{"gene":"DPM1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1998,"finding":"DPM2, an 84-amino acid ER membrane protein, forms a complex with DPM1 that is essential for ER localization and stable expression of DPM1; DPM2 also enhances binding of dolichol phosphate (a substrate) to the synthase complex. DPM1 alone is catalytically sufficient when artificially tethered to the ER via a fusion protein.","method":"Expression cloning in Lec15 mutant CHO cells, co-immunoprecipitation, fusion-protein complementation assay, subcellular fractionation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal complex identification, functional complementation, substrate-binding assay, replicated across multiple cell-line models in a single rigorous study","pmids":["9724629"],"is_preprint":false},{"year":2000,"finding":"Human DPM synthase is a heterotrimer of DPM1 (catalytic), DPM2 (regulatory), and DPM3 (structural stabilizer). DPM3 associates with DPM1 via its C-terminal domain and with DPM2 via its N-terminal portion; DPM2 stabilizes DPM3, and DPM3 in turn stabilizes DPM1. Overexpression of DPM3 in DPM2-null (Lec15) cells restores DPM biosynthesis with increased DPM1 levels. DPM2 also contributes to enzymatic activity (~10-fold enhancement).","method":"Genetic complementation in Lec15 cells, co-purification, overexpression, DPM synthase activity assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-purification, genetic complementation, enzymatic activity assays), replicated with S. pombe orthologs","pmids":["10835346"],"is_preprint":false},{"year":2000,"finding":"Mutations in DPM1 (point mutation R92G / C274G, and a 13-bp deletion) cause ~95% deficiency in dolichol-phosphate-mannose (Dol-P-Man) synthase activity in patient fibroblasts, with an ~6-fold elevated apparent Km for GDP-mannose, leading to production of a truncated Man5 dolichol-linked oligosaccharide precursor instead of the normal Man9 form. Addition of exogenous mannose corrected the truncation.","method":"Metabolic labeling with [3H]mannose, microsomal enzyme activity assay (Km determination), Sanger sequencing, mannose supplementation rescue","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzyme activity with kinetic parameters, mutation identification, metabolic rescue experiment; single lab but multiple orthogonal methods","pmids":["10642597"],"is_preprint":false},{"year":1990,"finding":"The S. cerevisiae DPM1 gene product (Dol-P-Man synthase) is the catalytic enzyme responsible for synthesis and membrane translocation of dolichol-phosphate-mannose, which donates mannose residues for N-linked glycosylation. S. cerevisiae DPM1 complemented a glycosylation-defective CHO cell line (B4-2-1), restoring Dol-P-Man synthase activity and correct oligosaccharide assembly. Indirect immunofluorescence showed reticular (ER) localization of the DPM1 protein.","method":"Stable transfection complementation, FACS lectin-binding analysis, enzymatic activity assay in cell lysates, HPLC of lipid-linked oligosaccharides, endoglycosidase H sensitivity assay, indirect immunofluorescence","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional readouts (enzyme activity, oligosaccharide profiling, glycoprotein sensitivity assay, localization); foundational complementation study","pmids":["2201896"],"is_preprint":false},{"year":2005,"finding":"DPM3 tethers DPM1 to the ER membrane via a coiled-coil domain near DPM3's C-terminus; this tethering is critical for DPM synthase activity. In the absence of DPM3, DPM1 is rapidly degraded by the proteasome. Free DPM1 associates strongly with CHIP (C-terminus of Hsc70-interacting protein), a chaperone-dependent E3 ubiquitin ligase, indicating DPM1 is ubiquitinated by CHIP when not incorporated into the complex.","method":"Generation of DPM3-deficient CHO2.38 cells, microsomal DPM synthase activity assay, domain-deletion mutagenesis of DPM3, proteasome inhibitor treatment, co-immunoprecipitation with CHIP","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutant cell line, enzyme activity assay, domain mutagenesis, proteasome inhibition, and co-IP for ubiquitin ligase; multiple orthogonal methods in a single study","pmids":["16280320"],"is_preprint":false},{"year":2006,"finding":"An intronic DPM1 mutation (g.IVS4-5T>A) causes exon skipping and a shortened transcript, reducing DPM1 mRNA expression by >90% (via a nonsense-mediated mRNA decay-independent mechanism), resulting in only residual Dol-P-Man synthase activity and accumulation of the immature Dol-PP-GlcNAc2Man5 species. Loss of DPM1 expression also secondarily reduces DPM2 expression.","method":"RT-PCR, Sanger sequencing, Dol-P-Man synthase activity assay in patient fibroblasts, lipid-linked oligosaccharide analysis, mRNA quantification","journal":"Pediatric research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzyme activity assay, transcript analysis, and oligosaccharide profiling; single lab, patient-derived cells","pmids":["16641202"],"is_preprint":false},{"year":2013,"finding":"A