{"gene":"NFASC","run_date":"2026-06-14T21:15:27+00:00","timeline":{"discoveries":[{"year":2003,"finding":"NF155 binds directly to contactin, but coexpression of Caspr inhibits this interaction by associating with contactin during biosynthesis and promoting a low-molecular-weight, endoglycosidase H-sensitive isoform of contactin at the cell membrane that cannot bind NF155. Deletion of Caspr in mice shifts contactin from the LMw to HMw glycoform, confirming Caspr regulates contactin processing and transport to the cell surface.","method":"Cell-based binding assays, co-expression studies, endoglycosidase H treatment, Caspr knockout mice with biochemical fractionation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding assay combined with genetic knockout confirmation and biochemical glycoform analysis, replicated across multiple orthogonal methods","pmids":["14676309"],"is_preprint":false},{"year":2005,"finding":"NF155 promotes neural cell adhesion and neurite outgrowth, and the RGD motif in its third FnIII repeat is critical for cell spreading and neurite outgrowth. Conversely, NF186 inhibits cell adhesion and neurite outgrowth, with inhibition associated with its mucin-like domain.","method":"Fc fusion protein binding assays, cell adhesion assays, neurite outgrowth assays with domain-deletion and RGD-mutant constructs","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping with Fc fusion proteins and functional assays in single study, multiple orthogonal readouts","pmids":["16061393"],"is_preprint":false},{"year":2012,"finding":"Doublecortin (DCX) promotes endocytosis of neurofascin from soma and dendrites, thereby increasing neurofascin accumulation at the axon initial segment. This endocytic adaptor function is independent of DCX's microtubule-binding activity, and the patient allele DCX-G253D retains microtubule binding but is deficient in promoting neurofascin endocytosis.","method":"Live imaging and surface distribution assays in cultured rat neurons, DCX mutant constructs (microtubule-binding mutants, patient allele G253D), endocytosis assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional dissection using multiple DCX mutants with orthogonal readouts (surface distribution, endocytosis), patient allele validation","pmids":["22649224"],"is_preprint":false},{"year":2014,"finding":"Inducible ablation of neuronal Neurofascin (Nfasc186) in adult mice causes >99% loss at PNS nodes and 94% loss at CNS nodes. Gliomedin and NrCAM at PNS nodes and brevican at CNS nodes are largely lost, Nav channels persist at nodes with ~40% reduction, and there is a 38% reduction in PNS conduction velocity. Loss of Nfasc186 also provokes CNS paranodal disorganization. This establishes distinct roles for Nfasc186 in node maintenance in PNS vs. CNS.","method":"Inducible conditional knockout mice (neuronal-specific Nfasc ablation), immunofluorescence, electrophysiology","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean inducible conditional KO with multiple protein readouts and electrophysiological functional validation","pmids":["24719087"],"is_preprint":false},{"year":2015,"finding":"Nfasc140 is a neuronal isoform strongly expressed during mouse embryonic development that can cluster voltage-gated sodium channels (Nav) at the developing node of Ranvier and restore electrophysiological function independently of Nfasc155 and Nfasc186. Nfasc140 is re-expressed in demyelinated white matter lesions of multiple sclerosis postmortem brain tissue.","method":"Immunostaining of knockout and wild-type mouse nerves, electrophysiology, human MS postmortem tissue immunostaining","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional rescue experiment in a knockout background with electrophysiological validation and human tissue confirmation","pmids":["25653379"],"is_preprint":false},{"year":2016,"finding":"The QKI RNA-binding proteins in oligodendrocytes regulate alternative splicing of the Nfasc gene to produce the Nfasc155 isoform. Deletion of QKI in oligodendrocytes results in loss of Nfasc155 and deterioration of axoglial junctions in the spinal cord, leading to demyelination and paralysis.","method":"Conditional knockout mice (Olig2-Cre and inducible PLP-CreERT), immunostaining, RNA splicing analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent genetic mouse models (developmental and inducible adult), multiple orthogonal readouts including splicing assays and histology","pmids":["27053216"],"is_preprint":false},{"year":2017,"finding":"Alternative splicing of Nfasc is spatio-temporally regulated in cerebellar neurons. High K+-induced depolarization triggers a shift from Nfasc140 to Nfasc186 splicing in cerebellar granule cells. The neural RNA-binding protein Rbfox controls isoform selection at exons 26–29.","method":"RT-PCR splicing analysis in mouse brain, depolarization experiments in cerebellar granule cells, Rbfox functional assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional splicing assays with depolarization and Rbfox manipulation, single lab","pmids":["28900163"],"is_preprint":false},{"year":2017,"finding":"NFASC silencing in non-small cell lung cancer (NSCLC) cell lines decreased cell migration and caused morphological changes including rearrangements of the actin cytoskeleton and changes in F-actin networks in migrating cells, without affecting proliferation or viability. This identifies NFASC as a regulator of NSCLC cell motility.","method":"siRNA knockdown in four NSCLC cell lines, migration assays, actin cytoskeleton staining","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA knockdown with functional readout in multiple cell lines, single lab","pmids":["28418179"],"is_preprint":false},{"year":2019,"finding":"Patient-derived anti-Nfasc155 IgG4 antibodies target Nfasc155 on Schwann cell surface, reduce Nfasc155 protein levels, and prevent paranodal complex formation in neonatal animals without inhibiting Nfasc155 binding to contactin-1/CASPR1 or inducing target internalization. Chronic intrathecal infusion in adult animals induces loss of Nfasc155, paranodal specialization disruption, and conduction alterations in motor nerves.","method":"Passive transfer experiments in neonatal animals, chronic intrathecal infusion in adult animals, immunofluorescence, nerve conduction studies, cell aggregation assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo passive transfer and intrathecal infusion with multiple functional and structural readouts, patient-derived antibodies","pmids":["30869655"],"is_preprint":false},{"year":2019,"finding":"Biallelic loss-of-function variants in NFASC (including a frameshift causing absent Nfasc155 expression and missense variants reducing expression) severely impair Nfasc155–CNTN1/CASPR1 complex interaction in cell aggregation assays, disrupt paranodal junction morphology in myelinated fibers of affected individuals, and cause neurodevelopmental disorder with central and peripheral demyelination.","method":"Exome/genome sequencing, immunostaining of patient myelinated fibers, cell aggregation assays, expression studies","journal":"Brain","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional assays (cell aggregation, patient tissue immunostaining) combined with genetic evidence across six families and multiple orthogonal methods","pmids":["31501903"],"is_preprint":false},{"year":2019,"finding":"Anti-Caspr1 IgG4 antibodies can penetrate paranodal regions and disrupt the integrity of the Nfasc155/CNTN1/Caspr1 complex, as shown by intraneural injection and immunohistochemistry on skin biopsy of a single patient.","method":"Immunohistochemistry on skin biopsy, intraneural injection, cell aggregation assay","journal":"Neurology(R) neuroimmunology & neuroinflammation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preliminary evidence from a single patient, single lab","pmids":["31753915"],"is_preprint":false},{"year":2019,"finding":"A homozygous p.V1122E mutation in NFASC affecting a conserved transmembrane domain residue leads to significant loss of Neurofascin protein in iPSC-derived neurons from affected siblings, establishing this residue as critical for protein stability.","method":"iPSC-derived neurons from patients, immunostaining for Neurofascin protein levels","journal":"Parkinsonism & related disorders","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — iPSC-derived neuron model with protein loss confirmed, single lab","pmids":["30850329"],"is_preprint":false},{"year":2020,"finding":"Neurofascin186 is transported to the soma and axon terminal via vesicles that fuse with the plasma membrane; after insertion, Nfasc186 is highly mobile in the axonal membrane and