Affinage

LGI1

Leucine-rich glioma-inactivated protein 1 · UniProt O95970

Length
557 aa
Mass
63.8 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LGI1 is a secreted neuronal glycoprotein that organizes a transsynaptic protein complex controlling synaptic strength and intrinsic neuronal excitability, and whose loss of function causes epilepsy (PMID:15857855, PMID:20133599). Secreted wild-type LGI1 bridges presynaptic ADAM23/Kv1 channel complexes and postsynaptic ADAM22/AMPA receptor scaffolds, and genetic deletion of LGI1 in mice produces lethal epilepsy that is rescued by neuronal LGI1 but not LGI3 (PMID:20133599). Through ADAM22, LGI1 instructs PSD-95-family MAGUKs to condense transsynaptic nanodomains that align Kv1 channels, NMDA/AMPA receptors and adhesion molecules, and this ADAM22-MAGUK linkage is required for PSD-95 to potentiate AMPA receptor-mediated transmission (PMID:26178195, PMID:33397806); the LGI1-ADAM22 complex is further stabilized by PKA-dependent phosphorylation of ADAM22 and 14-3-3 binding that protects it from endocytic degradation (PMID:34910912). Presynaptically, LGI1 is a subunit of Kv1.1-containing channels and prevents Kvβ1-mediated N-type inactivation, and LGI1 deficiency post-transcriptionally reduces Kv1.1/Kv1.2 density at the axon initial segment, lowering D-type current and raising excitability (PMID:16504945, PMID:28673977). The crystal structure of the LGI1-ADAM22 complex defines a 2:2 heterotetramer in which the EPTP domain binds the ADAM22 metalloprotease-like domain while the LRR and EPTP domains mediate LGI1 dimerization (PMID:29670100). Autosomal dominant lateral temporal epilepsy mutations act either by blocking LGI1 secretion or by abolishing ADAM22/23 binding and higher-order assembly without affecting secretion (PMID:15857855, PMID:27760137, PMID:29670100), and limbic encephalitis patient autoantibodies against the LRR or EPTP domains disrupt LGI1-ADAM22/23 interactions or internalize the complex, reducing Kv1.1 and AMPA receptors and producing hyperexcitability, impaired LTP and reversible memory deficits (PMID:30346486, PMID:32437528). Beyond the nervous system, LGI1 binds the oligodendrocyte receptor OPALIN to promote myelination (PMID:39083419), and was originally identified as a candidate glioma tumor suppressor that, when re-expressed, suppresses proliferation and invasion via ERK1/2 inhibition (PMID:9879993, PMID:12821932).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1998 Medium

    Established LGI1 as a leucine-rich-repeat protein and candidate tumor suppressor, the first functional clue to the gene before its neuronal role was known.

    Evidence Positional cloning and expression analysis in glioblastoma cell lines and gliomas

    PMID:9879993

    Open questions at the time
    • No mechanism for tumor suppression defined
    • Neuronal function not yet addressed
  2. 2004 Medium

    Showed LGI1 re-expression suppresses glioma malignancy through MAPK signaling, providing the first mechanistic pathway for its tumor-suppressor activity.

    Evidence Gain-of-function transfection in null glioma lines with proliferation/invasion assays and ERK1/2-AKT pathway analysis

    PMID:12821932 PMID:15047712

    Open questions at the time
    • Cell-line-based, no in vivo tumor model
    • Relationship to neuronal ADAM-receptor signaling unclear
  3. 2002 Medium

    Linked LGI1 to human disease by showing truncating mutations segregate with autosomal dominant lateral temporal epilepsy, reframing the gene as neurological.

    Evidence Mutation analysis in epilepsy families and brain immunohistochemistry

    PMID:11978770

    Open questions at the time
    • Pathogenic mechanism of mutations unknown
    • Molecular partners undefined
  4. 2005 High

    Defined secretion failure as a primary pathogenic mechanism, showing wild-type LGI1 is secreted while many ADPEAF mutants are retained or unstable.

    Evidence Secretion assays of wild-type and mutant LGI1 in HEK293T cells

    PMID:15857855

    Open questions at the time
    • Did not identify a receptor or downstream effector
    • Secretion-competent disease mutants not yet explained
  5. 2006 High

    Identified the receptor and synaptic output of LGI1 — ADAM22 binding enhances AMPA transmission and disease mutants fail to bind — and revealed LGI1 as a Kv1.1 channel subunit that blocks N-type inactivation.

    Evidence Co-IP, hippocampal slice electrophysiology, Kv1.1 complex co-purification/proteomics and mutant analysis

    PMID:16504945 PMID:16990550 PMID:17067999

    Open questions at the time
    • Whether ADAM22 was the sole receptor unresolved
    • Pre- vs postsynaptic site of action unclear
  6. 2009 High

    Expanded the receptor repertoire to multiple ADAM family members and established ADAM23 as the high-affinity partner regulating neurite outgrowth and seizure threshold.