DPM1 missense mutation (p.Gly152Val) reduces DPM1 binding to DPM3 without decreasing the enzyme's affinity for substrate, suggesting Gly152 is important for DPM3 interaction rather than catalysis. Overall DPM1 enzyme activity in patient fibroblasts was reduced by ~80%.","method":"DPM1 enzyme activity assay in patient fibroblasts, transfection of tagged wild-type and mutant DPM1 constructs, co-immunoprecipitation with DPM3","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzyme activity assay and co-IP with mutagenesis in a single lab; two orthogonal methods","pmids":["23856421"],"is_preprint":false},{"year":2022,"finding":"In a Drosophila CRISPR screen, inhibition of Dpm1 (the DPM1 ortholog) rescued cell survival and glycoprotein levels under DPAGT1 inhibition and alleviated ER stress in two in vivo models, demonstrating a genetic epistatic relationship where reduced Dpm1 activity suppresses consequences of deficient upstream N-glycosylation initiation. A novel interaction between fructose/glycolytic metabolism and ER stress was also identified in this context.","method":"Genome-wide CRISPR knockout screen in Drosophila cells, in vivo genetic epistasis in Drosophila models, glycoprotein level measurement, metabolic analysis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen validated in vivo in two independent Drosophila models; single lab, Drosophila ortholog","pmids":["36166480"],"is_preprint":false},{"year":2024,"finding":"Deletion of DPM1 in human keratinocytes impairs desmosomal adhesion, disrupts localization of desmoplakin and desmoglein-2, and causes cytoskeletal organization defects. Proteomic analysis identified SERPINB5 as a DPM1-dependent interaction partner of desmoplakin; mechanistically, SERPINB5 reduces desmoplakin phosphorylation at serine 176, which is required for strong intercellular adhesion.","method":"CRISPR knockout of DPM1 in keratinocytes, 3D organotypic epidermis model, immunofluorescence localization, mass spectrometry-based proteomics, co-immunoprecipitation, phosphorylation analysis","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined cellular phenotype, proteomic identification of interaction partner, phosphorylation mechanistic follow-up; single lab, multiple orthogonal methods","pmids":["38477878"],"is_preprint":false},{"year":2026,"finding":"DPM1 was identified as a direct regulator of IRE1α expression and activity via a BioID proximity screen. DPM1 ablation in colorectal cancer cells reduces protein glycosylation, leading to chronic IRE1 activation, which in turn enhances cytotoxic T cell-mediated immunosurveillance. IRE1 inhibition or knockout reverses this immune phenotype.","method":"BioID proximity labeling screen, DPM1 knockout, IRE1 activity assays, IRE1 inhibition/KO epistasis, T cell cytotoxicity assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID interaction screen, genetic KO, epistasis with IRE1 KO/inhibitor; single lab, multiple orthogonal methods","pmids":["42230629"],"is_preprint":false}],"current_model":"DPM1 is the catalytic subunit of the heterotrimeric dolichol-phosphate-mannose (Dol-P-Man) synthase complex, which transfers mannose from GDP-mannose onto dolichol phosphate in the ER membrane to generate the mannosyl donor required for GPI anchor biosynthesis, N-glycan precursor elongation, and O- and C-mannosylation; DPM1 activity and ER membrane tethering depend on its assembly with regulatory subunit DPM2 (which enhances substrate binding and enzymatic rate) and structural subunit DPM3 (which anchors DPM1 to the ER via a coiled-coil domain and prevents its proteasomal degradation via CHIP-mediated ubiquitination when free); beyond glycan synthesis, DPM1 modulates desmosomal adhesion through a SERPINB5–desmoplakin phosphorylation axis and restrains IRE1α-mediated ER stress signaling, with loss of DPM1 causing chronic IRE1 activation and enhanced anti-tumor immunity."},"narrative":{"mechanistic_narrative":"DPM1 is the catalytic subunit of dolichol-phosphate-mannose (Dol-P-Man) synthase, the ER enzyme that transfers mannose from GDP-mannose onto dolichol phosphate to generate the mannosyl donor required for lipid-linked oligosaccharide assembly and N-linked glycosylation [PMID:2201896]. Its catalytic activity depends on assembly into a heterotrimer with the regulatory subunit DPM2, which enhances dolichol-phosphate substrate binding and raises enzymatic rate, and the structural subunit DPM3, which bridges DPM1 and DPM2 and tethers DPM1 to the ER membrane via a C-terminal coiled-coil domain [PMID:9724629, PMID:10835346, PMID:16280320]. DPM1 is catalytically sufficient on its own when artificially anchored to the ER, indicating the partner subunits provide membrane localization and stability rather than catalysis [PMID:9724629]; in the absence of DPM3 tethering, free DPM1 associates with the chaperone-dependent E3 ligase CHIP and is rapidly degraded by the proteasome [PMID:16280320]. Loss-of-function DPM1 mutations cause a congenital disorder of