diffuses bidirectionally until immobilized at the axon initial segment through interaction with AnkyrinG. Kv7.3 is recruited to the AIS by the same mechanism.","method":"Live imaging (time-lapse fluorescence microscopy), FRAP, surface diffusion tracking in neurons","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — live imaging with FRAP and single-molecule tracking, direct mechanistic characterization of trafficking and immobilization","pmids":["32903174"],"is_preprint":false},{"year":2022,"finding":"Crystal structures of the contactin 1–NF155 adhesion complex reveal that conserved Ig1–2 interfaces form competing heterophilic contactin 1–NF155 and homophilic NF155 complexes. The Ig1–Ig4 horseshoe structure of the complex defines the ~7.4 nm paranodal spacing. Post-translational glycosylation and splice differences modulate complex formation. Contactin 1 also forms low-affinity clusters through Ig3–6 interfaces.","method":"X-ray crystallography, biophysical binding assays, cell-clustering assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of both individual and complexed proteins validated by biophysical and cell-clustering assays","pmids":["36329006"],"is_preprint":false},{"year":2023,"finding":"Anti-pan-neurofascin antibodies (recognizing all NF isoforms) have direct access to nodes of Ranvier in myelinating dorsal root ganglia co-cultures and impair paranode formation, cause destruction of paranodal architecture, and alter paranodal myelin and sensory neurons in a titre-dependent manner. IgG3 subclass pan-neurofascin antibodies bind complement and exert cytotoxic effects in vitro, distinct from IgG4 NF155 antibodies which do not activate complement.","method":"Myelinating DRG co-cultures, immunofluorescence, complement binding and cytotoxicity assays, ELISA, cell-based assays","journal":"Brain","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vitro functional assays with mechanistic dissection of IgG subclass effects, multicentre study","pmids":["36346134"],"is_preprint":false},{"year":2025,"finding":"Super-resolution imaging (dSTORM) of anti-pan-neurofascin nodopathy nerve biopsy reveals decreased NF155 and Caspr-1 density at paranodes and decreased NF186 density at nodes with preserved colocalization of adhesion proteins and intact sodium channel distribution. Axonal beta-IV spectrin is altered only in severely damaged nodes, indicating largely preserved axonal integrity with potentially reversible decreases in nodal/paranodal adhesion proteins.","method":"dSTORM super-resolution fluorescence microscopy on sural nerve biopsy teased fibers","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — advanced imaging method (dSTORM) providing nanoscale structural data, but single patient biopsy","pmids":["40051618"],"is_preprint":false},{"year":2025,"finding":"The epitope for anti-NF155 IgG4 autoantibodies in autoimmune nodopathy patients is located in the Fn3-Fn4 region (third to fourth fibronectin type III domain) of NF155 but not in the Fn3 or Fn4 domains alone. Autoantibodies in 104/104 anti-NF155+ patients bound Fn3-Fn4, and none reacted with NF186.","method":"Flow cytometric cell-based assay with truncation variants of NF155 stably/transiently expressed in HEK293 cells, Western blotting","journal":"Annals of clinical and translational neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic domain mapping with multiple truncation constructs in a large cohort (104 patients), replicated by Western blotting","pmids":["40129269"],"is_preprint":false},{"year":2026,"finding":"NF186 at the axon initial segment (AIS) of pyramidal neurons is necessary for chandelier cells (ChCs) to develop synaptic axon cartridges along the AIS. Gliomedin, a known NF186 receptor at nodes of Ranvier, is preferentially expressed in ChCs and mediates ChC axon cartridge development by acting as a major receptor for NF186 at the AIS.","method":"Conditional knockout mice (NF186 deletion in pyramidal neurons), immunostaining, synaptic connectivity analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic knockout with specific cellular phenotype, identification of NF186-Gliomedin as the intercellular ligand-receptor pair mediating chandelier cell synapse formation","pmids":["41260922"],"is_preprint":false},{"year":2019,"finding":"Oligodendrocyte Neurofascin (Nfasc155) regulates two independent aspects of CNS myelination: (1) it prevents mistargeting of myelin to neuronal cell bodies (myelin targeting), and (2) it promotes myelin sheath growth. Disruption of Caspr (the neuronal binding partner of oligodendrocyte Neurofascin) impairs myelin sheath growth but does not affect myelin targeting, indicating these two functions are separable.","method":"Genetic screen in zebrafish, complementary knockout analyses in mice, time-lapse live imaging","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent model organisms (zebrafish genetic screen + mouse KO) with time-lapse imaging providing mechanistic dissection of targeting vs. growth functions","pmids":["31761670"],"is_preprint":false}],"current_model":"Neurofascin (NFASC) is a multi-isoform immunoglobulin superfamily cell adhesion molecule whose isoforms (NF186, NF155, NF140) play distinct, context-dependent roles: NF186 anchors voltage-gated sodium channels and the nodal complex at nodes of Ranvier and the axon initial segment (AIS) via AnkyrinG after lateral membrane diffusion, interacts with Gliomedin to mediate chandelier cell synapse formation at the AIS, and its loss destabilizes nodal proteins differentially in PNS versus CNS; NF155, whose alternative splicing is regulated by QKI RNA-binding proteins and Rbfox, binds directly to contactin-1 at the Fn3-Fn4 domain interface (defined by X-ray crystal structure) to form paranodal axoglial junctions at a defined 7.4 nm spacing, with Caspr regulating contactin processing to control this interaction; NF140 is an embryonic neuronal isoform that can cluster Nav channels at nascent nodes and is re-expressed after demyelination; and pathogenic autoantibodies targeting these isoforms disrupt paranodal complex formation and node integrity in autoimmune nodopathies through IgG4-mediated complex blockade or IgG1/IgG3-mediated complement activation."},"narrative":{"mechanistic_narrative":"Neurofascin (NFASC) is an immunoglobulin-superfamily cell adhesion molecule that organizes the molecular architecture of myelinated axons, producing distinct isoforms through spatio-temporally regulated alternative splicing that serve separable roles at the node of Ranvier, paranode, and axon initial segment (AIS) [PMID:24719087, PMID:28900163]. The glial isoform NF155 binds directly to a contactin-1/Caspr1 complex to assemble paranodal axoglial junctions; crystallography of the contactin-1–NF155 adhesion complex defines an Ig1–Ig4 horseshoe architecture that sets the characteristic ~7.4 nm paranodal spacing, with competing heterophilic and homophilic interfaces and glycosylation/splice differences tuning complex formation [PMID:36329006]. Caspr controls this interaction by regulating contactin glycoform processing and surface transport during biosynthesis [PMID:14676309], and NF155 production depends on QKI-mediated splicing in oligodendrocytes, whose loss collapses axoglial junctions and causes demyelination [PMID:27053216]; NF155 separately governs both correct myelin targeting and myelin sheath growth [PMID:31761670]. The neuronal isoform NF186 traffics to the membrane and diffuses laterally until immobilized at the AIS through AnkyrinG, where it also recruits Kv7.3 [PMID:32903174], is endocytically concentrated to the AIS via the adaptor Doublecortin [PMID:22649224], maintains nodal complexes differentially in PNS versus CNS [PMID:24719087], and serves as the AIS receptor for gliomedin to direct chandelier-cell synapse formation [PMID:41260922]. The embryonic isoform NF140 independently clusters Nav channels at nascent nodes and is re-expressed in demyelinated multiple sclerosis lesions [PMID:25653379]. Biallelic loss-of-function NFASC variants that abolish or destabilize NF155 disrupt paranodal junctions and cause a neurodevelopmental disorder with central and peripheral demyelination [PMID:31501903, PMID:30850329]. NFASC isoforms are also targets of pathogenic autoantibodies in autoimmune nodopathies, where IgG4 antibodies against an NF155 Fn3–Fn4 epitope block paranodal assembly without complement activation, whereas IgG3 pan-neurofascin antibodies fix complement and are cytotoxic [PMID:30869655, PMID:40129269, PMID:36346134].","teleology":[{"year":2003,"claim":"Established that paranodal assembly is gated upstream of NF155 binding by Caspr-dependent control of contactin