Affinage

CNTNAP2

Contactin-associated protein-like 2 · UniProt Q9UHC6

Length
1331 aa
Mass
148.2 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CNTNAP2 encodes Caspr2, a neurexin-superfamily transmembrane cell adhesion molecule that organizes the axonal membrane and regulates cortical circuit development and synaptic function (PMID:21962519, PMID:25378149). At myelinated axons, Caspr2 clusters Kv1 potassium channels at juxtaparanodes by binding contactin-2/TAG-1 (CNTN2) through its ectodomain with low-nanomolar affinity (PMID:27621318, PMID:29244234) and by anchoring to the actin cytoskeleton via its intracellular GNP motif binding to protein 4.1B (PMID:12542678, PMID:20164332); this juxtaparanodal targeting requires 4.1B early in myelination and PKC-dependent somatodendritic endocytosis (via Thr1292) to achieve polarized axonal expression (PMID:19706678, PMID:26840208). Caspr2 and the related Caspr act compensatorily to organize the internodal axolemma and node geometry (PMID:25378149). At synapses, Caspr2 localizes to dendritic spines and stabilizes newly formed spines, controls GluA1 AMPA-receptor trafficking, and mediates homeostatic synaptic scaling, acting through a tripartite Caspr2–CASK–GluA1 complex (PMID:25918374, PMID:25951243, PMID:30843029, PMID:30779956); through direct C-terminal binding to CASK it also stabilizes interneuron dendritic arbors (PMID:29610457). Cntnap2 loss reduces cortical interneurons, disrupts neuronal migration and network activity, cell-autonomously impairs parvalbumin-positive fast-spiking interneurons, and reduces prefrontal synaptic connectivity with disrupted oscillatory phase-locking (PMID:21962519, PMID:29028946, PMID:31141683). Caspr2 is sequentially processed by furin, ADAM10/17 α-secretase, and γ-secretase to liberate an intracellular domain (CICD) that drives CASK nuclear translocation to regulate Necdin transcription, and exogenous cleavage fragments rescue social and repetitive behaviors in mutant mice (PMID:37271769, PMID:38424048). CNTNAP2 lies downstream of FOXP2 in a language-related gene-regulatory pathway (PMID:28488276), and its loss causes hyperactive Akt-mTOR signaling whose pharmacological inhibition rescues social and pain phenotypes (PMID:30816216, PMID:31874168). Caspr2 is the pathological autoantigen in autoimmune encephalitis and peripheral nerve hyperexcitability, where patient antibodies impair the Caspr2–TAG-1 interaction, alter Kv1 and GluA1 levels, and cause reversible memory impairment and pain hypersensitivity via Kv1 downregulation in DRG neurons (PMID:21387375, PMID:29429934, PMID:35253937).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2003 High

    Established how Caspr2 is physically linked to the cytoskeleton, identifying the intracellular GNP motif as the binding site for protein 4.1B at juxtaparanodes.

    Evidence Co-IP from brain homogenates, pull-down binding assays, and developmental immunostaining of CNS/PNS

    PMID:12542678

    Open questions at the time
    • Did not show functional consequence of disrupting the interaction in vivo
    • Role of 4.1R versus 4.1B not resolved
  2. 2009 High

    Resolved how Caspr2 achieves polarized axonal localization, showing PKC-dependent dynamin-mediated endocytosis from the somatodendritic compartment requires Thr1292.

    Evidence HA-tagged constructs, dominant-negative dynamin, Dynasore, PKC inhibition and T1292A mutagenesis in hippocampal neurons

    PMID:19706678

    Open questions at the time
    • The PKC isoform responsible was not identified
    • Whether this mechanism operates in vivo not tested
  3. 2010 High

    Demonstrated that the 4.1B interaction is functionally required for clustering of both Caspr2 and Kv1 channels at juxtaparanodes in vivo.

    Evidence Transgenic rescue of Caspr2-null mice with a 4.1-binding-deficient mutant plus 4.1B knockout mice and immunofluorescence

    PMID:20164332

    Open questions at the time
    • Mechanism connecting 4.1B to Kv1 retention not detailed
    • Did not address synaptic roles
  4. 2011 High

    Defined the developmental requirement for CNTNAP2 in cortex, showing it is needed for interneuron placement and normal network activity prior to seizure onset.