glycosylation, producing ~95% deficiency in Dol-P-Man synthase activity, elevated apparent Km for GDP-mannose, and accumulation of truncated Man5 dolichol-linked precursors that is correctable by exogenous mannose [PMID:10642597, PMID:16641202]; distinct mutations selectively disrupt either catalysis or DPM3 binding [PMID:23856421]. Beyond glycan synthesis, DPM1 supports desmosomal adhesion through a SERPINB5-dependent control of desmoplakin serine-176 phosphorylation [PMID:38477878] and restrains IRE1α ER-stress signaling, such that DPM1 loss drives chronic IRE1 activation and enhanced cytotoxic T-cell immunosurveillance [PMID:42230629].","teleology":[{"year":1990,"claim":"Established DPM1 as the catalytic enzyme generating dolichol-phosphate-mannose and showed it is conserved and ER-localized, defining its core glycosylation role.","evidence":"S. cerevisiae DPM1 complementation of a glycosylation-defective CHO line with enzyme, oligosaccharide, and immunofluorescence readouts","pmids":["2201896"],"confidence":"High","gaps":["Did not resolve subunit composition of the mammalian enzyme","No structural basis for catalysis defined"]},{"year":1998,"claim":"Resolved why mammalian DPM1 requires partners by identifying DPM2 as an ER membrane subunit needed for DPM1 localization, stability, and substrate binding.","evidence":"Expression cloning in Lec15 CHO mutants, co-IP, fusion-protein complementation showing DPM1 is catalytically sufficient when ER-tethered","pmids":["9724629"],"confidence":"High","gaps":["Third subunit not yet identified","Mechanism of substrate-binding enhancement not structurally defined"]},{"year":2000,"claim":"Defined the synthase as a DPM1-DPM2-DPM3 heterotrimer and mapped the stabilization hierarchy in which DPM2 stabilizes DPM3 and DPM3 stabilizes DPM1.","evidence":"Genetic complementation in Lec15 cells, co-purification, overexpression, and activity assays with S. pombe orthologs","pmids":["10835346"],"confidence":"High","gaps":["Membrane-tethering domain of DPM3 not yet localized","Degradation pathway of unassembled DPM1 unknown"]},{"year":2000,"claim":"Linked DPM1 to human disease by showing point and deletion mutations cripple Dol-P-Man synthase kinetics and truncate the N-glycan precursor, with metabolic rescue by mannose.","evidence":"Metabolic [3H]mannose labeling, microsomal Km determination, sequencing, and mannose supplementation in patient fibroblasts","pmids":["10642597"],"confidence":"High","gaps":["Genotype-phenotype range across patients not established","In vivo therapeutic value of mannose not addressed"]},{"year":2005,"claim":"Explained how DPM3 controls DPM1 by showing its coiled-coil tethers DPM1 to the ER and that untethered DPM1 is ubiquitinated by CHIP and proteasomally degraded.","evidence":"DPM3-deficient CHO cells, domain-deletion mutagenesis, proteasome inhibition, and CHIP co-IP","pmids":["16280320"],"confidence":"High","gaps":["CHIP ubiquitination sites on DPM1 not mapped","Reciprocal validation of CHIP-DPM1 interaction limited"]},{"year":2006,"claim":"Extended the disease spectrum to a splice-altering intronic mutation that depletes DPM1 mRNA and secondarily reduces DPM2, reinforcing subunit interdependence in vivo.","evidence":"RT-PCR, sequencing, synthase activity, and oligosaccharide profiling in patient fibroblasts","pmids":["16641202"],"confidence":"Medium","gaps":["NMD-independent decay mechanism not fully defined","Single patient-derived cell source"]},{"year":2013,"claim":"Separated catalytic from assembly functions of DPM1 by identifying a missense mutation that disrupts DPM3 binding without altering substrate affinity.","evidence":"Enzyme activity assays, tagged WT/mutant transfection, and DPM3 co-IP in patient fibroblasts","pmids":["23856421"],"confidence":"Medium","gaps":["Structural basis of the DPM1-DPM3 interface not resolved","Single-lab co-IP evidence"]},{"year":2022,"claim":"Placed DPM1 in a pathway context with upstream N-glycosylation initiation, showing reduced Dpm1 activity suppresses ER stress caused by DPAGT1 deficiency.","evidence":"Genome-wide CRISPR screen and in vivo genetic epistasis in two Drosophila models with glycoprotein and metabolic readouts","pmids":["36166480"],"confidence":"Medium","gaps":["Mechanism of epistatic suppression not molecularly defined","Demonstrated in Drosophila ortholog, not human"]},{"year":2024,"claim":"Revealed a non-glycosylation role for DPM1 in desmosomal adhesion via SERPINB5-dependent control of desmoplakin phosphorylation.","evidence":"DPM1 CRISPR knockout in keratinocytes, 3D organotypic epidermis, proteomics, co-IP, and phosphorylation analysis","pmids":["38477878"],"confidence":"Medium","gaps":["Whether the adhesion defect is downstream of glycosylation loss not fully separated","Kinase regulating Ser176 not identified"]},{"year":2026,"claim":"Connected DPM1 to ER-stress and immune signaling by showing its loss drives chronic IRE1α activation that enhances T-cell-mediated immunosurveillance.","evidence":"BioID proximity