maturation, explaining how the adhesion partner is licensed for surface engagement.","evidence":"Cell-based binding assays, co-expression, endoglycosidase H treatment, and Caspr knockout mice with biochemical fractionation","pmids":["14676309"],"confidence":"High","gaps":["Did not resolve the structural basis of the NF155-contactin contact","Did not address how the complex achieves defined paranodal geometry"]},{"year":2005,"claim":"Distinguished opposing cell-biological activities of the two major isoforms, mapping NF155 adhesion/neurite outgrowth to an RGD motif and NF186 anti-adhesive activity to its mucin-like domain.","evidence":"Fc fusion protein binding, cell adhesion and neurite outgrowth assays with domain-deletion and RGD-mutant constructs","pmids":["16061393"],"confidence":"Medium","gaps":["Single-study domain mapping not confirmed in vivo","RGD-mediated partner identity not defined"]},{"year":2012,"claim":"Identified a trafficking mechanism for AIS enrichment of neurofascin, showing DCX acts as an endocytic adaptor clearing somatodendritic neurofascin independently of its microtubule role.","evidence":"Live imaging and surface-distribution assays in cultured rat neurons with DCX microtubule and patient-allele (G253D) mutants","pmids":["22649224"],"confidence":"High","gaps":["Molecular bridge between DCX and the endocytic machinery not defined","Relationship to AnkyrinG immobilization not addressed"]},{"year":2014,"claim":"Defined NF186 as a maintenance factor with PNS/CNS-distinct dependencies, showing nodal complex proteins are differentially destabilized while Nav channels partially persist.","evidence":"Inducible neuronal-specific conditional knockout mice with immunofluorescence and electrophysiology","pmids":["24719087"],"confidence":"High","gaps":["Mechanism underlying differential PNS vs CNS protein stability unresolved","Did not separate nodal from paranodal contributions"]},{"year":2015,"claim":"Revealed a developmentally expressed NF140 isoform capable of independently clustering Nav channels and re-expressed in MS lesions, expanding isoform-specific node assembly mechanisms.","evidence":"Immunostaining of KO and WT mouse nerves, electrophysiology, and human MS postmortem tissue staining","pmids":["25653379"],"confidence":"High","gaps":["Partner that recruits NF140 to nascent nodes not identified","Functional consequence of MS-lesion re-expression unknown"]},{"year":2016,"claim":"Linked NF155 isoform production to glial RNA processing, establishing QKI-dependent alternative splicing as required for axoglial junction integrity.","evidence":"Conditional (Olig2-Cre, inducible PLP-CreERT) knockout mice with immunostaining and splicing analysis","pmids":["27053216"],"confidence":"High","gaps":["Direct QKI binding sites on Nfasc pre-mRNA not mapped","Whether QKI regulates other myelin transcripts contributing to phenotype not isolated"]},{"year":2017,"claim":"Demonstrated activity-dependent, Rbfox-controlled isoform switching, connecting neuronal depolarization to a shift from NF140 to NF186 splicing.","evidence":"RT-PCR splicing analysis, depolarization experiments in cerebellar granule cells, Rbfox manipulation","pmids":["28900163"],"confidence":"Medium","gaps":["Single-lab finding","Signaling pathway coupling depolarization to splicing not defined"]},{"year":2017,"claim":"Extended NFASC function beyond myelinated axons by implicating it in NSCLC cell motility and actin cytoskeletal remodeling.","evidence":"siRNA knockdown in four NSCLC cell lines with migration assays and actin staining","pmids":["28418179"],"confidence":"Medium","gaps":["Isoform responsible not specified","Molecular link to actin regulation not established"]},{"year":2019,"claim":"Resolved the trafficking-to-immobilization itinerary of NF186, showing vesicular delivery, bidirectional lateral diffusion, and AnkyrinG-dependent capture at the AIS that co-recruits Kv7.3.","evidence":"Live imaging, FRAP, and single-molecule surface diffusion tracking in neurons","pmids":["32903174"],"confidence":"High","gaps":["Trigger that initiates AnkyrinG capture not defined","Relationship to DCX-mediated somatodendritic clearance not integrated"]},{"year":2019,"claim":"Established NFASC as a Mendelian disease gene, with biallelic loss-of-function variants abolishing NF155–CNTN1/Caspr1 binding and causing a neurodevelopmental disorder with central and peripheral demyelination.","evidence":"Exome/genome sequencing across families, patient tissue immunostaining, cell aggregation assays, plus iPSC-neuron protein-stability analysis of a transmembrane variant","pmids":["31501903","30850329"],"confidence":"High","gaps":["Genotype-phenotype correlation across variant classes incomplete","No therapeutic rescue demonstrated"]},{"year":2019,"claim":"Dissected NF155's glial role into two separable functions, preventing mistargeting of myelin to neuronal somata and promoting sheath growth, with only the growth function requiring Caspr.","evidence":"Zebrafish genetic screen, complementary mouse knockout analyses, and time-lapse live imaging","pmids":["31761670"],"confidence":"High","gaps":["Caspr-independent targeting partner not identified","Signaling downstream of NF155 driving growth not defined"]},{"year":2019,"claim":"Defined the pathogenic mechanism of anti-NF155 IgG4 autoantibodies as blockade of paranodal complex assembly with reduced NF155 levels, without competing with contactin-1/Caspr1 binding or driving internalization.","evidence":"Passive transfer in neonates, chronic intrathecal infusion in adults, nerve conduction studies, immunofluorescence, cell aggregation assays; plus a low-confidence single-patient anti-Caspr1 IgG4 study","pmids":["30869655","31753915"],"confidence":"High","gaps":["Precise molecular step blocked by antibody not pinpointed at the time","Anti-Caspr1 finding limited to a single patient"]},{"year":2022,"claim":"Provided the structural basis for paranodal geometry, with crystal structures showing the contactin-1–NF155 Ig1–Ig4 horseshoe sets ~7.4 nm spacing and competing homophilic/heterophilic interfaces tuned by glycosylation and splicing.","evidence":"X-ray crystallography, biophysical binding assays, and cell-clustering assays","pmids":["36329006"],"confidence":"High","gaps":["Caspr1 contribution to the structural complex not visualized","In vivo confirmation of competing interface usage absent"]},{"year":2023,"claim":"Mechanistically separated autoantibody pathogenicity by subclass, showing IgG3 pan-neurofascin antibodies fix complement and are cytotoxic whereas IgG4 NF155 antibodies act without complement.","evidence":"Myelinating DRG co-cultures, complement binding and cytotoxicity assays, ELISA, cell-based assays","pmids":["36346134"],"confidence":"High","gaps":["In vivo correlation of complement effects with clinical severity not established","Access of antibodies to intact nodes in vivo not fully resolved"]},{"year":2025,"claim":"Localized the dominant anti-NF155 IgG4 epitope to the Fn3–Fn4 region, requiring both domains together and explaining isoform selectivity since none reacted with NF186.","evidence":"Flow-cytometric cell-based assay with NF155 truncation variants in HEK293 across 104 patients, with Western blotting","pmids":["40129269"],"confidence":"High","gaps":["Structural map of how the Fn3-Fn4 epitope relates to the contactin-binding interface not provided","Why this epitope is immunogenic unknown"]},{"year":2025,"claim":"Characterized the nanoscale structural pathology of pan-neurofascin nodopathy, showing reduced NF155/Caspr-1 and NF186 density with preserved colocalization and sodium channel distribution, indicating potentially reversible adhesion loss.","evidence":"dSTORM super-resolution imaging of sural nerve biopsy teased fibers","pmids":["40051618"],"confidence":"Medium","gaps":["Single-patient biopsy","Reversibility inferred structurally, not demonstrated functionally"]},{"year":2026,"claim":"Identified an inhibitory-circuit role for AIS NF186, showing it is required for chandelier-cell axon cartridge development with gliomedin serving as the intercellular receptor.","evidence":"Conditional NF186 deletion in pyramidal neurons, immunostaining, synaptic connectivity analysis","pmids":["41260922"],"confidence":"High","gaps":["Downstream signaling driving cartridge assembly not defined","Whether gliomedin engagement at the AIS and at nodes uses identical machinery unclear"]},{"year":null,"claim":"How activity-dependent splicing, isoform-specific trafficking, and adhesion-complex geometry are coordinately controlled across development and disease remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model linking