Affinage

LGI1

Leucine-rich glioma-inactivated protein 1 · UniProt O95970

Length
557 aa
Mass
63.8 kDa
Annotated
2026-04-28
100 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LGI1 is a secreted neuronal glycoprotein that organizes excitatory synaptic architecture and controls seizure threshold by forming a transsynaptic ligand–receptor bridge between presynaptic ADAM23 and postsynaptic ADAM22. The LGI1–ADAM22 complex anchors PSD-95/MAGUK scaffolds to establish transsynaptic nanoalignment, regulate AMPA receptor–mediated synaptic transmission, and coordinate synapse maturation and pruning; the complex is stabilized by PKA-dependent phosphorylation of ADAM22 and 14-3-3 binding (PMID:20133599, PMID:33397806, PMID:34910912). LGI1 also assembles into presynaptic Kv1.1/Kvβ1 potassium channel complexes, where it suppresses Kvβ1-mediated N-type inactivation to control neuronal excitability (PMID:16504945, PMID:33104247). Loss-of-function mutations in LGI1 cause autosomal dominant partial epilepsy with auditory features (ADPEAF) through impaired secretion or disrupted ADAM22/23 binding, while autoantibodies targeting LGI1 cause limbic encephalitis by internalizing or blocking the LGI1–ADAM complex, reducing synaptic AMPA receptors and Kv1.1 levels, and producing reversible memory deficits (PMID:11810107, PMID:20580615, PMID:30346486).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1998 Medium

    Cloning of LGI1 established its identity as a leucine-rich repeat–containing secreted protein lost in glioblastomas, initially framing it as a candidate tumor suppressor before its neuronal role was recognized.

    Evidence Positional cloning and translocation mapping of the t(10;19) breakpoint in glioblastoma cell lines, Northern blot expression analysis

    PMID:9879993

    Open questions at the time
    • Tumor-suppressor function was never confirmed in vivo
    • Expression outside brain was not deeply characterized
  2. 2002 High

    Discovery that LGI1 loss-of-function mutations cause ADPEAF reframed the gene from a tumor suppressor to the first non-ion-channel epilepsy gene, raising the question of how a secreted protein controls seizure threshold.

    Evidence Resequencing of candidate genes in multiple ADPEAF/ADLTE families identifying truncating and missense mutations, replicated independently

    PMID:11810107 PMID:11978770

    Open questions at the time
    • Mechanism by which LGI1 loss produces seizures was unknown
    • Whether mutations act through haploinsufficiency or dominant-negative effects was unresolved
  3. 2005 High

    Demonstrating that ADPEAF mutations block LGI1 secretion from cells established loss-of-function (impaired extracellular availability) as the shared pathogenic mechanism, directing the search toward extracellular receptors.

    Evidence Transfection of wild-type and mutant LGI1 into 293T cells with conditioned medium analysis

    PMID:15857855

    Open questions at the time
    • The receptor for secreted LGI1 was unknown
    • Whether some mutations might act by a mechanism other than impaired secretion was not addressed
  4. 2006 High

    Identification of ADAM22 as the postsynaptic receptor for LGI1 and of presynaptic Kv1.1/Kvβ1 complexes as a second LGI1 binding partner revealed two distinct effector arms—AMPA receptor regulation and Kv1 channel inactivation gating—explaining how a single secreted protein controls both synaptic strength and intrinsic excitability.

    Evidence Co-immunoprecipitation from rat brain, electrophysiology in hippocampal slices and HEK cells, mass spectrometry, mutant analysis

    PMID:16504945 PMID:16990550

    Open questions at the time
    • Whether ADAM23 serves as a presynaptic receptor bridging to ADAM22 was not yet established
    • Structural basis of binding was unknown
    • Relative contribution of Kv1 vs AMPA receptor arm to seizures was undetermined
  5. 2010 High

    Knockout mouse studies and identification of LGI1 as the autoantigen in limbic encephalitis (previously attributed to 'VGKC antibodies') unified the genetic and autoimmune mechanisms: LGI1 bridges presynaptic ADAM23 to postsynaptic ADAM22 to maintain both AMPA receptor signaling and Kv1 function, and either genetic loss or antibody-mediated disruption is pathogenic.

