{"gene":"GLDN","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2016,"finding":"Biallelic loss-of-function mutations in GLDN abolish cell surface localization of gliomedin and disrupt its interaction with its axonal partner neurofascin-186 (NF186), as demonstrated in a cell-based assay. This axoglial contact between gliomedin and NF186 is essential for the initial clustering of Na+ channels at developing nodes of Ranvier. Transmission electron microscopy of sciatic nerve from an affected individual confirmed marked lengthening defects of the nodes.","method":"Cell-based localization assay, co-interaction assay with NF186, transmission electron microscopy of human sciatic nerve, exome sequencing/linkage analysis in human families","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-based functional assay with direct protein interaction readout, complemented by ultrastructural evidence in human tissue; findings replicated across four unrelated families with multiple orthogonal methods","pmids":["27616481"],"is_preprint":false},{"year":2020,"finding":"Functional assays of GLDN patient variants (including novel p.Leu365Phe and p.Arg393Lys) demonstrated that specific missense mutations impair gliomedin function, supporting their pathogenicity in arthrogryposis multiplex congenita. Experimental data confirmed that loss of gliomedin function leads to defects consistent with fetal akinesia.","method":"Functional variant assays (cell-based) for multiple patient-derived GLDN variants","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based functional assays for multiple variants in a single study, but limited mechanistic detail in abstract","pmids":["32812332"],"is_preprint":false},{"year":2026,"finding":"GLDN is essential for maintaining the phenotype and function of GLDN+ odontogenic stem cells (OSCs) in the dental papilla through BMP5 signaling via autocrine and paracrine mechanisms. GLDN+ OSCs exhibit enhanced self-renewal, migratory capacity, odontogenic differentiation, and ability to induce endothelial cell migration and tube formation compared to GLDN- DPSCs. In vivo ectopic transplantation confirmed that GLDN+ OSCs can regenerate vascularized dental pulp with an odontoblast layer.","method":"Single-cell sequencing, in vitro functional assays (self-renewal, migration, differentiation, tube formation), in vivo ectopic dental pulp regeneration model, mechanistic analysis of BMP5 signaling","journal":"International journal of oral science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in vitro and in vivo in a single study; BMP5 pathway placement is novel but from single lab","pmids":["41760598"],"is_preprint":false}],"current_model":"Gliomedin (GLDN) is a secreted cell adhesion molecule expressed at the nodes of Ranvier where it localizes to the cell surface and directly binds the axonal protein neurofascin-186 (NF186), an interaction essential for clustering Na+ channels at developing nodes; loss-of-function mutations abolish this surface localization and NF186 interaction, causing peripheral neuropathy and lethal arthrogryposis, while in the dental papilla GLDN maintains odontogenic stem cell identity and function through BMP5 autocrine/paracrine signaling."},"narrative":{"mechanistic_narrative":"Gliomedin (GLDN) is a cell-surface adhesion molecule that organizes the nodes of Ranvier by mediating axoglial contact required for the initial clustering of Na+ channels at developing nodes [PMID:27616481]. It localizes to the cell surface and directly binds the axonal protein neurofascin-186 (NF186); biallelic loss-of-function mutations abolish both this surface localization and the NF186 interaction, and ultrastructural analysis of patient sciatic nerve reveals marked node-lengthening defects [PMID:27616481]. Patient-derived missense variants impair gliomedin function and produce defects consistent with fetal akinesia, establishing GLDN loss as a cause of lethal arthrogryposis multiplex congenita [PMID:27616481, PMID:32812332]. Beyond its nodal role, GLDN marks a population of odontogenic stem cells in the dental papilla, where it sustains their self-renewal, migratory, and odontogenic differentiation capacity through autocrine and paracrine BMP5 signaling, enabling regeneration of vascularized dental pulp [PMID:41760598].","teleology":[{"year":2016,"claim":"Established that GLDN functions as a surface adhesion molecule whose binding to axonal NF186 is required to initiate Na+ channel clustering at nodes of Ranvier, and that human loss-of-function disrupts this in disease.","evidence":"Cell-based localization and NF186 co-interaction assays, TEM of human sciatic nerve, and exome/linkage analysis across four unrelated families","pmids":["27616481"],"confidence":"High","gaps":["Does not resolve the structural basis of the GLDN-NF186 interaction","Does not define how surface localization is regulated","Mechanism linking nodal disruption to arthrogryposis phenotype not detailed"]},{"year":2020,"claim":"Extended