screen, DPM1 knockout, IRE1 activity assays, IRE1 KO/inhibitor epistasis, and T-cell cytotoxicity assays in colorectal cancer cells","pmids":["42230629"],"confidence":"Medium","gaps":["Direct biochemical mechanism of DPM1-IRE1 regulation not defined","Single-lab, single cancer-cell context"]},{"year":null,"claim":"How DPM1's catalytic glycosylation function mechanistically gives rise to its distinct roles in desmosomal adhesion and IRE1α signaling remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the human DPM1-DPM2-DPM3 complex","Whether adhesion and immune phenotypes are direct or secondary to glycan loss is unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,3,4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[7,9]}],"complexes":["Dol-P-Man synthase (DPM1-DPM2-DPM3 heterotrimer)"],"partners":["DPM2","DPM3","CHIP","SERPINB5","DSP","ERN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60762","full_name":"Dolichol-phosphate mannosyltransferase subunit 1","aliases":["Dolichol-phosphate mannose synthase subunit 1","DPM synthase subunit 1","Dolichyl-phosphate beta-D-mannosyltransferase subunit 1","Mannose-P-dolichol synthase subunit 1","MPD synthase subunit 1"],"length_aa":260,"mass_kda":29.6,"function":"Transfers mannose from GDP-mannose to dolichol monophosphate to form dolichol phosphate mannose (Dol-P-Man) which is the mannosyl donor in pathways leading to N-glycosylation, glycosyl phosphatidylinositol membrane anchoring, and O-mannosylation of proteins; catalytic subunit of the dolichol-phosphate mannose (DPM) synthase complex","subcellular_location":"Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/O60762/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DPM1","classification":"Not Classified","n_dependent_lines":223,"n_total_lines":1208,"dependency_fraction":0.18460264900662252},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TMED10","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DPM1","total_profiled":1310},"omim":[{"mim_id":"615042","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Iu; CDG1U","url":"https://www.omim.org/entry/615042"},{"mim_id":"608799","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ie; CDG1E","url":"https://www.omim.org/entry/608799"},{"mim_id":"605951","title":"DOLICHYL-PHOSPHATE MANNOSYLTRANSFERASE 3; DPM3","url":"https://www.omim.org/entry/605951"},{"mim_id":"604041","title":"MANNOSE-P-DOLICHOL UTILIZATION DEFECT 1; MPDU1","url":"https://www.omim.org/entry/604041"},{"mim_id":"603564","title":"DOLICHYL-PHOSPHATE MANNOSYLTRANSFERASE 2, REGULATORY SUBUNIT; DPM2","url":"https://www.omim.org/entry/603564"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DPM1"},"hgnc":{"alias_symbol":["MPDS","CDGIE"],"prev_symbol":[]},"alphafold":{"accession":"O60762","domains":[{"cath_id":"3.90.550.10","chopping":"26-257","consensus_level":"high","plddt":92.8962,"start":26,"end":257}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60762","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60762-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60762-F1-predicted_aligned_error_v6.png","plddt_mean":88.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DPM1","jax_strain_url":"https://www.jax.org/strain/search?query=DPM1"},"sequence":{"accession":"O60762","fasta_url":"https://rest.uniprot.org/uniprotkb/O60762.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60762/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60762"}},"corpus_meta":[{"pmid":"10642597","id":"PMC_10642597","title":"Dolichol phosphate mannose synthase (DPM1) mutations define congenital disorder of glycosylation Ie (CDG-Ie).","date":"2000","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/10642597","citation_count":140,"is_preprint":false},{"pmid":"10835346","id":"PMC_10835346","title":"Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3.","date":"2000","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10835346","citation_count":117,"is_preprint":false},{"pmid":"9724629","id":"PMC_9724629","title":"DPM2 regulates biosynthesis of dolichol phosphate-mannose in mammalian cells: correct subcellular localization and stabilization of DPM1, and binding of dolichol phosphate.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9724629","citation_count":96,"is_preprint":false},{"pmid":"23856421","id":"PMC_23856421","title":"Congenital disorder of glycosylation due to DPM1 mutations presenting with dystroglycanopathy-type congenital muscular dystrophy.","date":"2013","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23856421","citation_count":62,"is_preprint":false},{"pmid":"2201896","id":"PMC_2201896","title":"The Saccharomyces cerevisiae DPM1 gene encoding dolichol-phosphate-mannose synthase is able to complement a glycosylation-defective mammalian cell line.","date":"1990","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2201896","citation_count":55,"is_preprint":false},{"pmid":"16280320","id":"PMC_16280320","title":"DPM1, the catalytic subunit of dolichol-phosphate mannose synthase, is tethered to and stabilized on the endoplasmic reticulum membrane by DPM3.