splicing regulators, trafficking adaptors, and structural assembly","Mechanism of reversibility in autoimmune nodopathy not established","Cancer-related NFASC function mechanistically uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,13,9]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[12,7]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[13,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[12,0,8]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,12,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[18,5,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,8]}],"complexes":["paranodal axoglial junction (NF155-contactin-1-Caspr1)","node of Ranvier nodal complex","axon initial segment AnkyrinG complex"],"partners":["CNTN1","CASPR1","ANK3","GLDN","KCNQ3","DCX","NRCAM"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94856","full_name":"Neurofascin","aliases":[],"length_aa":1347,"mass_kda":150.0,"function":"Cell adhesion, ankyrin-binding protein which may be involved in neurite extension, axonal guidance, synaptogenesis, myelination and neuron-glial cell interactions","subcellular_location":"Cell junction, paranodal septate junction","url":"https://www.uniprot.org/uniprotkb/O94856/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NFASC","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NFASC","total_profiled":1310},"omim":[{"mim_id":"618356","title":"NEURODEVELOPMENTAL DISORDER WITH CENTRAL AND PERIPHERAL MOTOR DYSFUNCTION; NEDCPMD","url":"https://www.omim.org/entry/618356"},{"mim_id":"609145","title":"NEUROFASCIN; NFASC","url":"https://www.omim.org/entry/609145"},{"mim_id":"602346","title":"CONTACTIN-ASSOCIATED PROTEIN 1; CNTNAP1","url":"https://www.omim.org/entry/602346"},{"mim_id":"602217","title":"SYNDECAN-BINDING PROTEIN; SDCBP","url":"https://www.omim.org/entry/602217"},{"mim_id":"601581","title":"NEURONAL CELL ADHESION MOLECULE; NRCAM","url":"https://www.omim.org/entry/601581"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":32.2}],"url":"https://www.proteinatlas.org/search/NFASC"},"hgnc":{"alias_symbol":["NRCAML","KIAA0756","FLJ46866","NF"],"prev_symbol":[]},"alphafold":{"accession":"O94856","domains":[{"cath_id":"2.60.40.10","chopping":"39-137","consensus_level":"high","plddt":88.9884,"start":39,"end":137},{"cath_id":"2.60.40.10","chopping":"148-241","consensus_level":"medium","plddt":88.1688,"start":148,"end":241},{"cath_id":"2.60.40.10","chopping":"242-336","consensus_level":"medium","plddt":88.4005,"start":242,"end":336},{"cath_id":"2.60.40.10","chopping":"343-426","consensus_level":"high","plddt":89.2381,"start":343,"end":426},{"cath_id":"2.60.40.10","chopping":"429-440_451-519","consensus_level":"high","plddt":84.541,"start":429,"end":519},{"cath_id":"2.60.40.10","chopping":"524-611","consensus_level":"high","plddt":89.5831,"start":524,"end":611},{"cath_id":"2.60.40.10","chopping":"633-723","consensus_level":"high","plddt":89.2824,"start":633,"end":723},{"cath_id":"2.60.40.10","chopping":"736-820","consensus_level":"high","plddt":89.6644,"start":736,"end":820},{"cath_id":"2.60.40.10","chopping":"831-928","consensus_level":"high","plddt":85.0095,"start":831,"end":928},{"cath_id":"2.60.40.10","chopping":"1120-1204","consensus_level":"medium","plddt":67.1889,"start":1120,"end":1204}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94856","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94856-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94856-F1-predicted_aligned_error_v6.png","plddt_mean":76.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NFASC","jax_strain_url":"https://www.jax.org/strain/search?query=NFASC"},"sequence":{"accession":"O94856","fasta_url":"https://rest.uniprot.org/uniprotkb/O94856.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94856/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94856"}},"corpus_meta":[{"pmid":"31753915","id":"PMC_31753915","title":"Antibodies to neurofascin, contactin-1, and contactin-associated protein 1 in CIDP: Clinical relevance of IgG isotype.","date":"2019","source":"Neurology(R) neuroimmunology & neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/31753915","citation_count":148,"is_preprint":false},{"pmid":"14676309","id":"PMC_14676309","title":"Caspr regulates the processing of contactin and inhibits its binding to neurofascin.","date":"2003","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14676309","citation_count":125,"is_preprint":false},{"pmid":"29187518","id":"PMC_29187518","title":"Neurofascin antibodies in autoimmune, genetic, and idiopathic neuropathies.","date":"2017","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/29187518","citation_count":89,"is_preprint":false},{"pmid":"30869655","id":"PMC_30869655","title":"Anti-Neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivo.","date":"2019","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/30869655","citation_count":83,"is_preprint":false},{"pmid":"22306302","id":"PMC_22306302","title":"Neurofascin: a switch between neuronal plasticity and stability.","date":"2012","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22306302","citation_count":65,"is_preprint":false},{"pmid":"9353344","id":"PMC_9353344","title":"Organization of the neurofascin gene and analysis of developmentally regulated alternative splicing.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9353344","citation_count":53,"is_preprint":false},{"pmid":"34400540","id":"PMC_34400540","title":"IgG1 pan-neurofascin antibodies identify a severe yet treatable neuropathy with a high mortality.","date":"2021","source":"Journal of neurology, neurosurgery, and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/34400540","citation_count":51,"is_preprint":false},{"pmid":"36346134","id":"PMC_36346134","title":"Anti-pan-neurofascin antibodies induce subclass-related complement activation and nodo-paranodal damage.","date":"2023","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36346134","citation_count":50,"is_preprint":false},{"pmid":"31501903","id":"PMC_31501903","title":"Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination.","date":"2019","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31501903","citation_count":47,"is_preprint":false},{"pmid":"24719087","id":"PMC_24719087","title":"Differential stability of PNS and CNS nodal complexes when neuronal neurofascin is lost.","date":"2014","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24719087","citation_count":44,"is_preprint":false},{"pmid":"30582947","id":"PMC_30582947","title":"Anti-neurofascin autoantibody and demyelination.","date":"2018","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/30582947","citation_count":42,"is_preprint":false},{"pmid":"25653379","id":"PMC_25653379","title":"Neurofascin 140 is an embryonic neuronal neurofascin isoform that promotes the assembly of the node of Ranvier.","date":"2015","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25653379","citation_count":41,"is_preprint":false},{"pmid":"34177770","id":"PMC_34177770","title":"Anti-Neurofascin 155 Antibody-Positive Chronic Inflammatory Demyelinating Polyneuropathy/Combined Central and Peripheral Demyelination: Strategies for Diagnosis and Treatment Based on the Disease Mechanism.","date":"2021","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/34177770","citation_count":40,"is_preprint":false},{"pmid":"27053216","id":"PMC_27053216","title":"Quaking Regulates Neurofascin 155 Expression for Myelin and Axoglial Junction Maintenance.","date":"2016","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/27053216","citation_count":40,"is_preprint":false},{"pmid":"22649224","id":"PMC_22649224","title":"Doublecortin (DCX) mediates endocytosis of neurofascin independently of microtubule binding.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22649224","citation_count":40,"is_preprint":false},{"pmid":"31761670","id":"PMC_31761670","title":"Oligodendrocyte Neurofascin Independently Regulates Both Myelin Targeting and Sheath Growth in the CNS.","date":"2019","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/31761670","citation_count":35,"is_preprint":false},{"pmid":"16061393","id":"PMC_16061393","title":"Cell adhesion and neurite outgrowth are promoted by neurofascin NF155 and inhibited by NF186.","date":"2005","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/16061393","citation_count":34,"is_preprint":false},{"pmid":"37060203","id":"PMC_37060203","title":"Clinical profile of autoimmune nodopathy with anti-neurofascin 186 antibody.","date":"2023","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/37060203","citation_count":28,"is_preprint":false},{"pmid":"30850329","id":"PMC_30850329","title":"Neurofascin (NFASC) gene mutation causes autosomal recessive ataxia with demyelinating neuropathy.","date":"2019","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/30850329","citation_count":21,"is_preprint":false},{"pmid":"26218529","id":"PMC_26218529","title":"Contactin-1 and Neurofascin-155/-186 Are Not Targets of Auto-Antibodies in Multifocal Motor Neuropathy.