the genotype-phenotype link by showing that specific patient missense variants impair gliomedin function, supporting pathogenicity in arthrogryposis multiplex congenita and a fetal akinesia mechanism.","evidence":"Cell-based functional assays of multiple patient-derived GLDN variants including p.Leu365Phe and p.Arg393Lys","pmids":["32812332"],"confidence":"Medium","gaps":["Limited mechanistic detail on how each variant impairs function","Single study without independent replication of variant-level effects"]},{"year":2026,"claim":"Revealed a function for GLDN outside the nervous system, defining it as a marker and effector of odontogenic stem cell identity acting through BMP5 signaling.","evidence":"Single-cell sequencing, in vitro self-renewal/migration/differentiation/tube-formation assays, and in vivo ectopic dental pulp regeneration with mechanistic analysis of BMP5","pmids":["41760598"],"confidence":"Medium","gaps":["Direct molecular link between GLDN and BMP5 signaling not biochemically resolved","Single-lab finding for the BMP5 pathway placement","Relationship between nodal adhesion role and stem cell role unknown"]},{"year":null,"claim":"How GLDN's adhesion-mediated nodal function mechanistically connects to its role in BMP5-dependent stem cell maintenance remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of GLDN domains or its NF186 interface","Mechanism by which GLDN engages BMP5 signaling not defined","No unifying model across neural and dental contexts"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0]}],"complexes":[],"partners":["NF186"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6ZMI3","full_name":"Gliomedin","aliases":[],"length_aa":551,"mass_kda":59.0,"function":"Ligand for NRCAM and NFASC/neurofascin that plays a role in the formation and maintenance of the nodes of Ranvier on myelinated axons. Mediates interaction between Schwann cell microvilli and axons via its interactions with NRCAM and NFASC. Nodes of Ranvier contain clustered sodium channels that are crucial for the saltatory propagation of action potentials along myelinated axons. During development, nodes of Ranvier are formed by the fusion of two heminodes. Required for normal clustering of sodium channels at heminodes; not required for the formation of mature nodes with normal sodium channel clusters. Required, together with NRCAM, for maintaining NFASC and sodium channel clusters at mature nodes of Ranvier","subcellular_location":"Secreted; Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/Q6ZMI3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GLDN","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GLDN","total_profiled":1310},"omim":[{"mim_id":"617194","title":"LETHAL CONGENITAL CONTRACTURE SYNDROME 11; LCCS11","url":"https://www.omim.org/entry/617194"},{"mim_id":"608603","title":"GLIOMEDIN; GLDN","url":"https://www.omim.org/entry/608603"},{"mim_id":"253310","title":"LETHAL CONGENITAL CONTRACTURE SYNDROME 1; LCCS1","url":"https://www.omim.org/entry/253310"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":17.3},{"tissue":"blood vessel","ntpm":20.7},{"tissue":"brain","ntpm":44.1}],"url":"https://www.proteinatlas.org/search/GLDN"},"hgnc":{"alias_symbol":["CRG-L2","CLOM","colmedin","UNC-122"],"prev_symbol":["COLM"]},"alphafold":{"accession":"Q6ZMI3","domains":[{"cath_id":"2.120.10.30","chopping":"305-545","consensus_level":"medium","plddt":96.1671,"start":305,"end":545}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZMI3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZMI3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZMI3-F1-predicted_aligned_error_v6.png","plddt_mean":72.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GLDN","jax_strain_url":"https://www.jax.org/strain/search?query=GLDN"},"sequence":{"accession":"Q6ZMI3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6ZMI3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6ZMI3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZMI3"}},"corpus_meta":[{"pmid":"19262477","id":"PMC_19262477","title":"Rationale, study design and implementation of the COLM study: the combination of OLMesartan and calcium channel blocker or diuretic in high-risk elderly hypertensive patients.","date":"2009","source":"Hypertension research : official journal of the Japanese Society of Hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/19262477","citation_count":279,"is_preprint":false},{"pmid":"20038590","id":"PMC_20038590","title":"Flavobacterium johnsoniae gldN and gldO are partially redundant genes required for gliding motility and surface localization of SprB.","date":"2009","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/20038590","citation_count":55,"is_preprint":false},{"pmid":"27616481","id":"PMC_27616481","title":"Mutations in GLDN, Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible for Lethal Arthrogryposis.