    Evidence IP/MS from brain, unbiased binding screen, neurite assays in ADAM23-/- neurons, in vivo seizure monitoring

    PMID:18974846 PMID:19796686

    Open questions at the time
    • Distinct roles of ADAM22 vs ADAM23 not separated
    • Mechanism of outgrowth promotion undefined
  7. 2010 High

    Demonstrated in vivo that LGI1 organizes a transsynaptic complex linking presynaptic ADAM23/Kv1 to postsynaptic ADAM22/AMPA scaffolds, with knockout causing lethal epilepsy rescued specifically by neuronal LGI1.

    Evidence LGI1 knockout/transgenic rescue, transsynaptic complex co-IP, electrophysiology

    PMID:20133599

    Open questions at the time
    • Molecular details of scaffold organization not resolved
    • Cell types secreting functional LGI1 not defined
  8. 2010 Medium

    Reported an additional ligand role for LGI1 as an NgR1 antagonist of myelin growth inhibition, with NgR1-ADAM22 forming a receptor complex.

    Evidence Myelin substrate growth assays, growth cone collapse, co-IP of NgR1-ADAM22

    PMID:20463223

    Open questions at the time
    • Relationship of NgR1 axis to synaptic functions unclear
    • Single-lab finding
  9. 2012 High

    Showed LGI1 dose bidirectionally controls developmental retinogeniculate axon pruning and single-fiber strengthening, extending its role to circuit refinement.

    Evidence Mutant and overexpression transgenic mice, retinogeniculate electrophysiology and anatomy

    PMID:22262888

    Open questions at the time
    • Receptor mediating pruning effect not identified
    • Link to ADAM22/23 transsynaptic complex not tested
  10. 2014 High

    Localized the protective source of LGI1 to glutamatergic neurons, since deletion there but not in PV interneurons caused seizures.

    Evidence Cell-type-specific conditional knockouts with EEG and seizure threshold testing

    PMID:25234641

    Open questions at the time
    • Pre- vs postsynaptic mechanism in excitatory neurons not separated
  11. 2015 High

    Defined the postsynaptic logic of LGI1-ADAM22 signaling: it enables mature PSD-95, but not SAP102, to modulate synaptic strength, identifying a MAGUK-specific maturation switch.

    Evidence Slice electrophysiology with ADAM22 domain mutants and viral replacement in LGI1-null neurons

    PMID:26178195

    Open questions at the time
    • Structural basis of ADAM22-MAGUK coupling unknown
    • How PSD-95 is selectively engaged unresolved
  12. 2013 High

    Established the autoimmune mechanism of limbic encephalitis by showing EPTP-targeting autoantibodies block LGI1-ADAM22/23 binding and reversibly reduce synaptic AMPA receptors.

    Evidence ELISA, co-IP, hippocampal neuron cultures, LGI1 knockout analysis

    PMID:24227725

    Open questions at the time
    • Effect on Kv1.1 not yet examined
    • In vivo behavioral consequences untested
  13. 2016 High

    Resolved the post-transcriptional and presynaptic arms of LGI1 function, showing it maintains AIS Kv1 channel density/D-current and negatively modulates presynaptic glutamate release before seizures, and identified secretion-competent mutants that fail receptor binding as a second loss-of-function class.

    Evidence D-type current recordings with recombinant LGI1, pre-seizure slice electrophysiology, and co-IP/modeling of S473L and R474Q mutants

    PMID:26878798 PMID:27760137 PMID:28673977

    Open questions at the time
    • Molecular machinery setting Kv1 density at the AIS undefined
    • How presynaptic and postsynaptic roles are coordinated unclear
  14. 2018 High

    Provided the atomic and in vivo basis of complex assembly — a 2:2 LGI1-ADAM22 heterotetramer with LGI1 dimerization — and demonstrated that disrupting LGI1 binding/internalization underlies both genetic and autoimmune disease.

    Evidence X-ray crystallography with R474Q knock-in mouse, and patient-IgG passive transfer with electrophysiology and behavior

    PMID:29670100 PMID:30346486

    Open questions at the time
    • Higher-order assembly stoichiometry in vivo not fully defined
    • Trafficking determinants of the complex not addressed
  15. 2019 High

    Showed ADAM22/23 reciprocally control LGI1 trafficking — promoting ER export, surface expression, axonal co-transport and AIS recruitment — explaining how the complex is delivered to functional sites.

    Evidence Live-cell axonal transport imaging and immunofluorescence with ADLTE mutants in hippocampal neurons

    PMID:30598502

    Open questions at the time
    • Vesicular trafficking machinery not identified
    • Single-lab imaging study
  16. 2020 High

    Dissected autoantibody mechanisms into domain-specific classes: LRR-directed antibodies internalize the complex and impair memory via Kv1.1, while EPTP-directed antibodies block ADAM22/23 docking, with both abolishing LTP.