    Evidence LGI1 KO mice with lethal epilepsy, transgene rescue, IP/MS from brain, patient serum immunoprecipitation, HEK cell-based assays, immunostaining of Lgi1-null brain

    PMID:20130004 PMID:20133599 PMID:20580615

    Open questions at the time
    • Cell-type-specific requirement for LGI1 was unclear
    • Precise epitopes and pathogenic mechanisms of patient antibodies were not resolved
    • Myelination role from KO phenotype needed further characterization
  6. 2013 High

    Mapping autoantibody epitopes to the EPTP domain and showing that disrupting LGI1–ADAM22 interaction alone (by soluble ADAM22 ectodomain) is sufficient to reduce synaptic AMPA receptor clusters established that the LGI1–ADAM22 interaction is the critical node for maintaining postsynaptic receptor density.

    Evidence ELISA domain mapping, cell-based inhibition assays, immunofluorescence of rat hippocampal neurons, LGI1 KO mouse dentate gyrus analysis

    PMID:24227725

    Open questions at the time
    • Whether antibodies also act through Kv1 channels was not tested
    • Reversibility in vivo was not established
  7. 2016 High

    Discovery that certain ADLTE mutations (T380A, R407C, S473L, R474Q) are secreted normally but fail to bind ADAM22/23 identified a second class of extracellular loss-of-function mechanism distinct from secretion defects, demonstrating that receptor engagement is an independent vulnerable step.

    Evidence Secretion assays, co-immunoprecipitation, cell surface immunofluorescence, 3D protein modeling with multiple mutants

    PMID:27760137

    Open questions at the time
    • Structural explanation for how each mutation disrupts binding was lacking
  8. 2018 High

    The crystal structure of the LGI1–ADAM22 2:2 heterotetramer revealed the molecular interface (EPTP hydrophobic pocket engaging ADAM22 metalloprotease-like domain) and showed that pathogenic mutation R474Q disrupts higher-order assembly rather than direct binding, explaining how some mutations are secretion- and binding-competent yet pathogenic.

    Evidence X-ray crystallography, mutagenesis, co-immunoprecipitation, mouse model validation

    PMID:29670100

    Open questions at the time
    • Structure of full transsynaptic ADAM23–LGI1–LGI1–ADAM22 complex was not determined
    • Structural basis of LGI1 interaction with Kv1 channels remained unknown
  9. 2018 High

    In vivo transfer of patient IgG demonstrated that LGI1 autoantibodies reduce presynaptic Kv1.1 levels before AMPA receptor loss, impair LTP, and cause reversible memory deficits, establishing a temporal hierarchy of pathogenic effects and linking autoimmune disruption directly to cognitive symptoms.

    Evidence Cerebroventricular IgG infusion in mice, live confocal imaging of hippocampal slices, patch-clamp electrophysiology, LTP recording, novel object recognition

    PMID:30346486

    Open questions at the time
    • Whether Kv1.1 loss is the primary driver of excitability or secondary to complex destabilization was not resolved
    • Chronic in vivo effects beyond 2 weeks were not studied
  10. 2020 High

    Patient-derived monoclonal antibodies with distinct domain specificity (LRR vs EPTP) operate through different pathomechanisms—LRR mAbs internalize the intact LGI1–ADAM complex while EPTP mAbs block docking—yet both impair LTP, demonstrating convergent synaptic pathology from diverse antibody populations; pharmacological occlusion experiments confirmed Kv1.1 as the mediating channel for LGI1 knockdown–induced excitability changes.