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16280320","citation_count":44,"is_preprint":false},{"pmid":"16641202","id":"PMC_16641202","title":"A new intronic mutation in the DPM1 gene is associated with a milder form of CDG Ie in two French siblings.","date":"2006","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/16641202","citation_count":24,"is_preprint":false},{"pmid":"34953839","id":"PMC_34953839","title":"Soil bioremediation by Pseudomonas brassicacearum MPDS and its enzyme involved in degrading PAHs.","date":"2021","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/34953839","citation_count":19,"is_preprint":false},{"pmid":"36166480","id":"PMC_36166480","title":"A genome-wide CRISPR screen identifies DPM1 as a modifier of DPAGT1 deficiency and ER stress.","date":"2022","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36166480","citation_count":15,"is_preprint":false},{"pmid":"30092360","id":"PMC_30092360","title":"Molecular property diagnostic suite for diabetes mellitus (MPDSDM): An integrated web portal for drug discovery and drug repurposing.","date":"2018","source":"Journal of biomedical informatics","url":"https://pubmed.ncbi.nlm.nih.gov/30092360","citation_count":12,"is_preprint":false},{"pmid":"38477878","id":"PMC_38477878","title":"DPM1 modulates desmosomal adhesion and epidermal differentiation through SERPINB5.","date":"2024","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/38477878","citation_count":8,"is_preprint":false},{"pmid":"35910228","id":"PMC_35910228","title":"Case Report: DPM1-CDG: Novel Variant with Severe Phenotype and Literature Review.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35910228","citation_count":5,"is_preprint":false},{"pmid":"37042760","id":"PMC_37042760","title":"Unique clinical presentations and follow-up outcomes from experience with congenital disorders of glycosylation: PMM2-PGM1-DPAGT1-MPI-POMT2-B3GALNT2-DPM1-SRD5A3-CDG.","date":"2023","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/37042760","citation_count":5,"is_preprint":false},{"pmid":"38471523","id":"PMC_38471523","title":"PUM1 and PGK1 are Favorable Housekeeping Genes over Established Biodosimetry-related Housekeeping Genes such as HPRT1, ITFG1, DPM1, MRPS5, 18S rRNA and Others after Radiation Exposure.","date":"2024","source":"Radiation research","url":"https://pubmed.ncbi.nlm.nih.gov/38471523","citation_count":2,"is_preprint":false},{"pmid":"41311987","id":"PMC_41311987","title":"Identification of Compound Heterozygous DPM1 Variants in a Pediatric Patient With Congenital Disorder of Glycosylation Type Ie.","date":"2025","source":"Case reports in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/41311987","citation_count":0,"is_preprint":false},{"pmid":"42230629","id":"PMC_42230629","title":"The mannosyltransferase DPM1 regulates the activity of ER-stress sensor IRE1 in colorectal cancer.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/42230629","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10408,"output_tokens":3084,"usd":0.038742,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10444,"output_tokens":3401,"usd":0.068623,"stage2_stop_reason":"end_turn"},"total_usd":0.107365,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"DPM2, an 84-amino acid ER membrane protein, forms a complex with DPM1 that is essential for ER localization and stable expression of DPM1; DPM2 also enhances binding of dolichol phosphate (a substrate) to the synthase complex. DPM1 alone is catalytically sufficient when artificially tethered to the ER via a fusion protein.\",\n      \"method\": \"Expression cloning in Lec15 mutant CHO cells, co-immunoprecipitation, fusion-protein complementation assay, subcellular fractionation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal complex identification, functional complementation, substrate-binding assay, replicated across multiple cell-line models in a single rigorous study\",\n      \"pmids\": [\"9724629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human DPM synthase is a heterotrimer of DPM1 (catalytic), DPM2 (regulatory), and DPM3 (structural stabilizer). DPM3 associates with DPM1 via its C-terminal domain and with DPM2 via its N-terminal portion; DPM2 stabilizes DPM3, and DPM3 in turn stabilizes DPM1. Overexpression of DPM3 in DPM2-null (Lec15) cells restores DPM biosynthesis with increased DPM1 levels. DPM2 also contributes to enzymatic activity (~10-fold enhancement).\",\n      \"method\": \"Genetic complementation in Lec15 cells, co-purification, overexpression, DPM synthase activity assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-purification, genetic complementation, enzymatic activity assays), replicated with S. pombe orthologs\",\n      \"pmids\": [\"10835346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Mutations in DPM1 (point mutation R92G / C274G, and a 13-bp deletion) cause ~95% deficiency in dolichol-phosphate-mannose (Dol-P-Man) synthase activity in patient fibroblasts, with an ~6-fold elevated apparent Km for GDP-mannose, leading to production of a truncated Man5 dolichol-linked oligosaccharide precursor instead of the normal Man9 form. Addition of exogenous mannose corrected the truncation.