    Evidence Patient-derived monoclonal antibodies, cell-based assays, intrahippocampal injection, LTP and behavior, plus CSF-derived mAb slice electrophysiology and pharmacological Kv1.1 block

    PMID:31900946 PMID:32437528 PMID:36078121

    Open questions at the time
    • Relative contribution of each antibody class in patients unknown
    • Long-term structural consequences of internalization undefined
  17. 2021 High

    Established that LGI1-ADAM22 instructs PSD-95-family MAGUKs to condense transsynaptic nanodomains, and that PKA phosphorylation/14-3-3 binding stabilizes the complex against degradation, with quantitative thresholds for epilepsy prevention.

    Evidence ADAM22-MAGUK-deficient knock-in mice, super-resolution microscopy, non-neuronal reconstitution, and structural/biochemical PTM analysis with hypomorphic mouse series

    PMID:33397806 PMID:34910912

    Open questions at the time
    • Physiological signals driving PKA-dependent stabilization in vivo unclear
    • How nanodomain condensation translates to channel/receptor density unresolved
  18. 2024 High

    Extended LGI1 signaling beyond neurons by identifying OPALIN as its oligodendrocyte receptor required for myelination, with binding-deficient OPALIN failing to rescue hypomyelination.

    Evidence LGI1 affinity chromatography/MS, conditional OPALIN knockout phenocopy, binding-deficient mutant rescue