    Evidence Patient-derived mAbs in HEK293T internalization assays, intrahippocampal injection in rodents with behavioral and electrophysiological readouts, shRNA knockdown in hippocampal slices with α-dendrotoxin occlusion

    PMID:31900946 PMID:32437528 PMID:33104247

    Open questions at the time
    • Relative pathogenic weight of internalization vs blocking mechanisms in patients in vivo was not determined
    • Whether non-ADAM22-blocking antibodies act entirely through Kv1 was not established
  11. 2021 High

    The LGI1–ADAM22 complex was shown to govern transsynaptic nanoalignment by instructing PSD-95 nanodomain condensation; PKA-dependent phosphorylation of ADAM22 recruits 14-3-3 proteins that protect the complex from endocytic degradation, and as little as ~50% of normal LGI1 is sufficient to prevent lethal epilepsy, defining the threshold and regulatory logic of the pathway.

    Evidence ADAM22 knock-in mice lacking MAGUK-binding domain, super-resolution microscopy, reconstitution in non-neuronal cells, hypomorphic mouse allelic series, in vitro phosphorylation and 14-3-3 binding assays

    PMID:33397806 PMID:34910912

    Open questions at the time
    • Whether PKA regulation is activity-dependent at synapses is unknown
    • How LGI1–ADAM22 nanodomains are spatially organized relative to presynaptic release sites needs further super-resolution characterization