\",\n      \"method\": \"Metabolic labeling with [3H]mannose, microsomal enzyme activity assay (Km determination), Sanger sequencing, mannose supplementation rescue\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzyme activity with kinetic parameters, mutation identification, metabolic rescue experiment; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"10642597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The S. cerevisiae DPM1 gene product (Dol-P-Man synthase) is the catalytic enzyme responsible for synthesis and membrane translocation of dolichol-phosphate-mannose, which donates mannose residues for N-linked glycosylation. S. cerevisiae DPM1 complemented a glycosylation-defective CHO cell line (B4-2-1), restoring Dol-P-Man synthase activity and correct oligosaccharide assembly. Indirect immunofluorescence showed reticular (ER) localization of the DPM1 protein.\",\n      \"method\": \"Stable transfection complementation, FACS lectin-binding analysis, enzymatic activity assay in cell lysates, HPLC of lipid-linked oligosaccharides, endoglycosidase H sensitivity assay, indirect immunofluorescence\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional readouts (enzyme activity, oligosaccharide profiling, glycoprotein sensitivity assay, localization); foundational complementation study\",\n      \"pmids\": [\"2201896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"DPM3 tethers DPM1 to the ER membrane via a coiled-coil domain near DPM3's C-terminus; this tethering is critical for DPM synthase activity. In the absence of DPM3, DPM1 is rapidly degraded by the proteasome. Free DPM1 associates strongly with CHIP (C-terminus of Hsc70-interacting protein), a chaperone-dependent E3 ubiquitin ligase, indicating DPM1 is ubiquitinated by CHIP when not incorporated into the complex.\",\n      \"method\": \"Generation of DPM3-deficient CHO2.38 cells, microsomal DPM synthase activity assay, domain-deletion mutagenesis of DPM3, proteasome inhibitor treatment, co-immunoprecipitation with CHIP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutant cell line, enzyme activity assay, domain mutagenesis, proteasome inhibition, and co-IP for ubiquitin ligase; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"16280320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"An intronic DPM1 mutation (g.IVS4-5T>A) causes exon skipping and a shortened transcript, reducing DPM1 mRNA expression by >90% (via a nonsense-mediated mRNA decay-independent mechanism), resulting in only residual Dol-P-Man synthase activity and accumulation of the immature Dol-PP-GlcNAc2Man5 species. Loss of DPM1 expression also secondarily reduces DPM2 expression.\",\n      \"method\": \"RT-PCR, Sanger sequencing, Dol-P-Man synthase activity assay in patient fibroblasts, lipid-linked oligosaccharide analysis, mRNA quantification\",\n      \"journal\": \"Pediatric research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzyme activity assay, transcript analysis, and oligosaccharide profiling; single lab, patient-derived cells\",\n      \"pmids\": [\"16641202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A DPM1 missense mutation (p.Gly152Val) reduces DPM1 binding to DPM3 without decreasing the enzyme's affinity for substrate, suggesting Gly152 is important for DPM3 interaction rather than catalysis. Overall DPM1 enzyme activity in patient fibroblasts was reduced by ~80%.\",\n      \"method\": \"DPM1 enzyme activity assay in patient fibroblasts, transfection of tagged wild-type and mutant DPM1 constructs, co-immunoprecipitation with DPM3\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzyme activity assay and co-IP with mutagenesis in a single lab; two orthogonal methods\",\n      \"pmids\": [\"23856421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In a Drosophila CRISPR screen, inhibition of Dpm1 (the DPM1 ortholog) rescued cell survival and glycoprotein levels under DPAGT1 inhibition and alleviated ER stress in two in vivo models, demonstrating a genetic epistatic relationship where reduced Dpm1 activity suppresses consequences of deficient upstream N-glycosylation initiation. A novel interaction between fructose/glycolytic metabolism and ER stress was also identified in this context.\",\n      \"method\": \"Genome-wide CRISPR knockout screen in Drosophila cells, in vivo genetic epistasis in Drosophila models, glycoprotein level measurement, metabolic analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen validated in vivo in two independent Drosophila models; single lab, Drosophila ortholog\",\n      \"pmids\": [\"36166480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Deletion of DPM1 in human keratinocytes impairs desmosomal adhesion, disrupts localization of desmoplakin and desmoglein-2, and causes cytoskeletal organization defects. Proteomic analysis identified SERPINB5 as a DPM1-dependent interaction partner of desmoplakin; mechanistically, SERPINB5 reduces desmoplakin phosphorylation at serine 176, which is required for strong intercellular adhesion.