    PMID:39083419

    Open questions at the time
    • Downstream OPALIN signaling in oligodendrocytes undefined
    • Whether ADAM receptors participate in the myelination axis unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple LGI1 receptor axes (ADAM22/23 synaptic, NgR1, OPALIN myelination) are integrated and differentially deployed across cell types and development remains unresolved.
  • No unified model linking synaptic, axon-guidance and myelination functions
  • Signal-transduction events downstream of LGI1 binding largely uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2
Partners
ADAM11ADAM22ADAM23DLG4KCNA1OPALINRTN4RYWHA (14-3-3)
Complex memberships
LGI1-ADAM22 (2:2 heterotetramer)presynaptic Kv1.1 channel complextranssynaptic ADAM23/Kv1 - ADAM22/PSD-95-AMPA complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 LGI1 encodes a ~60 kDa protein containing leucine-rich repeats; the gene is rearranged and its expression is absent in glioblastoma cell lines and significantly reduced in malignant gliomas, establishing it as a candidate tumor suppressor at 10q24. Positional cloning, immunohistochemistry, expression analysis in glioblastoma cell lines Oncogene Medium 9879993
2002 Mutations in LGI1 (including premature stop codons) segregate with autosomal dominant lateral temporal epilepsy (EPT/ADLTE), and LGI1 protein is expressed ubiquitously in neuronal cell bodies of the brain. Mutation analysis in epilepsy families, immunohistochemistry Human molecular genetics Medium 11978770
2005 Wild-type LGI1 is a secreted protein; ADPEAF-linked mutations cause either failure of secretion or protein instability, establishing loss of secretion as the pathogenic mechanism for this epilepsy. Transfection of HEK293T cells, secretion assay for wild-type and mutant LGI1 constructs Human molecular genetics High 15857855
2006 ADAM22, a transmembrane protein whose mutation causes seizures, serves as a receptor for secreted LGI1. LGI1 binding to ADAM22 enhances AMPA receptor-mediated synaptic transmission in hippocampal slices; ADPEAF-causing mutant LGI1 fails to bind ADAM22. Co-immunoprecipitation, electrophysiology in rat hippocampal slices, binding assay with mutant LGI1 Science High 16990550
2006 LGI1 is a novel subunit of presynaptic Kv1.1-containing channel complexes in hippocampal axon terminals, where it selectively prevents N-type inactivation mediated by the Kvβ1 subunit; ADLTE-associated LGI1 mutants fail to prevent this inactivation, resulting in channels with rapid inactivation kinetics. Biochemical co-purification/proteomics of Kv1.1 complexes from rat brain, electrophysiology, analysis of disease mutants Neuron High 16504945
2006 LGI1 is expressed as two isoforms (~60 and ~65 kDa) that reside in different subcellular compartments; the long isoform is secreted while the short isoform is retained intracellularly. ADLTE mutants of the long form are retained in the ER and Golgi. Secreted LGI1 specifically binds to the cell surface of differentiated PC12 cells. Subcellular fractionation, immunocytochemistry, secretion assays in transfected cells, cell surface binding assay Human molecular genetics High 17067999
2008 LGI1 binds to ADAM22, ADAM23, and ADAM11, but not ADAM12, establishing that ADAM22 is not the sole receptor for LGI1 and that the LGI-ADAM interaction system involves multiple ADAM family members. Immunoprecipitation and mass spectrometric analysis from mouse brain, quantitative cell-ELISA binding assays International journal of biological sciences Medium 18974846
2009 ADAM23 is identified as the primary high-affinity LGI1-binding protein in an unbiased brain screen. LGI1 binding to ADAM23 promotes neurite outgrowth; ADAM23-null neurons show reduced dendritic arborization and ADAM23-null mice exhibit spontaneous seizures and decreased seizure thresholds. Unbiased brain binding screen, neurite outgrowth assays in wild-type vs. ADAM23-/- neurons, in vivo seizure monitoring Molecular and cellular neurosciences High 19796686
2010 LGI1-/- mice develop lethal epilepsy rescued specifically by neuronal LGI1 transgene but not LGI3. Extracellularly secreted LGI1 organizes a transsynaptic protein complex linking presynaptic ADAM23/Kv1 channels and postsynaptic ADAM22/AMPA receptor scaffolds; loss of LGI1 selectively reduces AMPA receptor-mediated synaptic transmission in hippocampus. Genetic knockout and transgenic rescue, co-immunoprecipitation of transsynaptic complex, electrophysiology Proceedings of the National Academy of Sciences of the United States of America High 20133599
2010 LGI1 functions as a specific Nogo receptor 1 (NgR1) ligand that antagonizes myelin-based growth inhibition. NgR1 and ADAM22 physically associate to form a receptor complex in which NgR1 facilitates LGI1 binding to ADAM22. Neuronal growth assays on myelin substrates, growth cone collapse assay, pulldown/co-immunoprecipitation of NgR1-ADAM22 complex The Journal of neuroscience Medium 20463223