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structure of the full transsynaptic ADAM23–LGI1–LGI1–ADAM22 complex, the structural basis of LGI1 interaction with Kv1 channels, whether the Kv1 and AMPA receptor arms are independently or coordinately regulated during synaptic plasticity, and the functional significance of LGI1 complexes in non-neuronal cells (oligodendrocytes, astrocytes).
  • No full transsynaptic complex structure
  • Kv1–LGI1 structural interface undefined
  • Functional role of LGI1 in glia is minimally characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 4 GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4
Partners
ADAM11ADAM22ADAM23DLG4KCNA1KCNAB1RTN4R
Complex memberships
Kv1.1/Kv1.4/Kvβ1-LGI1 presynaptic complexLGI1-ADAM22-ADAM23 transsynaptic complexLGI1-ADAM22-PSD-95/MAGUK postsynaptic 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 secreted protein containing leucine-rich repeats (LRR); the gene is rearranged and its expression is absent in glioblastoma cell lines and malignant gliomas, identifying it as a candidate tumor suppressor. Positional cloning, translocation mapping, Northern blot/expression analysis Oncogene Medium 9879993
2002 Mutations in LGI1 (including premature stop codons) cause autosomal dominant partial epilepsy with auditory features (ADPEAF/ADLTE), establishing LGI1 as a non-ion-channel epilepsy gene; mouse Lgi1 expression is predominantly neuronal in temporal lobe regions. Resequencing of candidate genes in ADPEAF families, immunohistochemistry in mouse brain Nature genetics High 11810107
2002 LGI1 mutations introducing premature stop codons (loss of function) segregate with autosomal dominant lateral temporal epilepsy; LGI1 protein is expressed in neuronal cell compartments throughout the brain. Mutation analysis in ADLTE families, immunohistochemistry Human molecular genetics High 11978770
2005 LGI1 is a secreted protein; ADPEAF-associated mutations (missense and truncating) reduce or abolish secretion of LGI1 from transfected 293T cells, demonstrating loss-of-function as the pathogenic mechanism. Transfection of wild-type and mutant LGI1 into 293T cells, conditioned medium analysis, Western blot Human molecular genetics High 15857855
2006 LGI1 binds ADAM22 (a postsynaptic transmembrane protein) as its receptor; this interaction enhances AMPA receptor-mediated synaptic transmission in hippocampal slices; ADPEAF-mutant LGI1 fails to bind ADAM22; ADAM22 is anchored to the postsynaptic density via stargazin-containing scaffolds. Co-immunoprecipitation, electrophysiology in hippocampal slices (rat brain), HEK293 cell binding assays, mutant analysis Science High 16990550
2006 Lgi1 assembles into presynaptic Kv1.1-containing potassium channel complexes (with Kv1.4 and Kvβ1) in hippocampal axonal terminals, and selectively prevents N-type (Kvβ1-mediated) inactivation; ADLTE-mutant Lgi1 fails to inhibit inactivation, resulting in channels with rapid inactivation kinetics. Immunoprecipitation/mass spectrometry from rat brain, electrophysiology, co-expression in HEK cells, mutant analysis Neuron High 16504945
2006 LGI1 is expressed as two protein isoforms (~60 and ~65 kDa) in human brain; the long isoform is secreted, whereas the short isoform is retained intracellularly; ADLTE mutants of the long form are retained in the ER and Golgi; secreted LGI1 binds specifically to the cell surface of differentiated PC12 cells. Western blot, subcellular fractionation, immunofluorescence of transfected cells, cell surface binding assay Human molecular genetics High 17067999
2008 LGI1 binds to ADAM22, ADAM23, and ADAM11 with distinct affinities; LGI4 also binds these ADAMs; binding was characterized by quantitative cell-ELISA and immunoprecipitation/mass spectrometry from mouse brain. Immunoprecipitation + mass spectrometry, quantitative cell-ELISA International journal of biological sciences High 18974846
2009 LGI1 interacts with synaptic vesicle proteins synaptotagmin, synaptophysin, syntaxin 1A, clathrin heavy chain 1, syntaxin binding protein 1, and ADAM23, implicating LGI1 in synaptic vesicle function in neurons. Co-immunoprecipitation of GFP-tagged LGI1 from human brain lysates + mass spectrometry + Western blot confirmation Journal of molecular neuroscience Medium 19387870
2010 Extracellular secreted LGI1 links presynaptic ADAM23 to postsynaptic ADAM22, forming a transsynaptic protein complex that includes presynaptic Kv1 potassium channels and postsynaptic AMPA receptor scaffolds; loss of LGI1 (knockout mice) causes lethal epilepsy, disrupts this synaptic connection, and selectively reduces AMPA receptor-mediated synaptic transmission in hippocampus. LGI1 knockout mice, LGI1 transgene rescue, co-immunoprecipitation from brain, electrophysiology Proceedings of the National Academy of Sciences of the United States of America High 20133599