\",\n      \"method\": \"CRISPR knockout of DPM1 in keratinocytes, 3D organotypic epidermis model, immunofluorescence localization, mass spectrometry-based proteomics, co-immunoprecipitation, phosphorylation analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined cellular phenotype, proteomic identification of interaction partner, phosphorylation mechanistic follow-up; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38477878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DPM1 was identified as a direct regulator of IRE1α expression and activity via a BioID proximity screen. DPM1 ablation in colorectal cancer cells reduces protein glycosylation, leading to chronic IRE1 activation, which in turn enhances cytotoxic T cell-mediated immunosurveillance. IRE1 inhibition or knockout reverses this immune phenotype.\",\n      \"method\": \"BioID proximity labeling screen, DPM1 knockout, IRE1 activity assays, IRE1 inhibition/KO epistasis, T cell cytotoxicity assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID interaction screen, genetic KO, epistasis with IRE1 KO/inhibitor; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"42230629\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DPM1 is the catalytic subunit of the heterotrimeric dolichol-phosphate-mannose (Dol-P-Man) synthase complex, which transfers mannose from GDP-mannose onto dolichol phosphate in the ER membrane to generate the mannosyl donor required for GPI anchor biosynthesis, N-glycan precursor elongation, and O- and C-mannosylation; DPM1 activity and ER membrane tethering depend on its assembly with regulatory subunit DPM2 (which enhances substrate binding and enzymatic rate) and structural subunit DPM3 (which anchors DPM1 to the ER via a coiled-coil domain and prevents its proteasomal degradation via CHIP-mediated ubiquitination when free); beyond glycan synthesis, DPM1 modulates desmosomal adhesion through a SERPINB5–desmoplakin phosphorylation axis and restrains IRE1α-mediated ER stress signaling, with loss of DPM1 causing chronic IRE1 activation and enhanced anti-tumor immunity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DPM1 is the catalytic subunit of dolichol-phosphate-mannose (Dol-P-Man) synthase, the ER enzyme that transfers mannose from GDP-mannose onto dolichol phosphate to generate the mannosyl donor required for lipid-linked oligosaccharide assembly and N-linked glycosylation [#3]. Its catalytic activity depends on assembly into a heterotrimer with the regulatory subunit DPM2, which enhances dolichol-phosphate substrate binding and raises enzymatic rate, and the structural subunit DPM3, which bridges DPM1 and DPM2 and tethers DPM1 to the ER membrane via a C-terminal coiled-coil domain [#0, #1, #4]. DPM1 is catalytically sufficient on its own when artificially anchored to the ER, indicating the partner subunits provide membrane localization and stability rather than catalysis [#0]; in the absence of DPM3 tethering, free DPM1 associates with the chaperone-dependent E3 ligase CHIP and is rapidly degraded by the proteasome [#4]. Loss-of-function DPM1 mutations cause a congenital disorder of glycosylation, producing ~95% deficiency in Dol-P-Man synthase activity, elevated apparent Km for GDP-mannose, and accumulation of truncated Man5 dolichol-linked precursors that is correctable by exogenous mannose [#2, #5]; distinct mutations selectively disrupt either catalysis or DPM3 binding [#6]. Beyond glycan synthesis, DPM1 supports desmosomal adhesion through a SERPINB5-dependent control of desmoplakin serine-176 phosphorylation [#8] and restrains IRE1\\u03b1 ER-stress signaling, such that DPM1 loss drives chronic IRE1 activation and enhanced cytotoxic T-cell immunosurveillance [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established DPM1 as the catalytic enzyme generating dolichol-phosphate-mannose and showed it is conserved and ER-localized, defining its core glycosylation role.\",\n      \"evidence\": \"S. cerevisiae DPM1 complementation of a glycosylation-defective CHO line with enzyme, oligosaccharide, and immunofluorescence readouts\",\n      \"pmids\": [\"2201896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve subunit composition of the mammalian enzyme\", \"No structural basis for catalysis defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Resolved why mammalian DPM1 requires partners by identifying DPM2 as an ER membrane subunit needed for DPM1 localization, stability, and substrate binding.