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27616481","citation_count":45,"is_preprint":false},{"pmid":"26066644","id":"PMC_26066644","title":"Preferable effects of olmesartan/calcium channel blocker to olmesartan/diuretic on blood pressure variability in very elderly hypertension: COLM study subanalysis.","date":"2015","source":"Journal of hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/26066644","citation_count":26,"is_preprint":false},{"pmid":"32245758","id":"PMC_32245758","title":"Cytophaga hutchinsonii gldN, Encoding a Core Component of the Type IX Secretion System, Is Essential for Ion Assimilation, Cellulose Degradation, and Cell Motility.","date":"2020","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32245758","citation_count":21,"is_preprint":false},{"pmid":"28726266","id":"PMC_28726266","title":"Survival among children with \"Lethal\" congenital contracture syndrome 11 caused by novel mutations in the gliomedin gene (GLDN).","date":"2017","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/28726266","citation_count":20,"is_preprint":false},{"pmid":"12642876","id":"PMC_12642876","title":"Identification and characterization of CRG-L2, a new marker for liver tumor development.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12642876","citation_count":16,"is_preprint":false},{"pmid":"29440573","id":"PMC_29440573","title":"The ColM Family, Polymorphic Toxins Breaching the Bacterial Cell Wall.","date":"2018","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/29440573","citation_count":14,"is_preprint":false},{"pmid":"25253582","id":"PMC_25253582","title":"Comparison of olmesartan combined with a calcium channel blocker or a diuretic in elderly hypertensive patients (COLM Study): safety and tolerability.","date":"2014","source":"Hypertension research : official journal of the Japanese Society of Hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/25253582","citation_count":14,"is_preprint":false},{"pmid":"32812332","id":"PMC_32812332","title":"The latest FADS: Functional analysis of GLDN patient variants and classification of GLDN-associated AMC as a type of viable fetal akinesia deformation sequence.","date":"2020","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/32812332","citation_count":8,"is_preprint":false},{"pmid":"41760598","id":"PMC_41760598","title":"Identification of GLDN+ odontogenic stem cells as crucial for human tooth development and regeneration.","date":"2026","source":"International journal of oral science","url":"https://pubmed.ncbi.nlm.nih.gov/41760598","citation_count":0,"is_preprint":false},{"pmid":"42151911","id":"PMC_42151911","title":"Anti-GLDN antibody-associated CIDP (nodopathy): transient IVIg response and B-cell depletion remission.","date":"2026","source":"BMC neurology","url":"https://pubmed.ncbi.nlm.nih.gov/42151911","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.15.24313713","title":"Whole-exome sequencing study of opioid dependence offers novel insights into the contributions of exome variants","date":"2024-09-17","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.15.24313713","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8261,"output_tokens":947,"usd":0.019494,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7474,"output_tokens":1530,"usd":0.03781,"stage2_stop_reason":"end_turn"},"total_usd":0.057304,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"Biallelic loss-of-function mutations in GLDN abolish cell surface localization of gliomedin and disrupt its interaction with its axonal partner neurofascin-186 (NF186), as demonstrated in a cell-based assay. This axoglial contact between gliomedin and NF186 is essential for the initial clustering of Na+ channels at developing nodes of Ranvier. Transmission electron microscopy of sciatic nerve from an affected individual confirmed marked lengthening defects of the nodes.\",\n      \"method\": \"Cell-based localization assay, co-interaction assay with NF186, transmission electron microscopy of human sciatic nerve, exome sequencing/linkage analysis in human families\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-based functional assay with direct protein interaction readout, complemented by ultrastructural evidence in human tissue; findings replicated across four unrelated families with multiple orthogonal methods\",\n      \"pmids\": [\"27616481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Functional assays of GLDN patient variants (including novel p.Leu365Phe and p.Arg393Lys) demonstrated that specific missense mutations impair gliomedin function, supporting their pathogenicity in arthrogryposis multiplex congenita. Experimental data confirmed that loss of gliomedin function leads to defects consistent with fetal akinesia.