    Evidence Constitutive Cntnap2 knockout mouse with neuropathology, electrophysiology, and behavior

    PMID:21962519

    Open questions at the time
    • Did not establish cell-autonomy of the interneuron phenotype
    • Molecular pathway downstream of loss unresolved
  5. 2012 High

    Identified Caspr2 as the pathological autoantigen in encephalitis and peripheral nerve hyperexcitability, linking the molecule to autoimmune disease.

    Evidence IP-mass spectrometry antigen identification, cell-based assay, immunoabsorption, and comparison to Caspr2-null mouse tissues

    PMID:21387375

    Open questions at the time
    • Did not establish how antibodies alter Caspr2 function
    • Epitope mapping not performed
  6. 2012 Medium

    Placed CNTNAP2 in a language gene-regulatory network as a direct transcriptional target of FOXP2.

    Evidence Lentiviral FoxP2 knockdown in zebra finch Area X, luciferase promoter assays, and qRT-PCR

    PMID:28488276

    Open questions at the time
    • Avian ortholog; mammalian regulation inferred
    • Direct promoter occupancy in human cells not shown
  7. 2012 Medium

    Showed that ASD-associated missense mutations cause ER retention and UPR activation, defining a loss-of-membrane-function mechanism for disease variants.

    Evidence Immunofluorescence, fractionation, and Western blot of mutant constructs in HEK-293 cells and neurons

    PMID:22872700

    Open questions at the time
    • Did not test variants in vivo
    • Quantitative impact on Kv1 clustering not measured
  8. 2014 High

    Revealed compensatory roles of Caspr and Caspr2 in organizing the internodal axolemma and node geometry through genetic epistasis.

    Evidence Caspr/Caspr2 double-knockout mice with immunofluorescence and electron microscopy

    PMID:25378149

    Open questions at the time
    • Molecular basis of compensation not defined
    • Functional electrophysiological consequence not measured
  9. 2015 High

    Extended Caspr2 function to synapses, showing it is required for spine density, spine stabilization, and GluA1 AMPA-receptor trafficking.

    Evidence Super-resolution microscopy, in vivo two-photon spine imaging, and biochemistry in Cntnap2 KO neurons and brain

    PMID:25918374 PMID:25951243

    Open questions at the time
    • Molecular mechanism of GluA1 trafficking control not yet identified
    • Adaptor linking Caspr2 to AMPA receptors unresolved at this stage
  10. 2015 Medium

    Mapped the Caspr2 interactome and subcellular partitioning, identifying CNTN2, Kv1 subunits, ADAM/LGI proteins, and MAGUKs as partners.

    Evidence Affinity purification-mass spectrometry, subcellular fractionation, and Western blot

    PMID:25707359

    Open questions at the time
    • Direct versus indirect interactions not distinguished for all partners
    • Functional relevance of ADAM22/LGI1 association not tested
  11. 2016 High

    Determined the three-lobed architecture of Caspr2 and confirmed direct low-nanomolar binding of its ectodomain to CNTN2.

    Evidence Electron microscopy with epitope labeling, domain-deletion fragment binding, and solid-phase binding assays

    PMID:27621318

    Open questions at the time
    • Atomic-resolution structure of the complex not determined
    • Stoichiometry in the membrane context unresolved
  12. 2018 High

    Identified CASK as the C-terminal partner stabilizing interneuron dendritic arbors, with a rescuable, interneuron-specific loss phenotype.

    Evidence Yeast two-hybrid, co-IP, proximity ligation assay, SIM/STED imaging, shRNA knockdown and rescue

    PMID:29610457

    Open questions at the time
    • Why the requirement is interneuron-specific not explained
    • Link between CASK at membrane and arbor maintenance not mechanistically detailed
  13. 2018 High

    Established cell-autonomous Caspr2 functions: in DRG neurons loss causes Kv1 downregulation and pain hypersensitivity, and in cortex it selectively impairs PV+ fast-spiking interneurons.

    Evidence Patient antibody passive transfer, Cntnap2 KO, MGE transplantation assay, and patch-clamp electrophysiology

    PMID:29028946 PMID:29429934

    Open questions at the time
    • Mechanism linking Caspr2 loss to reduced Kv1 expression at soma not fully defined
    • Why PV+ but not SST+ interneurons are affected unresolved
  14. 2018 Medium

    Showed that ASD variants impair CNTN2 binding and axon growth, with R1119H acting dominant-negatively, and that single-allele loss is sufficient.