2012 LGI1 regulates postnatal pruning of retinal axons in the visual relay thalamus; mutant truncated LGI1 (836delC) blocks retinogeniculate axon pruning and arrests normal single-fiber strengthening, while excess wild-type LGI1 accelerates both processes. Transgenic mouse models expressing mutant or wild-type LGI1, retinogeniculate synapse electrophysiology and anatomical analysis The Journal of neuroscience High 22262888
2013 LGI1 autoantibodies from limbic encephalitis patients target the EPTP repeat domain of LGI1, specifically inhibit LGI1-ADAM22/23 interaction, and reversibly reduce synaptic AMPA receptor clusters in hippocampal neurons. Disruption of the LGI1-ADAM22 interaction alone (by soluble ADAM22 ectodomain) is sufficient to reduce synaptic AMPA receptors. LGI1 knockout mice show greatly reduced hippocampal AMPA receptor levels. ELISA, co-immunoprecipitation, rat hippocampal neuron cultures, LGI1 knockout mouse analysis The Journal of neuroscience High 24227725
2014 Selective deletion of LGI1 in glutamatergic pyramidal neurons (Emx1-Cre or CaMKIIα-Cre) causes spontaneous seizures, whereas deletion in GABAergic parvalbumin interneurons does not alter seizure thresholds, establishing that LGI1 secreted from excitatory neurons is required for epilepsy prevention. Conditional knockout mice with cell-type specific Cre drivers, EEG monitoring, convulsant seizure threshold testing Brain High 25234641
2015 LGI1 acts as a paracrine signal from both pre- and postsynaptic neurons, functioning specifically through ADAM22 to set postsynaptic strength. ADAM22 maintains excitatory synapses through PDZ domain interactions. In the absence of LGI1, the mature scaffolding protein PSD-95 cannot modulate synaptic transmission, but SAP102 function is unaffected, revealing that LGI1-ADAM22 coordinates synapse maturation by regulating PSD-95 function. Hippocampal slice electrophysiology, molecular replacement with ADAM22 mutants, viral expression constructs in LGI1-null neurons Proceedings of the National Academy of Sciences of the United States of America High 26178195
2016 LGI1 deficiency (>50% down-regulation) causes posttranscriptional reduction of axonal Kv1.1 and Kv1.2 channel density at the axon initial segment of hippocampal CA3 neurons, reducing D-type potassium current and intrinsic excitability control; recombinant LGI1 restores Kv1 channel density and D-current. Electrophysiology (D-type current recording), immunofluorescence, recombinant LGI1 application, LGI1 knockout and heterozygous mice Proceedings of the National Academy of Sciences of the United States of America High 28673977
2016 LGI1 acts presynaptically as a negative modulator of excitatory synaptic transmission during early postnatal development; LGI1 deficiency causes increased presynaptic glutamate release without altering postsynaptic AMPA receptor activity, leading to hyperexcitable networks before seizure onset. Electrophysiology in hippocampal slices from Lgi1-/- mice at pre-seizure stages, postsynaptic AMPA receptor recording, morphological analysis Scientific reports High 26878798
2016 LGI1 missense mutations S473L and R474Q (secretion-positive) fail to interact with ADAM22 and ADAM23 on the cell surface, establishing a second loss-of-function mechanism (impaired receptor binding) distinct from secretion failure. Immunofluorescence, co-immunoprecipitation with cell-surface ADAM22/23, 3D protein modeling PLoS genetics High 27760137
2018 Crystal structure of the human LGI1-ADAM22 complex reveals a 2:2 heterotetrameric assembly: the hydrophobic pocket of LGI1's C-terminal EPTP domain binds to the metalloprotease-like domain of ADAM22; LGI1's LRR and EPTP domains mediate LGI1-LGI1 dimerization. Pathogenic R474Q mutation disrupts the LGI1-LGI1 interface and the higher-order assembly in vitro and in a mouse epilepsy model. X-ray crystallography, in vitro binding assays, knock-in mouse model for R474Q mutation Nature communications High 29670100
2018 Patient-derived LGI1 IgG antibodies prevent LGI1 binding to both ADAM23 and ADAM22; epitopes reside in the LRR1 and EPTP1 domains. In mice infused with patient IgG, Kv1.1 and AMPA receptor synaptic levels decrease (Kv1.1 effects precede AMPA effects), causing neuronal hyperexcitability, increased glutamatergic transmission, impaired LTP, and reversible memory deficits. Epitope mapping with LGI1 domain constructs, cerebroventricular patient IgG infusion in mice, confocal analysis, patch-clamp electrophysiology, LTP recording, behavioral memory testing Brain High 30346486
2019 ADAM22 and ADAM23 modulate LGI1 trafficking: they promote ER export and expression of LGI1 at the neuronal cell surface, and co-transport with LGI1 in axonal vesicles. LGI1 is recruited to the axon initial segment where it colocalizes with ADAM22 and Kv1 channels; ADLTE mutations S473L and R474Q prevent LGI1 association with ADAM22 and enrichment at the AIS. Hippocampal neuron cultures, immunofluorescence, live-cell axonal transport imaging, expression of ADLTE mutants Journal of cell science High 30598502