2010 LGI1 is a specific ligand for Nogo receptor 1 (NgR1) that antagonizes myelin-based growth inhibition and myelin-induced growth cone collapse; NgR1 and ADAM22 physically associate to form a receptor complex in which NgR1 facilitates LGI1 binding to ADAM22. Neurite outgrowth assay, growth cone collapse assay, co-immunoprecipitation, binding assays The Journal of neuroscience Medium 20463223
2010 LGI1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability with enhanced excitatory synaptic transmission (increased glutamate release), providing mechanistic basis for seizure phenotype. Mouse chromosome engineering (null mutation), EEG, electrophysiology Human molecular genetics High 20130004
2010 LGI1 is identified as the primary autoantigen in limbic encephalitis previously attributed to voltage-gated potassium channels (VGKC); LGI1 interacts with presynaptic ADAM23 and postsynaptic ADAM22; patient antibodies recognize LGI1 and reactivity is abrogated by immunoabsorption with LGI1-expressing cells and absent in Lgi1-null mouse brain. Immunoprecipitation + mass spectrometry, HEK293 cell-based assay, immunoabsorption, immunostaining of Lgi1-null mice The Lancet. Neurology High 20580615
2010 Homozygous deletion of LGI1 causes hypomyelination of axons in both peripheral (sciatic nerve, Schwann cells) and central nervous systems, establishing a role for LGI1 in myelination. Electron microscopy of sciatic nerve, histological analysis of CNS in Lgi1 null mice Journal of neuroscience research Medium 20857514
2012 LGI1 regulates postnatal pruning of retinogeniculate synapses; ADLTE-associated truncated mutant LGI1 blocks retinogeniculate axon pruning and arrests normal postnatal single fiber strengthening, whereas excess wild-type LGI1 accelerates pruning. Transgenic mice expressing mutant or excess wild-type LGI1, retinogeniculate axon tracing, electrophysiology The Journal of neuroscience Medium 22262888
2013 LGI1 autoantibodies from limbic encephalitis patients target the EPTP repeat domain of LGI1, specifically inhibit LGI1-ADAM22/23 interactions, and reversibly reduce synaptic AMPA receptor clusters in rat hippocampal neurons; disruption of LGI1-ADAM22 interaction alone (via soluble ADAM22 ectodomain) reduces synaptic AMPA receptors; LGI1 knockout mouse shows greatly reduced AMPA receptors in hippocampal dentate gyrus. ELISA arrays, cell-based inhibition assays, immunofluorescence of rat hippocampal neurons, LGI1 KO mouse analysis The Journal of neuroscience High 24227725
2014 LGI1 deletion restricted to glutamatergic pyramidal neurons (Emx1-Cre or CaMKIIα-Cre conditional knockouts) is sufficient to generate seizures; deletion in GABAergic parvalbumin interneurons does not produce spontaneous seizures or increased seizure susceptibility, establishing that LGI1 secreted from excitatory neurons is required for circuit homeostasis. Conditional knockout mice using cell-type-specific Cre drivers, EEG, behavioral analysis Brain : a journal of neurology High 25234641
2015 LGI1 acts as a paracrine signal from both pre- and postsynaptic neurons, acting specifically through ADAM22 to set postsynaptic strength; ADAM22 maintains excitatory synapses through PDZ domain interactions; in the absence of LGI1, PSD-95 (but not SAP102) cannot modulate synaptic transmission, indicating that LGI1-ADAM22 coordinates synapse maturation by regulating PSD-95 functional incorporation. Organotypic slice electrophysiology, lentiviral knockdown, rescue experiments with domain mutants of ADAM22, co-immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America High 26178195
2016 Four secretion-positive LGI1 missense mutations (T380A, R407C, S473L, R474Q) causing ADLTE do not impair protein secretion but significantly impair LGI1 interaction with ADAM22 and ADAM23 receptors on the cell surface, identifying a second extracellular loss-of-function mechanism. Transfection of mutant LGI1 in cultured cells, secretion assay, immunofluorescence, co-immunoprecipitation, 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 the EPTP domain of LGI1 binds the metalloprotease-like domain of ADAM22; the LRR and EPTP domains mediate LGI1-LGI1 dimerization; a pathogenic mutation R474Q disrupts higher-order LGI1-ADAM22 assembly in vitro and in a mouse model without affecting secretion or direct ADAM22 binding. X-ray crystallography, mutagenesis, co-immunoprecipitation, mouse model Nature communications High 29670100