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26218529","citation_count":21,"is_preprint":false},{"pmid":"28418179","id":"PMC_28418179","title":"Copy number variation, increased gene expression, and molecular mechanisms of neurofascin in lung cancer.","date":"2017","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/28418179","citation_count":20,"is_preprint":false},{"pmid":"36329006","id":"PMC_36329006","title":"Structural insights into the contactin 1 - neurofascin 155 adhesion complex.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36329006","citation_count":19,"is_preprint":false},{"pmid":"35313093","id":"PMC_35313093","title":"Clinical and diagnostic features of anti-neurofascin-155 antibody-positive neuropathy in Han Chinese.","date":"2022","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35313093","citation_count":17,"is_preprint":false},{"pmid":"30240176","id":"PMC_30240176","title":"Association of neurofascin IgG4 and atypical chronic inflammatory demyelinating polyneuropathy: A systematic review and meta-analysis.","date":"2018","source":"Brain and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/30240176","citation_count":16,"is_preprint":false},{"pmid":"37639464","id":"PMC_37639464","title":"Pan-Neurofascin autoimmune nodopathy - a life-threatening, but reversible neuropathy.","date":"2023","source":"Current opinion in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/37639464","citation_count":16,"is_preprint":false},{"pmid":"28900163","id":"PMC_28900163","title":"Spatio-temporal and dynamic regulation of neurofascin alternative splicing in mouse cerebellar neurons.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28900163","citation_count":13,"is_preprint":false},{"pmid":"32903174","id":"PMC_32903174","title":"Neurofascin and Kv7.3 are delivered to somatic and axon terminal surface membranes en route to the axon initial segment.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32903174","citation_count":13,"is_preprint":false},{"pmid":"31657126","id":"PMC_31657126","title":"Intrathecal cytokine profile in neuropathy with anti-neurofascin 155 antibody.","date":"2019","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31657126","citation_count":12,"is_preprint":false},{"pmid":"29615965","id":"PMC_29615965","title":"Neurofascin and Compact Myelin Antigen-Specific T Cell Response Pattern in Chronic Inflammatory Demyelinating Polyneuropathy Subtypes.","date":"2018","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/29615965","citation_count":11,"is_preprint":false},{"pmid":"25300139","id":"PMC_25300139","title":"Organisation and control of neuronal connectivity and myelination by cell adhesion molecule neurofascin.","date":"2014","source":"Advances in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/25300139","citation_count":10,"is_preprint":false},{"pmid":"37056784","id":"PMC_37056784","title":"Anti-rituximab antibodies in patients with refractory autoimmune nodopathy with anti-neurofascin-155 antibody.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37056784","citation_count":10,"is_preprint":false},{"pmid":"38171501","id":"PMC_38171501","title":"Clinical Features of Autoimmune Nodopathy With Anti-Neurofascin-155 Antibodies in South Koreans.","date":"2024","source":"Journal of clinical neurology (Seoul, Korea)","url":"https://pubmed.ncbi.nlm.nih.gov/38171501","citation_count":9,"is_preprint":false},{"pmid":"33782779","id":"PMC_33782779","title":"Neurofascin antibodies in chronic inflammatory demyelinating polyradiculoneuropathy: from intrinsic genetic background to clinical manifestations.","date":"2021","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/33782779","citation_count":5,"is_preprint":false},{"pmid":"33998675","id":"PMC_33998675","title":"The prevalence of anti-neurofascin-155 antibodies in patients with neuromyelitis optica spectrum disorders.","date":"2021","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33998675","citation_count":5,"is_preprint":false},{"pmid":"38771386","id":"PMC_38771386","title":"Anti-neurofascin-155 antibody mediated a distinct phenotype of chronic inflammatory demyelinating polyradiculoneuropathy.","date":"2024","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/38771386","citation_count":4,"is_preprint":false},{"pmid":"40051618","id":"PMC_40051618","title":"Super-resolution of nodal and paranodal disruption in anti-pan-neurofascin-associated autoimmune nodopathy.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40051618","citation_count":2,"is_preprint":false},{"pmid":"40969295","id":"PMC_40969295","title":"Clinical characteristics of anti-neurofascin 155 antibody-positive autoimmune nodopathy in children.","date":"2025","source":"Pediatric investigation","url":"https://pubmed.ncbi.nlm.nih.gov/40969295","citation_count":1,"is_preprint":false},{"pmid":"40129269","id":"PMC_40129269","title":"Epitope Mapping of Anti-Neurofascin 155 Antibody in a Large Cohort of Autoimmune Nodopathy Patients.","date":"2025","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/40129269","citation_count":1,"is_preprint":false},{"pmid":"41236406","id":"PMC_41236406","title":"Clinical and Radiological Heterogeneity in Anti-Neurofascin-155 Autoimmune Nodopathy: A Case Series Analysis.","date":"2025","source":"Journal of the peripheral nervous system : JPNS","url":"https://pubmed.ncbi.nlm.nih.gov/41236406","citation_count":0,"is_preprint":false},{"pmid":"41260922","id":"PMC_41260922","title":"The Highly Localized Interaction between Neurofascin-186 and Gliomedin Promotes Subcellular Innervation by the Chandelier Cell.","date":"2026","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/41260922","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"sonnet_model":"claude-sonnet-4-6","sonnet_input_tokens":23315,"sonnet_output_tokens":4860,"sonnet_usd":0.1428,"sonnet_elapsed_seconds":90.4,"stage1_stop_reason":"end_turn"},"stage2":{"opus_model":"claude-opus-4-8","opus_input_tokens":13092,"opus_output_tokens":5288,"opus_usd":0.1977,"opus_elapsed_seconds":59.0,"stage2_stop_reason":"end_turn"},"total_usd":0.3405},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"NF155 binds directly to contactin, but coexpression of Caspr inhibits this interaction by associating with contactin during biosynthesis and promoting a low-molecular-weight, endoglycosidase H-sensitive isoform of contactin at the cell membrane that cannot bind NF155. Deletion of Caspr in mice shifts contactin from the LMw to HMw glycoform, confirming Caspr regulates contactin processing and transport to the cell surface.\",\n      \"method\": \"Cell-based binding assays, co-expression studies, endoglycosidase H treatment, Caspr knockout mice with biochemical fractionation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding assay combined with genetic knockout confirmation and biochemical glycoform analysis, replicated across multiple orthogonal methods\",\n      \"pmids\": [\"14676309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"NF155 promotes neural cell adhesion and neurite outgrowth, and the RGD motif in its third FnIII repeat is critical for cell spreading and neurite outgrowth. Conversely, NF186 inhibits cell adhesion and neurite outgrowth, with inhibition associated with its mucin-like domain.\",\n      \"method\": \"Fc fusion protein binding assays, cell adhesion assays, neurite outgrowth assays with domain-deletion and RGD-mutant constructs\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping with Fc fusion proteins and functional assays in single study, multiple orthogonal readouts\",\n      \"pmids\": [\"16061393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Doublecortin (DCX) promotes endocytosis of neurofascin from soma and dendrites, thereby increasing neurofascin accumulation at the axon initial segment. This endocytic adaptor function is independent of DCX's microtubule-binding activity, and the patient allele DCX-G253D retains microtubule binding but is deficient in promoting neurofascin endocytosis.