2020 Patient-derived monoclonal LGI1 antibodies (mAbs) segregate into two populations targeting either the LRR or EPTP domains with distinct properties: LRR-specific mAbs bind brain sections and induce internalization of the LGI1-ADAM22/23 complex in neurons; EPTP-specific mAbs inhibit LGI1 docking to ADAM22/23 but show less brain binding. Both types abolish LTP induction; LRR-directed high-affinity mAbs induce memory impairment after hippocampal injection. Generation of patient-derived mAbs from peripheral B cells, live cell-based assays, intrahippocampal injection in rodents, LTP recording, behavioral testing Brain High 32437528
2020 CSF-derived monoclonal LGI1 antibodies from patients increase intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures; both ADAM22-competing and non-competing antibodies produce this effect, demonstrating that LGI1 antibodies alone are sufficient to promote neuronal hyperexcitability. Cloning of antibodies from CSF B cells/ASCs, application to hippocampal slice cultures, patch-clamp electrophysiology Annals of neurology High 31900946
2021 LGI1-ADAM22 instructs PSD-95 family MAGUKs to organize transsynaptic protein networks including NMDA/AMPA receptors, Kv1 channels, and LRRTM4-Neurexin adhesion molecules. ADAM22 knock-in mice lacking the ADAM22-MAGUK interaction develop lethal epilepsy with less-condensed PSD-95 nanodomains, disordered transsynaptic nanoalignment, and decreased excitatory synaptic transmission. Without ADAM22-MAGUK interaction, PSD-95 cannot potentiate AMPA receptor-mediated synaptic transmission. Forced co-expression of ADAM22 and PSD-95 reconstitutes nano-condensates in non-neuronal cells. ADAM22 knock-in mouse (MAGUK interaction-deficient), super-resolution microscopy, electrophysiology, reconstitution in non-neuronal cells Proceedings of the National Academy of Sciences of the United States of America High 33397806
2021 PKA-mediated dual phosphorylation of ADAM22 promotes high-affinity binding to dimerized 14-3-3 proteins, protecting LGI1-ADAM22 complexes from endocytosis-dependent degradation. Forskolin-induced PKA activation increases ADAM22 levels. Approximately 50% of normal LGI1 levels and only ~10% of ADAM22 levels are sufficient to prevent lethal epilepsy in hypomorphic mice. Genetic analysis of hypomorphic mice, structural analysis of 14-3-3/ADAM22 interaction, PKA activation experiments with forskolin Cell reports High 34910912
2020 Subacute shRNA-mediated reduction of LGI1 in hippocampus increases dentate granule cell excitability and low-frequency facilitation of mossy fiber to CA3 transmission; α-dendrotoxin (Kv1 blocker) occludes this effect, implicating Kv1.1 as the downstream effector. shRNA knockdown in hippocampal slices and neuronal cultures, electrophysiology, pharmacological occlusion with α-dendrotoxin Epilepsia Medium 33104247
2022 An LRR domain-specific (but not EPTP domain-specific) patient-derived monoclonal LGI1 antibody increases intrinsic excitability of CA3 pyramidal neurons correlated with reduced sensitivity to a selective Kv1.1 channel blocker, demonstrating that LRR-domain antibodies modulate neuronal excitability via Kv1.1. Domain-specific patient mAb application to organotypic hippocampal cultures, patch-clamp electrophysiology, pharmacological Kv1.1 block Cells Medium 36078121
2004 Reintroduction of LGI1 into LGI1-null glioma cell lines (T98G, A172) significantly reduces cell proliferation, inhibits invasion in Matrigel assays, and reduces anchorage-independent growth, demonstrating a functional role in suppressing malignant phenotypes via ERK1/2 pathway inhibition. Retroviral/stable transfection of LGI1 into null glioma cell lines, proliferation assays, Matrigel invasion assays, soft agar colony assays Oncogene Medium 12821932
2004 LGI1 re-expression in T98G glioma cells downregulates MMP1 and MMP3 gene expression through inhibition of ERK1/2 phosphorylation (not p38) and promotion of AKT phosphorylation leading to Raf1(Ser-259) phosphorylation; pharmacological inhibition of MAPK pathway mimics LGI1 effects, and phorbol ester treatment reverses LGI1-mediated suppression of MMP1/3 and ERK1/2 phosphorylation. Affymetrix gene chip, pharmacological inhibitors (PD98059, U0126, SB203580), Western blot for ERK1/2 and AKT phosphorylation, phorbol ester treatment The Journal of biological chemistry Medium 15047712
2024 OPALIN, an oligodendrocyte-specific membrane protein, is identified as an LGI1 receptor on oligodendrocytes via LGI1 affinity chromatography and mass spectrometry. Conditional knockout of OPALIN in the oligodendrocyte lineage causes hypomyelination and white matter abnormalities phenocopying LGI1 deficiency; re-expression of LGI1-binding-deficient OPALIN (K23A/D26A) fails to rescue hypomyelination. LGI1 affinity chromatography with mouse brain lysates and mass spectrometry, conditional knockout mice, viral rescue with wild-type and mutant OPALIN Proceedings of the National Academy of Sciences of the United States of America High 39083419