2018 Patient-derived IgG against LGI1 disrupts LGI1 binding to both ADAM23 (presynaptic) and ADAM22 (postsynaptic); antibody epitopes map to both LRR and EPTP domains; infusion of patient IgG into mouse ventricles decreases synaptic levels of Kv1.1 (presynaptically, preceding AMPA receptor changes) and AMPA receptors, causes neuronal hyperexcitability, impairs long-term potentiation, and produces reversible memory deficits. Live confocal imaging of hippocampal slices, patch-clamp electrophysiology, field potential LTP recordings, mouse cerebroventricular IgG transfer, behavioral testing (novel object recognition) Brain : a journal of neurology High 30346486
2019 ADAM22 and ADAM23 modulate trafficking of LGI1: they promote ER export and surface expression of LGI1, co-transport LGI1 in axonal vesicles (live-cell imaging), and are required for LGI1 enrichment at the axon initial segment (AIS); ADLTE missense mutations S473L and R474Q prevent LGI1 association with ADAM22 and its enrichment at the AIS. Rat hippocampal neuron culture, immunofluorescence, live-cell imaging, co-immunoprecipitation Journal of cell science High 30598502
2020 CSF-derived patient monoclonal antibodies against LGI1 recognize either the LRR or EPTP domain; LRR-specific mAbs bind ADAM22/23-docked LGI1 and induce internalization of the LGI1-ADAM22/23 complex in HEK293T cells and live hippocampal neurons; EPTP-specific mAbs inhibit LGI1 docking to ADAM22/23; both domain-specific mAbs abrogate LTP and LRR-directed mAbs with higher binding strength induce memory impairment after intrahippocampal injection. Monoclonal antibody generation from patient B cells, live cell-based assay, internalization assay, intrahippocampal injection in rodents, LTP recording, behavioral testing Brain : a journal of neurology High 32437528
2020 CSF-derived monoclonal LGI1 autoantibodies (IgG1, IgG2, IgG4 isotypes) increase intrinsic cellular excitability and glutamatergic synaptic transmission in hippocampal CA3 neurons in slice cultures; 7/26 antibodies blocked LGI1-ADAM22 interaction in vitro, while all antibodies promoted excitability regardless of ADAM22-blocking activity. Antibody cloning from CSF ASCs and B cells, patch-clamp electrophysiology in hippocampal slice cultures, in vitro LGI1-ADAM22 competition assay Annals of neurology High 31900946
2020 Subacute reduction of LGI1 expression by shRNA in hippocampal slices increases dentate granule cell excitability and low-frequency facilitation of mossy fiber-CA3 neurotransmission; this effect is occluded by Kv1 family blocker α-dendrotoxin, implicating Kv1.1 as the mediating channel; LGI1 knockdown in neuronal primary culture also increases network activity. shRNA knockdown in ex vivo hippocampal slices and primary neuronal cultures, patch-clamp electrophysiology, pharmacological occlusion with α-dendrotoxin Epilepsia High 33104247
2021 LGI1-ADAM22 governs transsynaptic nanoalignment by instructing PSD-95 family MAGUKs to organize a transsynaptic protein network including NMDA/AMPA receptors, Kv1 channels, and LRRTM4-Neurexin adhesion molecules; ADAM22 knock-in mice lacking the ADAM22-MAGUK interaction exhibit lethal hippocampal epilepsy, less-condensed PSD-95 nanodomains, disordered nanoalignment, and decreased excitatory synaptic transmission; forced coexpression of ADAM22 and PSD-95 reconstitutes nano-condensates in non-neuronal cells. ADAM22 knock-in mice (MAGUK-binding domain deleted), super-resolution microscopy, electrophysiology, reconstitution in non-neuronal cells, co-immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America High 33397806
2021 14-3-3 proteins bind phosphorylated ADAM22 (dual phosphorylation by PKA) and protect the LGI1-ADAM22 complex from endocytosis-dependent degradation; PKA activation by forskolin increases ADAM22 levels; ~50% of normal LGI1 levels and ~10% of normal ADAM22 levels are sufficient to prevent lethal epilepsy in hypomorphic mice. Genetic and structural analysis, hypomorphic mouse series, in vitro phosphorylation and binding assays, pharmacological PKA activation Cell reports High 34910912
2022 LGI1 is enriched in excitatory and inhibitory synaptic contact sites (most densely in CA3 hippocampus), is secreted from both somatodendritic and axonal compartments, and occurs in oligodendrocytic, neuro-oligodendrocytic, and astro-microglial protein complexes; proteomics reveals LGI1-Kv1-MAGUK complexes but does not identify LGI1 complexes with postsynaptic glutamate receptors. Patient-derived recombinant monoclonal antibody-based immunofluorescence, co-immunoprecipitation + mass spectrometry from mouse brain Brain : a journal of neurology Medium 35727946
2022 An LRR-domain-specific LGI1 autoantibody (but not an EPTP-domain-specific mAb) increases intrinsic excitability of CA3 pyramidal neurons and reduces sensitivity to the selective Kv1.1 channel blocker, indicating that LRR mAbs modulate Kv1.1 channel function to promote neuronal excitability. Patient-derived recombinant monoclonal antibodies applied to organotypic rat hippocampal slice cultures, patch-clamp electrophysiology, pharmacological Kv1.1 blockade Cells Medium 36078121