\",\n      \"method\": \"Functional variant assays (cell-based) for multiple patient-derived GLDN variants\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based functional assays for multiple variants in a single study, but limited mechanistic detail in abstract\",\n      \"pmids\": [\"32812332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"GLDN is essential for maintaining the phenotype and function of GLDN+ odontogenic stem cells (OSCs) in the dental papilla through BMP5 signaling via autocrine and paracrine mechanisms. GLDN+ OSCs exhibit enhanced self-renewal, migratory capacity, odontogenic differentiation, and ability to induce endothelial cell migration and tube formation compared to GLDN- DPSCs. In vivo ectopic transplantation confirmed that GLDN+ OSCs can regenerate vascularized dental pulp with an odontoblast layer.\",\n      \"method\": \"Single-cell sequencing, in vitro functional assays (self-renewal, migration, differentiation, tube formation), in vivo ectopic dental pulp regeneration model, mechanistic analysis of BMP5 signaling\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in vitro and in vivo in a single study; BMP5 pathway placement is novel but from single lab\",\n      \"pmids\": [\"41760598\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Gliomedin (GLDN) is a secreted cell adhesion molecule expressed at the nodes of Ranvier where it localizes to the cell surface and directly binds the axonal protein neurofascin-186 (NF186), an interaction essential for clustering Na+ channels at developing nodes; loss-of-function mutations abolish this surface localization and NF186 interaction, causing peripheral neuropathy and lethal arthrogryposis, while in the dental papilla GLDN maintains odontogenic stem cell identity and function through BMP5 autocrine/paracrine signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Gliomedin (GLDN) is a cell-surface adhesion molecule that organizes the nodes of Ranvier by mediating axoglial contact required for the initial clustering of Na+ channels at developing nodes [#0]. It localizes to the cell surface and directly binds the axonal protein neurofascin-186 (NF186); biallelic loss-of-function mutations abolish both this surface localization and the NF186 interaction, and ultrastructural analysis of patient sciatic nerve reveals marked node-lengthening defects [#0]. Patient-derived missense variants impair gliomedin function and produce defects consistent with fetal akinesia, establishing GLDN loss as a cause of lethal arthrogryposis multiplex congenita [#0, #1]. Beyond its nodal role, GLDN marks a population of odontogenic stem cells in the dental papilla, where it sustains their self-renewal, migratory, and odontogenic differentiation capacity through autocrine and paracrine BMP5 signaling, enabling regeneration of vascularized dental pulp [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that GLDN functions as a surface adhesion molecule whose binding to axonal NF186 is required to initiate Na+ channel clustering at nodes of Ranvier, and that human loss-of-function disrupts this in disease.\",\n      \"evidence\": \"Cell-based localization and NF186 co-interaction assays, TEM of human sciatic nerve, and exome/linkage analysis across four unrelated families\",\n      \"pmids\": [\"27616481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve the structural basis of the GLDN-NF186 interaction\", \"Does not define how surface localization is regulated\", \"Mechanism linking nodal disruption to arthrogryposis phenotype not detailed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the genotype-phenotype link by showing that specific patient missense variants impair gliomedin function, supporting pathogenicity in arthrogryposis multiplex congenita and a fetal akinesia mechanism.\",\n      \"evidence\": \"Cell-based functional assays of multiple patient-derived GLDN variants including p.Leu365Phe and p.Arg393Lys\",\n      \"pmids\": [\"32812332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited mechanistic detail on how each variant impairs function\", \"Single study without independent replication of variant-level effects\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed a function for GLDN outside the nervous system, defining it as a marker and effector of odontogenic stem cell identity acting through BMP5 signaling.\",\n      \"evidence\": \"Single-cell sequencing, in vitro self-renewal/migration/differentiation/tube-formation assays, and in vivo ectopic dental pulp regeneration with mechanistic analysis of BMP5\",\n      \"pmids\": [\"41760598\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between GLDN and BMP5 signaling not biochemically resolved\", \"Single-lab finding for the BMP5 pathway placement\", \"Relationship between nodal adhesion role and stem cell role unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GLDN's adhesion-mediated nodal function mechanistically connects to its role in BMP5-dependent stem cell maintenance remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of GLDN domains or its NF186 interface\", \"Mechanism by which GLDN engages BMP5 signaling not defined\", \"No unifying model across neural and dental contexts\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NF186\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}