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Anti-LGI1 encephalitis: Clinical syndrome and long-term follow-up. Neurology 471 27590293
2006 Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission. Science (New York, N.Y.) 311 16990550
2013 Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 269 24227725
2002 Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. Human molecular genetics 260 11978770
2006 The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvbeta1. Neuron 251 16504945
2010 Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy. Proceedings of the National Academy of Sciences of the United States of America 250 20133599
2019 Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. Neurology 196 30979857
2018 LGI1 antibodies alter Kv1.1 and AMPA receptors changing synaptic excitability, plasticity and memory. Brain : a journal of neurology 186 30346486
2013 VGKC-complex/LGI1-antibody encephalitis: clinical manifestations and response to immunotherapy. Journal of neuroimmunology 169 24176648
2017 LGI1, CASPR2 and related antibodies: a molecular evolution of the phenotypes. Journal of neurology, neurosurgery, and psychiatry 161 29055902
1998 A novel gene, LGI1, from 10q24 is rearranged and downregulated in malignant brain tumors. Oncogene 156 9879993
2004 LGI1 mutations in autosomal dominant partial epilepsy with auditory features. Neurology 154 15079011
2016 Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis. Brain : a journal of neurology 152 26945884
2013 Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA neurology 148 23407760
2017 Anti-LGI1 encephalitis is associated with unique HLA subtypes. Annals of neurology 147 28026029
2005 ADPEAF mutations reduce levels of secreted LGI1, a putative tumor suppressor protein linked to epilepsy. Human molecular genetics 133 15857855
2018 Distinct HLA associations of LGI1 and CASPR2-antibody diseases. Brain : a journal of neurology 132 29788256
2019 Randomized Placebo-Controlled Trial of Intravenous Immunoglobulin in Autoimmune LGI1/CASPR2 Epilepsy. Annals of neurology 120 31782181
2018 Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis. Annals of neurology 116 29572931
2009 LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy. Human mutation 115 19191227
2021 LGI1 antibody encephalitis: acute treatment comparisons and outcome. Journal of neurology, neurosurgery, and psychiatry 104 34824144
2020 Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability. Annals of neurology 101 31900946
2020 Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms. Brain : a journal of neurology 101 32437528
2008 LGI1 and LGI4 bind to ADAM22, ADAM23 and ADAM11. International journal of biological sciences 95 18974846
2015 The LGI1-ADAM22 protein complex directs synapse maturation through regulation of PSD-95 function. Proceedings of the National Academy of Sciences of the United States of America 82 26178195
2004 LGI1, a putative tumor metastasis suppressor gene, controls in vitro invasiveness and expression of matrix metalloproteinases in glioma cells through the ERK1/2 pathway. The Journal of biological chemistry 82 15047712
2009 LGI1-associated epilepsy through altered ADAM23-dependent neuronal morphology. Molecular and cellular neurosciences 78 19796686
2006 The epilepsy gene LGI1 encodes a secreted glycoprotein that binds to the cell surface. Human molecular genetics 74 17067999
2017 LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels. Proceedings of the National Academy of Sciences of the United States of America 72 28673977
2021 LGI1-ADAM22-MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention. Proceedings of the National Academy of Sciences of the United States of America 71 33397806
2020 Seizures and risk of epilepsy in anti-NMDAR, anti-LGI1, and anti-GABAB R encephalitis. Annals of clinical and translational neurology 71 32710704
2010 LGI1 is a Nogo receptor 1 ligand that antagonizes myelin-based growth inhibition. The Journal of neuroscience : the official journal of the Society for Neuroscience 69 20463223
2004 LGI1 mutations in temporal lobe epilepsies. Neurology 67 15079010
2021 CSF Findings in Acute NMDAR and LGI1 Antibody-Associated Autoimmune Encephalitis. Neurology(R) neuroimmunology & neuroinflammation 61 34697224
2018 Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM22. Nature communications 61 29670100
2007 Defining the expression pattern of the LGI1 gene in BAC transgenic mice. Mammalian genome : official journal of the International Mammalian Genome Society 57 17565425
2003 Suppression of the cell proliferation and invasion phenotypes in glioma cells by the LGI1 gene. Oncogene 53 12821932
2020 Anti-LGI1, anti-GABABR, and Anti-CASPR2 encephalitides in Asia: A systematic review. Brain and behavior 51 32783406
2017 Clinical features of limbic encephalitis with LGI1 antibody. Neuropsychiatric disease and treatment 50 28670128
2018 LGI1 and CASPR2 neurological autoimmunity in children. Annals of neurology 48 30076629
2008 Penetrance of LGI1 mutations in autosomal dominant partial epilepsy with auditory features. Neurology 48 18711109
2020 Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2. Practical neurology 43 32595134
2019 LGI1 and CASPR2 autoimmunity in children: Systematic literature review and report of a young girl with Morvan syndrome. Journal of neuroimmunology 39 31352183
2014 Glutamatergic neuron-targeted loss of LGI1 epilepsy gene results in seizures. Brain : a journal of neurology 39 25234641
2022 Clinical characteristics, long-term functional outcomes and relapse of anti-LGI1/Caspr2 encephalitis: a prospective cohort study in Western China. Therapeutic advances in neurological disorders 37 35069805
2019 ADAM22 and ADAM23 modulate the targeting of the Kv1 channel-associated protein LGI1 to the axon initial segment. Journal of cell science 37 30598502
2005 LGI1: a gene involved in epileptogenesis and glioma progression? Neurogenetics 37 15827762
2008 CPA6, FMO2, LGI1, SIAT1 and TNC are differentially expressed in early- and late-stage oral squamous cell carcinoma--a pilot study. Oral oncology 36 18234543
2020 Intrathecal B-cell activation in LGI1 antibody encephalitis. Neurology(R) neuroimmunology & neuroinflammation 35 32029531
2007 Two novel epilepsy-linked mutations leading to a loss of function of LGI1. Archives of neurology 35 17296837
2024 Ultrahigh frequencies of peripherally matured LGI1- and CASPR2-reactive B cells characterize the cerebrospinal fluid in autoimmune encephalitis. Proceedings of the National Academy of Sciences of the United States of America 34 38319973
2021 Role of LGI1 protein in synaptic transmission: From physiology to pathology. Neurobiology of disease 34 34695575
2019 Insights into the mechanisms of epilepsy from structural biology of LGI1-ADAM22. Cellular and molecular life sciences : CMLS 34 31432233