\",\n      \"method\": \"Live imaging and surface distribution assays in cultured rat neurons, DCX mutant constructs (microtubule-binding mutants, patient allele G253D), endocytosis assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional dissection using multiple DCX mutants with orthogonal readouts (surface distribution, endocytosis), patient allele validation\",\n      \"pmids\": [\"22649224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Inducible ablation of neuronal Neurofascin (Nfasc186) in adult mice causes >99% loss at PNS nodes and 94% loss at CNS nodes. Gliomedin and NrCAM at PNS nodes and brevican at CNS nodes are largely lost, Nav channels persist at nodes with ~40% reduction, and there is a 38% reduction in PNS conduction velocity. Loss of Nfasc186 also provokes CNS paranodal disorganization. This establishes distinct roles for Nfasc186 in node maintenance in PNS vs. CNS.\",\n      \"method\": \"Inducible conditional knockout mice (neuronal-specific Nfasc ablation), immunofluorescence, electrophysiology\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean inducible conditional KO with multiple protein readouts and electrophysiological functional validation\",\n      \"pmids\": [\"24719087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nfasc140 is a neuronal isoform strongly expressed during mouse embryonic development that can cluster voltage-gated sodium channels (Nav) at the developing node of Ranvier and restore electrophysiological function independently of Nfasc155 and Nfasc186. Nfasc140 is re-expressed in demyelinated white matter lesions of multiple sclerosis postmortem brain tissue.\",\n      \"method\": \"Immunostaining of knockout and wild-type mouse nerves, electrophysiology, human MS postmortem tissue immunostaining\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional rescue experiment in a knockout background with electrophysiological validation and human tissue confirmation\",\n      \"pmids\": [\"25653379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The QKI RNA-binding proteins in oligodendrocytes regulate alternative splicing of the Nfasc gene to produce the Nfasc155 isoform. Deletion of QKI in oligodendrocytes results in loss of Nfasc155 and deterioration of axoglial junctions in the spinal cord, leading to demyelination and paralysis.\",\n      \"method\": \"Conditional knockout mice (Olig2-Cre and inducible PLP-CreERT), immunostaining, RNA splicing analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent genetic mouse models (developmental and inducible adult), multiple orthogonal readouts including splicing assays and histology\",\n      \"pmids\": [\"27053216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Alternative splicing of Nfasc is spatio-temporally regulated in cerebellar neurons. High K+-induced depolarization triggers a shift from Nfasc140 to Nfasc186 splicing in cerebellar granule cells. The neural RNA-binding protein Rbfox controls isoform selection at exons 26–29.\",\n      \"method\": \"RT-PCR splicing analysis in mouse brain, depolarization experiments in cerebellar granule cells, Rbfox functional assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional splicing assays with depolarization and Rbfox manipulation, single lab\",\n      \"pmids\": [\"28900163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NFASC silencing in non-small cell lung cancer (NSCLC) cell lines decreased cell migration and caused morphological changes including rearrangements of the actin cytoskeleton and changes in F-actin networks in migrating cells, without affecting proliferation or viability. This identifies NFASC as a regulator of NSCLC cell motility.\",\n      \"method\": \"siRNA knockdown in four NSCLC cell lines, migration assays, actin cytoskeleton staining\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA knockdown with functional readout in multiple cell lines, single lab\",\n      \"pmids\": [\"28418179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Patient-derived anti-Nfasc155 IgG4 antibodies target Nfasc155 on Schwann cell surface, reduce Nfasc155 protein levels, and prevent paranodal complex formation in neonatal animals without inhibiting Nfasc155 binding to contactin-1/CASPR1 or inducing target internalization. Chronic intrathecal infusion in adult animals induces loss of Nfasc155, paranodal specialization disruption, and conduction alterations in motor nerves.\",\n      \"method\": \"Passive transfer experiments in neonatal animals, chronic intrathecal infusion in adult animals, immunofluorescence, nerve conduction studies, cell aggregation assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo passive transfer and intrathecal infusion with multiple functional and structural readouts, patient-derived antibodies\",\n      \"pmids\": [\"30869655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Biallelic loss-of-function variants in NFASC (including a frameshift causing absent Nfasc155 expression and missense variants reducing expression) severely impair Nfasc155–CNTN1/CASPR1 complex interaction in cell aggregation assays, disrupt paranodal junction morphology in myelinated fibers of affected individuals, and cause neurodevelopmental disorder with central and peripheral demyelination.\",\n      \"method\": \"Exome/genome sequencing, immunostaining of patient myelinated fibers, cell aggregation assays, expression studies\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional assays (cell aggregation, patient tissue immunostaining) combined with genetic evidence across six families and multiple orthogonal methods\",\n      \"pmids\": [\"31501903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Anti-Caspr1 IgG4 antibodies can penetrate paranodal regions and disrupt the integrity of the Nfasc155/CNTN1/Caspr1 complex, as shown by intraneural injection and immunohistochemistry on skin biopsy of a single patient.\",\n      \"method\": \"Immunohistochemistry on skin biopsy, intraneural injection, cell aggregation assay\",\n      \"journal\": \"Neurology(R) neuroimmunology & neuroinflammation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preliminary evidence from a single patient, single lab\",\n      \"pmids\": [\"31753915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A homozygous p.V1122E mutation in NFASC affecting a conserved transmembrane domain residue leads to significant loss of Neurofascin protein in iPSC-derived neurons from affected siblings, establishing this residue as critical for protein stability.\",\n      \"method\": \"iPSC-derived neurons from patients, immunostaining for Neurofascin protein levels\",\n      \"journal\": \"Parkinsonism & related disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — iPSC-derived neuron model with protein loss confirmed, single lab\",\n      \"pmids\": [\"30850329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Neurofascin186 is transported to the soma and axon terminal via vesicles that fuse with the plasma membrane; after insertion, Nfasc186 is highly mobile in the axonal membrane and diffuses bidirectionally until immobilized at the axon initial segment through interaction with AnkyrinG. Kv7.3 is recruited to the AIS by the same mechanism.\",\n      \"method\": \"Live imaging (time-lapse fluorescence microscopy), FRAP, surface diffusion tracking in neurons\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live imaging with FRAP and single-molecule tracking, direct mechanistic characterization of trafficking and immobilization\",\n      \"pmids\": [\"32903174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structures of the contactin 1–NF155 adhesion complex reveal that conserved Ig1–2 interfaces form competing heterophilic contactin 1–NF155 and homophilic NF155 complexes. The Ig1–Ig4 horseshoe structure of the complex defines the ~7.4 nm paranodal spacing. Post-translational glycosylation and splice differences modulate complex formation. Contactin 1 also forms low-affinity clusters through Ig3–6 interfaces.\",\n      \"method\": \"X-ray crystallography, biophysical binding assays, cell-clustering assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of both individual and complexed proteins validated by biophysical and cell-clustering assays\",\n      \"pmids\": [\"36329006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Anti-pan-neurofascin antibodies (recognizing all NF isoforms) have direct access to nodes of Ranvier in myelinating dorsal root ganglia co-cultures and impair paranode formation, cause destruction of paranodal architecture, and alter paranodal myelin and sensory neurons in a titre-dependent manner. IgG3 subclass pan-neurofascin antibodies bind complement and exert cytotoxic effects in vitro, distinct from IgG4 NF155 antibodies which do not activate complement.