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. The Lancet. Neurology 771 20580615
2016 Anti-LGI1 encephalitis: Clinical syndrome and long-term follow-up. Neurology 463 27590293
2002 Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features. Nature genetics 459 11810107
2006 Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission. Science (New York, N.Y.) 310 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 265 24227725
2002 Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. Human molecular genetics 259 11978770
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 249 20133599
2006 The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvbeta1. Neuron 248 16504945
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 182 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 156 29055902
1998 A novel gene, LGI1, from 10q24 is rearranged and downregulated in malignant brain tumors. Oncogene 156 9879993
2016 Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis. Brain : a journal of neurology 150 26945884
2013 Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA neurology 148 23407760
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 127 29788256
2019 Randomized Placebo-Controlled Trial of Intravenous Immunoglobulin in Autoimmune LGI1/CASPR2 Epilepsy. Annals of neurology 120 31782181
2009 LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy. Human mutation 115 19191227
2018 Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis. Annals of neurology 113 29572931
2021 LGI1 antibody encephalitis: acute treatment comparisons and outcome. Journal of neurology, neurosurgery, and psychiatry 101 34824144
2020 Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability. Annals of neurology 98 31900946
2020 Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms. Brain : a journal of neurology 98 32437528
2010 Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability. Human molecular genetics 96 20130004
2008 LGI1 and LGI4 bind to ADAM22, ADAM23 and ADAM11. International journal of biological sciences 94 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
2006 The epilepsy gene LGI1 encodes a secreted glycoprotein that binds to the cell surface. Human molecular genetics 74 17067999
2020 Seizures and risk of epilepsy in anti-NMDAR, anti-LGI1, and anti-GABAB R encephalitis. Annals of clinical and translational neurology 71 32710704
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 70 33397806
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
2021 CSF Findings in Acute NMDAR and LGI1 Antibody-Associated Autoimmune Encephalitis. Neurology(R) neuroimmunology & neuroinflammation 60 34697224
2018 Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM22. Nature communications 60 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 Epilepsy with auditory features: a LGI1 gene mutation suggests a loss-of-function mechanism. Annals of neurology 53 12601709
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
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 42 32595134
1992 The mouse Enhancer trap locus 1 (Etl-1): a novel mammalian gene related to Drosophila and yeast transcriptional regulator genes. Mechanisms of development 41 1489724
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
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
1999 Skeletal dysplasias, growth retardation, reduced postnatal survival, and impaired fertility in mice lacking the SNF2/SWI2 family member ETL1. Mechanisms of development 36 10415348
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 35 35069805
2007 Two novel epilepsy-linked mutations leading to a loss of function of LGI1. Archives of neurology 35 17296837
2004 Autosomal dominant lateral temporal epilepsy: two families with novel mutations in the LGI1 gene. Epilepsia 34 15009222
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 33 38319973
2020 Intrathecal B-cell activation in LGI1 antibody encephalitis. Neurology(R) neuroimmunology & neuroinflammation 33 32029531
2021 Role of LGI1 protein in synaptic transmission: From physiology to pathology. Neurobiology of disease 32 34695575
2019 Insights into the mechanisms of epilepsy from structural biology of LGI1-ADAM22. Cellular and molecular life sciences : CMLS 31 31432233
2016 The LGI1-ADAM22 protein complex in synaptic transmission and synaptic disorders. Neuroscience research 31 27717669
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 30 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) 30 36155116
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