2016 LGI1 acts presynaptically to regulate excitatory synaptic transmission during early postnatal development. Scientific reports 34 26878798
2024 Neurological, psychiatric, and sleep investigations after treatment of anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis in Spain: a prospective cohort study. The Lancet. Neurology 32 38365378
2022 Characteristics of immune checkpoint inhibitor-induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis: A retrospective multicentre cohort study. European journal of cancer (Oxford, England : 1990) 32 36155116
2016 The LGI1-ADAM22 protein complex in synaptic transmission and synaptic disorders. Neuroscience research 31 27717669
2012 A rat model for LGI1-related epilepsies. Human molecular genetics 30 22589250
2008 A novel loss-of-function LGI1 mutation linked to autosomal dominant lateral temporal epilepsy. Archives of neurology 30 18625862
2022 Contemporary advances in antibody-mediated encephalitis: anti-LGI1 and anti-Caspr2 antibody (Ab)-mediated encephalitides. Autoimmunity reviews 29 35247644
2021 CSF-Neurofilament Light Chain Levels in NMDAR and LGI1 Encephalitis: A National Cohort Study. Frontiers in immunology 29 34975832
2021 Trans-synaptic LGI1-ADAM22-MAGUK in AMPA and NMDA receptor regulation. Neuropharmacology 28 34089731
2012 Molecular binding of self-assembling peptide EAK16-II with anticancer agent EPT and its implication in cancer cell inhibition. Journal of controlled release : official journal of the Controlled Release Society 28 22465389
2022 Seizure underreporting in LGI1 and CASPR2 antibody encephalitis. Epilepsia 27 35735209
2011 A computational model of the LGI1 protein suggests a common binding site for ADAM proteins. PloS one 27 21479274
2017 Global brain atrophy and metabolic dysfunction in LGI1 encephalitis: A prospective multimodal MRI study. Journal of the neurological sciences 26 28431605
2012 Domain-dependent clustering and genotype-phenotype analysis of LGI1 mutations in ADPEAF. Neurology 26 22323750
2022 Cortical and Subcortical Dysmetabolism Are Dynamic Markers of Clinical Disability and Course in Anti-LGI1 Encephalitis. Neurology(R) neuroimmunology & neuroinflammation 25 35091466
2021 Mechanism and Role of the Neuropeptide LGI1 Receptor ADAM23 in Regulating Biomarkers of Ferroptosis and Progression of Esophageal Cancer. Disease markers 25 35003396
2006 The LGI1/epitempin gene encodes two protein isoforms differentially expressed in human brain. Journal of neurochemistry 25 16787412
2001 Physical and functional characterization of the human LGI1 gene and its possible role in glioma development. Acta neuropathologica 25 11907806
2018 LGI1 expression and human brain asymmetry: insights from patients with LGI1-antibody encephalitis. Journal of neuroinflammation 24 30253786
2007 Absence of mutations in the LGI1 receptor ADAM22 gene in autosomal dominant lateral temporal epilepsy. Epilepsy research 24 17681454
2021 The LGI1 protein: molecular structure, physiological functions and disruption-related seizures. Cellular and molecular life sciences : CMLS 22 34967933
2019 Acquired neuromyotonia in children with CASPR2 and LGI1 antibodies. Developmental medicine and child neurology 22 30724344
2012 Epilepsy gene LGI1 regulates postnatal developmental remodeling of retinogeniculate synapses. The Journal of neuroscience : the official journal of the Society for Neuroscience 22 22262888
2011 Low penetrance and effect on protein secretion of LGI1 mutations causing autosomal dominant lateral temporal epilepsy. Epilepsia 22 21504429
2012 LGI1 microdeletion in autosomal dominant lateral temporal epilepsy. Neurology 21 22496201
2006 Increased expression of LGI1 gene triggers growth inhibition and apoptosis of neuroblastoma cells. Journal of cellular physiology 21 16518856
2003 Expression of the LGI1 gene product in astrocytic gliomas: downregulation with malignant progression. Virchows Archiv : an international journal of pathology 21 12942323
2000 Identification of the promoter, genomic structure, and mouse ortholog of LGI1. Mammalian genome : official journal of the International Mammalian Genome Society 21 10920229
2020 Novel findings of HLA association with anti-LGI1 encephalitis: HLA-DRB1*03:01 and HLA-DQB1*02:01. Journal of neuroimmunology 20 32417596
2020 Serum and CSF cytokine levels mirror different neuroimmunological mechanisms in patients with LGI1 and Caspr2 encephalitis. Cytokine 20 32799011
2006 Expression studies in gliomas and glial cells do not support a tumor suppressor role for LGI1. Neuro-oncology 20 16533756
2022 Objective sleep profile in LGI1/CASPR2 autoimmunity. Sleep 19 34953167
2022 The diagnosis of anti-LGI1 encephalitis varies with the type of immunodetection assay and sample examined. Frontiers in immunology 19 36591253
2018 Distinction between anti-VGKC-complex seropositive patients with and without anti-LGI1/CASPR2 antibodies. Journal of the neurological sciences 19 30103974
2016 Secretion-Positive LGI1 Mutations Linked to Lateral Temporal Epilepsy Impair Binding to ADAM22 and ADAM23 Receptors. PLoS genetics 19 27760137
2024 Resolution of anti-LGI1-associated autoimmune encephalitis in a patient after treatment with efgartigimod. Journal of neurology 18 38981871
2025 Efgartigimod treatment for therapy-refractory autoimmune encephalitis with coexistent NMDAR and LGI1 antibodies: a case report and literature review. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 17 39820999
2020 LGI1 downregulation increases neuronal circuit excitability. Epilepsia 17 33104247
2011 The temporal and spatial expression pattern of the LGI1 epilepsy predisposition gene during mouse embryonic cranial development. BMC neuroscience 17 21569517
2023 Comparison of quantitative FDG-PET and MRI in anti-LGI1 autoimmune encephalitis. Neuroradiology 16 37264220
2022 An Epitope-Specific LGI1-Autoantibody Enhances Neuronal Excitability by Modulating Kv1.1 Channel. Cells 16 36078121
2008 Analysis of LGI1 promoter sequence, PDYN and GABBR1 polymorphisms in sporadic and familial lateral temporal lobe epilepsy. Neuroscience letters 16 18355961
2021 14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice. Cell reports 15 34910912
2024 OPALIN is an LGI1 receptor promoting oligodendrocyte differentiation. Proceedings of the National Academy of Sciences of the United States of America 14 39083419
2023 Electrolyte Imbalance in Anti-LGI1 Encephalitis: It Is Not All in Your Head. Neurology(R) neuroimmunology & neuroinflammation 14 37591767
2014 LGI1: from zebrafish to human epilepsy. Progress in brain research 14 25194489
2024 Innovation and optimization in autoimmune encephalitis trials: the design and rationale for the Phase 3, randomized study of satralizumab in patients with NMDAR-IgG-antibody-positive or LGI1-IgG-antibody-positive autoimmune encephalitis (CIELO). Frontiers in neurology 13 39193150

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