\",\n      \"evidence\": \"Expression cloning in Lec15 CHO mutants, co-IP, fusion-protein complementation showing DPM1 is catalytically sufficient when ER-tethered\",\n      \"pmids\": [\"9724629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Third subunit not yet identified\", \"Mechanism of substrate-binding enhancement not structurally defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the synthase as a DPM1-DPM2-DPM3 heterotrimer and mapped the stabilization hierarchy in which DPM2 stabilizes DPM3 and DPM3 stabilizes DPM1.\",\n      \"evidence\": \"Genetic complementation in Lec15 cells, co-purification, overexpression, and activity assays with S. pombe orthologs\",\n      \"pmids\": [\"10835346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Membrane-tethering domain of DPM3 not yet localized\", \"Degradation pathway of unassembled DPM1 unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Linked DPM1 to human disease by showing point and deletion mutations cripple Dol-P-Man synthase kinetics and truncate the N-glycan precursor, with metabolic rescue by mannose.\",\n      \"evidence\": \"Metabolic [3H]mannose labeling, microsomal Km determination, sequencing, and mannose supplementation in patient fibroblasts\",\n      \"pmids\": [\"10642597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype range across patients not established\", \"In vivo therapeutic value of mannose not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Explained how DPM3 controls DPM1 by showing its coiled-coil tethers DPM1 to the ER and that untethered DPM1 is ubiquitinated by CHIP and proteasomally degraded.\",\n      \"evidence\": \"DPM3-deficient CHO cells, domain-deletion mutagenesis, proteasome inhibition, and CHIP co-IP\",\n      \"pmids\": [\"16280320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CHIP ubiquitination sites on DPM1 not mapped\", \"Reciprocal validation of CHIP-DPM1 interaction limited\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended the disease spectrum to a splice-altering intronic mutation that depletes DPM1 mRNA and secondarily reduces DPM2, reinforcing subunit interdependence in vivo.\",\n      \"evidence\": \"RT-PCR, sequencing, synthase activity, and oligosaccharide profiling in patient fibroblasts\",\n      \"pmids\": [\"16641202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NMD-independent decay mechanism not fully defined\", \"Single patient-derived cell source\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Separated catalytic from assembly functions of DPM1 by identifying a missense mutation that disrupts DPM3 binding without altering substrate affinity.\",\n      \"evidence\": \"Enzyme activity assays, tagged WT/mutant transfection, and DPM3 co-IP in patient fibroblasts\",\n      \"pmids\": [\"23856421\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the DPM1-DPM3 interface not resolved\", \"Single-lab co-IP evidence\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed DPM1 in a pathway context with upstream N-glycosylation initiation, showing reduced Dpm1 activity suppresses ER stress caused by DPAGT1 deficiency.\",\n      \"evidence\": \"Genome-wide CRISPR screen and in vivo genetic epistasis in two Drosophila models with glycoprotein and metabolic readouts\",\n      \"pmids\": [\"36166480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of epistatic suppression not molecularly defined\", \"Demonstrated in Drosophila ortholog, not human\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a non-glycosylation role for DPM1 in desmosomal adhesion via SERPINB5-dependent control of desmoplakin phosphorylation.\",\n      \"evidence\": \"DPM1 CRISPR knockout in keratinocytes, 3D organotypic epidermis, proteomics, co-IP, and phosphorylation analysis\",\n      \"pmids\": [\"38477878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the adhesion defect is downstream of glycosylation loss not fully separated\", \"Kinase regulating Ser176 not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected DPM1 to ER-stress and immune signaling by showing its loss drives chronic IRE1\\u03b1 activation that enhances T-cell-mediated immunosurveillance.\",\n      \"evidence\": \"BioID proximity screen, DPM1 knockout, IRE1 activity assays, IRE1 KO/inhibitor epistasis, and T-cell cytotoxicity assays in colorectal cancer cells\",\n      \"pmids\": [\"42230629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical mechanism of DPM1-IRE1 regulation not defined\", \"Single-lab, single cancer-cell context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DPM1's catalytic glycosylation function mechanistically gives rise to its distinct roles in desmosomal adhesion and IRE1\\u03b1 signaling remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the human DPM1-DPM2-DPM3 complex\", \"Whether adhesion and immune phenotypes are direct or secondary to glycan loss is unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0016758\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [7, 9]}\n    ],\n    \"complexes\": [\"Dol-P-Man synthase (DPM1-DPM2-DPM3 heterotrimer)\"],\n    \"partners\": [\"DPM2\", \"DPM3\", \"CHIP\", \"SERPINB5\", \"DSP\", \"ERN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}