2021 CSF-Neurofilament Light Chain Levels in NMDAR and LGI1 Encephalitis: A National Cohort Study. Frontiers in immunology 28 34975832
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 Contemporary advances in antibody-mediated encephalitis: anti-LGI1 and anti-Caspr2 antibody (Ab)-mediated encephalitides. Autoimmunity reviews 27 35247644
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
2008 Autosomal dominant lateral temporal epilepsy: absence of mutations in ADAM22 and Kv1 channel genes encoding LGI1-associated proteins. Epilepsy research 27 18440780
2017 Global brain atrophy and metabolic dysfunction in LGI1 encephalitis: A prospective multimodal MRI study. Journal of the neurological sciences 26 28431605
2021 Trans-synaptic LGI1-ADAM22-MAGUK in AMPA and NMDA receptor regulation. Neuropharmacology 25 34089731
2012 Domain-dependent clustering and genotype-phenotype analysis of LGI1 mutations in ADPEAF. Neurology 25 22323750
2022 Cortical and Subcortical Dysmetabolism Are Dynamic Markers of Clinical Disability and Course in Anti-LGI1 Encephalitis. Neurology(R) neuroimmunology & neuroinflammation 24 35091466
2007 Absence of mutations in the LGI1 receptor ADAM22 gene in autosomal dominant lateral temporal epilepsy. Epilepsy research 24 17681454
2006 The LGI1/epitempin gene encodes two protein isoforms differentially expressed in human brain. Journal of neurochemistry 24 16787412
2019 Acquired neuromyotonia in children with CASPR2 and LGI1 antibodies. Developmental medicine and child neurology 22 30724344
2019 Down-Regulation of Astrocytic Kir4.1 Channels during the Audiogenic Epileptogenesis in Leucine-Rich Glioma-Inactivated 1 (Lgi1) Mutant Rats. International journal of molecular sciences 22 30813600
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
2009 Mutations in LGI1 gene in Japanese families with autosomal dominant lateral temporal lobe epilepsy: the first report from Asian families. Epilepsia 22 19780791
2010 Evaluation of depression risk in LGI1 mutation carriers. Epilepsia 21 20659151
2010 Homozygous inactivation of the LGI1 gene results in hypomyelination in the peripheral and central nervous systems. Journal of neuroscience research 21 20857514
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 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
2003 No evidence for a seriously increased malignancy risk in LGI1-caused epilepsy. Epilepsy research 20 14643004
2022 Objective sleep profile in LGI1/CASPR2 autoimmunity. Sleep 19 34953167
2021 The LGI1 protein: molecular structure, physiological functions and disruption-related seizures. Cellular and molecular life sciences : CMLS 19 34967933
2020 Novel findings of HLA association with anti-LGI1 encephalitis: HLA-DRB1*03:01 and HLA-DQB1*02:01. Journal of neuroimmunology 19 32417596
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
2022 Patient-derived antibodies reveal the subcellular distribution and heterogeneous interactome of LGI1. Brain : a journal of neurology 17 35727946
2009 Mass spectrometry identifies LGI1-interacting proteins that are involved in synaptic vesicle function in the human brain. Journal of molecular neuroscience : MN 17 19387870
1993 The Etl-1 gene encodes a nuclear protein differentially expressed during early mouse development. Developmental dynamics : an official publication of the American Association of Anatomists 17 8219362
2020 LGI1 downregulation increases neuronal circuit excitability. Epilepsia 16 33104247
2008 Analysis of LGI1 promoter sequence, PDYN and GABBR1 polymorphisms in sporadic and familial lateral temporal lobe epilepsy. Neuroscience letters 16 18355961
2022 An Epitope-Specific LGI1-Autoantibody Enhances Neuronal Excitability by Modulating Kv1.1 Channel. Cells 15 36078121
2022 The diagnosis of anti-LGI1 encephalitis varies with the type of immunodetection assay and sample examined. Frontiers in immunology 15 36591253
2021 14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice. Cell reports 15 34910912
2014 Homozygous Deletion of the LGI1 Gene in Mice Leads to Developmental Abnormalities Resulting in Cortical Dysplasia. Brain pathology (Zurich, Switzerland) 15 25346110
2024 Resolution of anti-LGI1-associated autoimmune encephalitis in a patient after treatment with efgartigimod. Journal of neurology 14 38981871
2023 Comparison of quantitative FDG-PET and MRI in anti-LGI1 autoimmune encephalitis. Neuroradiology 14 37264220
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
2020 Psychiatric Manifestation of Anti-LGI1 Encephalitis. Brain sciences 13 32560097
2018 Effect of LGI1 antibody-positive IgG on hippocampal neuron survival: a preliminary study. Neuroreport 13 29771820