliary microtubules in immotile cilia of rod and cone photoreceptors and motile cilia of lung epithelial cells, as shown by ultrastructure expansion microscopy and immuno-gold transmission electron microscopy. Cross-linking mass spectrometry identified a direct interaction between SAXO6 and α-tubulin, classifying SAXO6 as a microtubule inner protein (MIP). Bi-allelic null variants in SAXO6 cause late-onset recessive retinal dystrophy in humans.\",\n      \"method\": \"Iterative ultrastructure expansion microscopy, immuno-gold transmission electron microscopy, cross-linking mass spectrometry, human genetics (bi-allelic null variants)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cross-linking MS establishes direct α-tubulin interaction, orthogonal structural imaging (expansion microscopy + immuno-gold TEM) confirms MIP localization, human loss-of-function variants validate in vivo role\",\n      \"pmids\": [\"41742423\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SAXO6/MDM1 encodes a microtubule inner protein (MIP) that directly binds α-tubulin and localizes within the ciliary axoneme of photoreceptor connecting cilia and lung motile cilia; in its yeast ortholog role it functions as an ER-anchored interorganelle tether at ER-vacuole membrane contact sites via its PX domain, regulates lipid droplet biogenesis by binding fatty acids and scaffolding fatty acyl-CoA activation, and mediates TORC1-dependent nucleolar dynamics and nucleophagy, while in mammalian dividing cells it localizes to the centriole lumen, binds microtubules through a repeat motif, and acts as a negative regulator of centriole duplication.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SAXO6/MDM1 is a microtubule-associated protein whose mammalian and yeast lineages reveal a dual role in ciliary microtubule architecture and ER-organelle membrane biology [#2, #7, #1]. In mammalian photoreceptors and lung epithelium, SAXO6 co-localizes with ciliary microtubules in both immotile and motile cilia and binds α-tubulin directly, classifying it as a microtubule inner protein (MIP); bi-allelic null variants cause late-onset recessive retinal dystrophy in humans [#7]. Consistent with a ciliary role, MDM1 localizes to the photoreceptor connecting cilium, where its loss in mice causes opsin mislocalization, intraflagellar transport defects, and progressive outer-segment degeneration [#5]. In dividing cells, MDM1 resides in the centriole lumen, binds microtubules in vitro through a repeat motif shared with CCSAP, and negatively regulates centriole duplication [#2]. The yeast ortholog functions in ER membrane biology as an ER-anchored interorganelle tether that contacts the vacuole in trans through its lipid-binding PX domain [#1], marks lipid-droplet budding sites and scaffolds fatty-acid activation with the acyl-CoA ligase Faa1 via its PXA domain [#3], and mediates TORC1-inactivation-induced nucleolar dynamics and nucleophagy at the nucleus-vacuole junction [#4]. In colorectal cancer cells, MDM1 overexpression limits YBX1 binding to the TP53 promoter, upregulating p53 and promoting apoptosis [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established that MDM1 is required for organelle inheritance, the first functional assignment for the gene.\",\n      \"evidence\": \"Indirect immunofluorescence and temperature-sensitive mutant analysis in yeast\",\n      \"pmids\": [\"1378448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular basis of inheritance defect not defined\",\n        \"Cytoplasmic 'spots/arrays' not assigned to a specific organelle or complex\",\n        \"Intermediate-filament cross-reactivity not mechanistically explained\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved yeast Mdm1 as an ER-anchored tether at ER-vacuole contact sites, defining a membrane contact site function and linking it to SNX14 disease alleles.\",\n      \"evidence\": \"Fluorescence screen, live-cell imaging, PX-domain truncation/mutagenesis and overexpression hypertethering in yeast\",\n      \"pmids\": [\"26283797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In trans vacuolar lipid ligand not identified\",\n        \"Relationship between tethering and the earlier organelle-inheritance phenotype unresolved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified mammalian MDM1 as a centriole-lumen microtubule-binding protein that restrains centriole duplication, establishing a microtubule-cytoskeletal role distinct from the yeast membrane function.\",\n      \"evidence\": \"3D-SIM microscopy, in vitro microtubule-binding assay, repeat-motif mutagenesis, siRNA depletion and overexpression in mammalian cells\",\n      \"pmids\": [\"26337392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which MDM1 suppresses duplication not defined\",\n        \"Centriolar recruitment partners unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed yeast Mdm1 in lipid-droplet biogenesis, showing it marks LD bud sites and couples to fatty-acid activation via its PXA domain.\",\n      \"evidence\": \"Domain mapping, co-enrichment with Faa1, lipid metabolomics, fatty-acid toxicity assay and EM in yeast\",\n      \"pmids\": [\"30808705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct enzymatic role versus scaffolding not separated\",\n        \"Conservation of LD function in mammalian MDM1 not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected Mdm1 to TORC1-dependent nucleolar remodeling and selective nucleophagy at the nucleus-vacuole junction.\",\n      \"evidence\": \"mdm1Δ deletion, fluorescence microscopy of nucleolar markers, rapamycin-induced TORC1 inactivation in yeast\",\n      \"pmids\": [\"33740659\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single primary method\",\n        \"Molecular link between NVJ tethering and nucleolar protein migration unresolved\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated MDM1 function at the photoreceptor connecting cilium, tying its loss to IFT defects and retinal degeneration in vivo.\",\n      \"evidence\": \"Immunofluorescence, Mdm1 knockout mouse, electroretinography, opsin mislocalization and histology\",\n      \"pmids\": [\"36171205\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct molecular role within the cilium not yet defined at this stage\",\n        \"Whether opsin mislocalization is a primary IFT defect or secondary not separated\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a transcriptional axis whereby MDM1 modulates p53 via YBX1, linking it to apoptosis and chemoradiation sensitivity in cancer.\",\n      \"evidence\": \"Promoter-binding assay, RNA-seq, MDM1 knockout/overexpression and xenografts in colorectal cancer cells\",\n      \"pmids\": [\"40200809\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of how a microtubule/ER protein influences YBX1-promoter occupancy unclear\",\n        \"Subcellular site of this activity not localized\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved SAXO6 as a microtubule inner protein binding α-tubulin directly within ciliary axonemes and established human disease causation.\",\n      \"evidence\": \"Ultrastructure expansion microscopy, immuno-gold TEM, cross-linking mass spectrometry, bi-allelic null human variants\",\n      \"pmids\": [\"41742423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural model of α-tubulin contact not determined\",\n        \"Reconciliation of MIP role with yeast membrane functions not addressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the divergent activities — ciliary MIP/microtubule binding versus ER-vacuole tethering and lipid-droplet biogenesis — relate within a single conserved protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model unifying microtubule-binding and lipid/PX-domain functions\",\n        \"No demonstration of which functions are conserved between yeast and mammalian orthologs\",\n        \"Mechanism connecting cytoskeletal localization to the p53/YBX1 transcriptional effect unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"TUBA1A\", \"FAA1\", \"YBX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}