\",\n      \"method\": \"Myelinating DRG co-cultures, immunofluorescence, complement binding and cytotoxicity assays, ELISA, cell-based assays\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vitro functional assays with mechanistic dissection of IgG subclass effects, multicentre study\",\n      \"pmids\": [\"36346134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Super-resolution imaging (dSTORM) of anti-pan-neurofascin nodopathy nerve biopsy reveals decreased NF155 and Caspr-1 density at paranodes and decreased NF186 density at nodes with preserved colocalization of adhesion proteins and intact sodium channel distribution. Axonal beta-IV spectrin is altered only in severely damaged nodes, indicating largely preserved axonal integrity with potentially reversible decreases in nodal/paranodal adhesion proteins.\",\n      \"method\": \"dSTORM super-resolution fluorescence microscopy on sural nerve biopsy teased fibers\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — advanced imaging method (dSTORM) providing nanoscale structural data, but single patient biopsy\",\n      \"pmids\": [\"40051618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The epitope for anti-NF155 IgG4 autoantibodies in autoimmune nodopathy patients is located in the Fn3-Fn4 region (third to fourth fibronectin type III domain) of NF155 but not in the Fn3 or Fn4 domains alone. Autoantibodies in 104/104 anti-NF155+ patients bound Fn3-Fn4, and none reacted with NF186.\",\n      \"method\": \"Flow cytometric cell-based assay with truncation variants of NF155 stably/transiently expressed in HEK293 cells, Western blotting\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic domain mapping with multiple truncation constructs in a large cohort (104 patients), replicated by Western blotting\",\n      \"pmids\": [\"40129269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NF186 at the axon initial segment (AIS) of pyramidal neurons is necessary for chandelier cells (ChCs) to develop synaptic axon cartridges along the AIS. Gliomedin, a known NF186 receptor at nodes of Ranvier, is preferentially expressed in ChCs and mediates ChC axon cartridge development by acting as a major receptor for NF186 at the AIS.\",\n      \"method\": \"Conditional knockout mice (NF186 deletion in pyramidal neurons), immunostaining, synaptic connectivity analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic knockout with specific cellular phenotype, identification of NF186-Gliomedin as the intercellular ligand-receptor pair mediating chandelier cell synapse formation\",\n      \"pmids\": [\"41260922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Oligodendrocyte Neurofascin (Nfasc155) regulates two independent aspects of CNS myelination: (1) it prevents mistargeting of myelin to neuronal cell bodies (myelin targeting), and (2) it promotes myelin sheath growth. Disruption of Caspr (the neuronal binding partner of oligodendrocyte Neurofascin) impairs myelin sheath growth but does not affect myelin targeting, indicating these two functions are separable.\",\n      \"method\": \"Genetic screen in zebrafish, complementary knockout analyses in mice, time-lapse live imaging\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent model organisms (zebrafish genetic screen + mouse KO) with time-lapse imaging providing mechanistic dissection of targeting vs. growth functions\",\n      \"pmids\": [\"31761670\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Neurofascin (NFASC) is a multi-isoform immunoglobulin superfamily cell adhesion molecule whose isoforms (NF186, NF155, NF140) play distinct, context-dependent roles: NF186 anchors voltage-gated sodium channels and the nodal complex at nodes of Ranvier and the axon initial segment (AIS) via AnkyrinG after lateral membrane diffusion, interacts with Gliomedin to mediate chandelier cell synapse formation at the AIS, and its loss destabilizes nodal proteins differentially in PNS versus CNS; NF155, whose alternative splicing is regulated by QKI RNA-binding proteins and Rbfox, binds directly to contactin-1 at the Fn3-Fn4 domain interface (defined by X-ray crystal structure) to form paranodal axoglial junctions at a defined 7.4 nm spacing, with Caspr regulating contactin processing to control this interaction; NF140 is an embryonic neuronal isoform that can cluster Nav channels at nascent nodes and is re-expressed after demyelination; and pathogenic autoantibodies targeting these isoforms disrupt paranodal complex formation and node integrity in autoimmune nodopathies through IgG4-mediated complex blockade or IgG1/IgG3-mediated complement activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Neurofascin (NFASC) is an immunoglobulin-superfamily cell adhesion molecule that organizes the molecular architecture of myelinated axons, producing distinct isoforms through spatio-temporally regulated alternative splicing that serve separable roles at the node of Ranvier, paranode, and axon initial segment (AIS) [#3, #6]. The glial isoform NF155 binds directly to a contactin-1/Caspr1 complex to assemble paranodal axoglial junctions; crystallography of the contactin-1–NF155 adhesion complex defines an Ig1–Ig4 horseshoe architecture that sets the characteristic ~7.4 nm paranodal spacing, with competing heterophilic and homophilic interfaces and glycosylation/splice differences tuning complex formation [#13]. Caspr controls this interaction by regulating contactin glycoform processing and surface transport during biosynthesis [#0], and NF155 production depends on QKI-mediated splicing in oligodendrocytes, whose loss collapses axoglial junctions and causes demyelination [#5]; NF155 separately governs both correct myelin targeting and myelin sheath growth [#18]. The neuronal isoform NF186 traffics to the membrane and diffuses laterally until immobilized at the AIS through AnkyrinG, where it also recruits Kv7.3 [#12], is endocytically concentrated to the AIS via the adaptor Doublecortin [#2], maintains nodal complexes differentially in PNS versus CNS [#3], and serves as the AIS receptor for gliomedin to direct chandelier-cell synapse formation [#17]. The embryonic isoform NF140 independently clusters Nav channels at nascent nodes and is re-expressed in demyelinated multiple sclerosis lesions [#4]. Biallelic loss-of-function NFASC variants that abolish or destabilize NF155 disrupt paranodal junctions and cause a neurodevelopmental disorder with central and peripheral demyelination [#9, #11]. NFASC isoforms are also targets of pathogenic autoantibodies in autoimmune nodopathies, where IgG4 antibodies against an NF155 Fn3–Fn4 epitope block paranodal assembly without complement activation, whereas IgG3 pan-neurofascin antibodies fix complement and are cytotoxic [#8, #16, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that paranodal assembly is gated upstream of NF155 binding by Caspr-dependent control of contactin maturation, explaining how the adhesion partner is licensed for surface engagement.\",\n      \"evidence\": \"Cell-based binding assays, co-expression, endoglycosidase H treatment, and Caspr knockout mice with biochemical fractionation\",\n      \"pmids\": [\"14676309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of the NF155-contactin contact\", \"Did not address how the complex achieves defined paranodal geometry\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Distinguished opposing cell-biological activities of the two major isoforms, mapping NF155 adhesion/neurite outgrowth to an RGD motif and NF186 anti-adhesive activity to its mucin-like domain.\",\n      \"evidence\": \"Fc fusion protein binding, cell adhesion and neurite outgrowth assays with domain-deletion and RGD-mutant constructs\",\n      \"pmids\": [\"16061393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-study domain mapping not confirmed in vivo\", \"RGD-mediated partner identity not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a trafficking mechanism for AIS enrichment of neurofascin, showing DCX acts as an endocytic adaptor clearing somatodendritic neurofascin independently of its microtubule role.\",\n      \"evidence\": \"Live imaging and surface-distribution assays in cultured rat neurons with DCX microtubule and patient-allele (G253D) mutants\",\n      \"pmids\": [\"22649224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular bridge between DCX and the endocytic machinery not defined\", \"Relationship to AnkyrinG immobilization not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined NF186 as a maintenance factor with PNS/CNS-distinct dependencies, showing nodal complex proteins are differentially destabilized while Nav channels partially persist.\",\n      \"evidence\": \"Inducible neuronal-specific conditional knockout mice with immunofluorescence and electrophysiology\",\n      \"pmids\": [\"24719087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism underlying differential PNS vs CNS protein stability unresolved\", \"Did not separate nodal from paranodal contributions\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a developmentally expressed NF140 isoform capable of independently clustering Nav channels and re-expressed in MS lesions, expanding isoform-specific node assembly mechanisms.\",\n      \"evidence\": \"Immunostaining of KO and WT mouse nerves, electrophysiology, and human MS postmortem tissue staining\",\n      \"pmids\": [\"25653379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Partner that recruits NF140 to nascent nodes not identified\", \"Functional consequence of MS-lesion re-expression unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked NF155 isoform production to glial RNA processing, establishing QKI-dependent alternative splicing as required for axoglial junction integrity.\",\n      \"evidence\": \"Conditional (Olig2-Cre, inducible PLP-CreERT) knockout mice with immunostaining and splicing analysis\",\n      \"pmids\": [\"27053216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct QKI binding sites on Nfasc pre-mRNA not mapped\", \"Whether QKI regulates other myelin transcripts contributing to phenotype not isolated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated activity-dependent, Rbfox-controlled isoform switching, connecting neuronal depolarization to a shift from NF140 to NF186 splicing.\",\n      \"evidence\": \"RT-PCR splicing analysis, depolarization experiments in cerebellar granule cells, Rbfox manipulation\",\n      \"pmids\": [\"28900163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Signaling pathway coupling depolarization to splicing not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended NFASC function beyond myelinated axons by implicating it in NSCLC cell motility and actin cytoskeletal remodeling.\",\n      \"evidence\": \"siRNA knockdown in four NSCLC cell lines with migration assays and actin staining\",\n      \"pmids\": [\"28418179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Isoform responsible not specified\", \"Molecular link to actin regulation not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the trafficking-to-immobilization itinerary of NF186, showing vesicular delivery, bidirectional lateral diffusion, and AnkyrinG-dependent capture at the AIS that co-recruits Kv7.3.\",\n      \"evidence\": \"Live imaging, FRAP, and single-molecule surface diffusion tracking in neurons\",\n      \"pmids\": [\"32903174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger that initiates AnkyrinG capture not defined\", \"Relationship to DCX-mediated somatodendritic clearance not integrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established NFASC as a Mendelian disease gene, with biallelic loss-of-function variants abolishing NF155–CNTN1/Caspr1 binding and causing a neurodevelopmental disorder with central and peripheral demyelination.\",\n      \"evidence\": \"Exome/genome sequencing across families, patient tissue immunostaining, cell aggregation assays, plus iPSC-neuron protein-stability analysis of a transmembrane variant\",\n      \"pmids\": [\"31501903\", \"30850329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype correlation across variant classes incomplete\", \"No therapeutic rescue demonstrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Dissected NF155's glial role into two separable functions, preventing mistargeting of myelin to neuronal somata and promoting sheath growth, with only the growth function requiring Caspr.\",\n      \"evidence\": \"Zebrafish genetic screen, complementary mouse knockout analyses, and time-lapse live imaging\",\n      \"pmids\": [\"31761670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Caspr-independent targeting partner not identified\", \"Signaling downstream of NF155 driving growth not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the pathogenic mechanism of anti-NF155 IgG4 autoantibodies as blockade of paranodal complex assembly with reduced NF155 levels, without competing with contactin-1/Caspr1 binding or driving internalization.\",\n      \"evidence\": \"Passive transfer in neonates, chronic intrathecal infusion in adults, nerve conduction studies, immunofluorescence, cell aggregation assays; plus a low-confidence single-patient anti-Caspr1 IgG4 study\",\n      \"pmids\": [\"30869655\", \"31753915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise molecular step blocked by antibody not pinpointed at the time\", \"Anti-Caspr1 finding limited to a single patient\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided the structural basis for paranodal geometry, with crystal structures showing the contactin-1–NF155 Ig1–Ig4 horseshoe sets ~7.4 nm spacing and competing homophilic/heterophilic interfaces tuned by glycosylation and splicing.\",\n      \"evidence\": \"X-ray crystallography, biophysical binding assays, and cell-clustering assays\",\n      \"pmids\": [\"36329006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Caspr1 contribution to the structural complex not visualized\", \"In vivo confirmation of competing interface usage absent\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mechanistically separated autoantibody pathogenicity by subclass, showing IgG3 pan-neurofascin antibodies fix complement and are cytotoxic whereas IgG4 NF155 antibodies act without complement.\",\n      \"evidence\": \"Myelinating DRG co-cultures, complement binding and cytotoxicity assays, ELISA, cell-based assays\",\n      \"pmids\": [\"36346134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo correlation of complement effects with clinical severity not established\", \"Access of antibodies to intact nodes in vivo not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Localized the dominant anti-NF155 IgG4 epitope to the Fn3–Fn4 region, requiring both domains together and explaining isoform selectivity since none reacted with NF186.\",\n      \"evidence\": \"Flow-cytometric cell-based assay with NF155 truncation variants in HEK293 across 104 patients, with Western blotting\",\n      \"pmids\": [\"40129269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural map of how the Fn3-Fn4 epitope relates to the contactin-binding interface not provided\", \"Why this epitope is immunogenic unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Characterized the nanoscale structural pathology of pan-neurofascin nodopathy, showing reduced NF155/Caspr-1 and NF186 density with preserved colocalization and sodium channel distribution, indicating potentially reversible adhesion loss.\",\n      \"evidence\": \"dSTORM super-resolution imaging of sural nerve biopsy teased fibers\",\n      \"pmids\": [\"40051618\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-patient biopsy\", \"Reversibility inferred structurally, not demonstrated functionally\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified an inhibitory-circuit role for AIS NF186, showing it is required for chandelier-cell axon cartridge development with gliomedin serving as the intercellular receptor.\",\n      \"evidence\": \"Conditional NF186 deletion in pyramidal neurons, immunostaining, synaptic connectivity analysis\",\n      \"pmids\": [\"41260922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling driving cartridge assembly not defined\", \"Whether gliomedin engagement at the AIS and at nodes uses identical machinery unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How activity-dependent splicing, isoform-specific trafficking, and adhesion-complex geometry are coordinately controlled across development and disease remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model linking splicing regulators, trafficking adaptors, and structural assembly\", \"Mechanism of reversibility in autoimmune nodopathy not established\", \"Cancer-related NFASC function mechanistically uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 13, 9]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [12, 7]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [13, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [12, 0, 8]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 12, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [18, 5, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 8]}\n    ],\n    \"complexes\": [\"paranodal axoglial junction (NF155-contactin-1-Caspr1)\", \"node of Ranvier nodal complex\", \"axon initial segment AnkyrinG complex\"],\n    \"partners\": [\"CNTN1\", \"CASPR1\", \"ANK3\", \"GLDN\", \"KCNQ3\", \"DCX\", \"NRCAM\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win"}}