    Evidence Cortical neuron axon growth assays, co-IP for oligomerization, binding assays, and ER-retention imaging

    PMID:29788201

    Open questions at the time
    • In vivo consequence of dominant-negative effect not tested
    • Single-lab variant set
  15. 2018 Medium

    Characterized how patient autoantibodies act, showing they block the Caspr2–TAG-1 interaction without internalizing surface Caspr2.

    Evidence Solid-phase binding, surface biotinylation in HEK and neurons, and live-neuron immunofluorescence

    PMID:29244234

    Open questions at the time
    • Discrepancy with later reports of internalization not reconciled here
    • Functional electrophysiological readout absent
  16. 2019 High

    Defined the prefrontal circuit consequences of CNTNAP2 loss, including reduced excitatory and inhibitory inputs and disrupted oscillatory phase-locking.

    Evidence Laser-scanning photostimulation, whole-cell and in vivo recordings, and electron microscopy in Cntnap2 KO mice

    PMID:31141683

    Open questions at the time
    • Cellular mechanism of synapse loss not identified
    • Relationship to interneuron phenotype not directly linked
  17. 2019 High

    Demonstrated a role in homeostatic synaptic plasticity, with loss blocking synaptic scaling and reducing AMPA-receptor currents, replicated by patient antibodies.

    Evidence shRNA knockdown, Cntnap2 KO, in vivo monocular deprivation, whole-cell recordings, and antibody application

    PMID:30843029

    Open questions at the time
    • Molecular signaling driving scaling defect not resolved
    • Link to CASK complex not established in this study
  18. 2019 Medium

    Assembled the synaptic mechanism into a tripartite Caspr2–CASK–GluA1 complex regulating AMPA-receptor levels in interneurons.

    Evidence Co-IP from mouse brain, SIM super-resolution microscopy, and shRNA knockdown

    PMID:30779956

    Open questions at the time
    • Stoichiometry and direct GluA1 contact not resolved
    • Whether complex operates in excitatory neurons unclear
  19. 2019 Medium

    Identified hyperactive Akt-mTOR signaling as a downstream consequence of CNTNAP2 loss that is pharmacologically rescuable.

    Evidence RNA-seq, phospho-Western validation, and Akt/mTOR inhibitor rescue of social deficits and pain in Cntnap2 KO mice

    PMID:30816216 PMID:31874168

    Open questions at the time
    • Mechanistic link from Caspr2 loss to Akt-mTOR activation not defined
    • Cell types driving the signaling change not pinpointed
  20. 2022 High

    Showed that intracerebral patient IgG causes reversible memory impairment via internalization of CASPR2 and reduction of Kv1.1 and GluA1, establishing antibody pathogenicity in vivo.

    Evidence Intracerebroventricular IgG infusion, STED microscopy, molecular quantification, behavioral testing, and reversibility controls

    PMID:35253937

    Open questions at the time
    • Apparent contradiction with earlier no-internalization report not reconciled
    • Epitope-specific differences in antibody effect not defined
  21. 2023 Medium

    Established a nuclear signaling arm in which γ-secretase-generated CICD drives CASK nuclear translocation to regulate Necdin transcription, rescuing behavior in mutants.

    Evidence γ-secretase cleavage assay, viral CICD/Necdin delivery, behavioral rescue, and nuclear fractionation in Cntnap2 KO mice

    PMID:37271769

    Open questions at the time
    • Direct CASK-dependent occupancy at the Necdin promoter not shown
    • Full set of CICD-regulated transcripts unknown
  22. 2024 High

    Defined the full sequential proteolytic cascade (furin → ADAM10/17 → γ-secretase) and showed ASD mutations impair α-cleavage, with the C79 fragment rescuing autism-like behaviors.

    Evidence In vitro ADAM/γ-secretase cleavage assays with mass-spectrometry site mapping, Cntnap2-I1254T knock-in and KO mice, behavioral phenotyping, and viral C79 delivery

    PMID:38424048

    Open questions at the time
    • How α-cleavage is regulated physiologically not defined
    • Relationship between C79 rescue and CICD transcriptional arm not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The mechanistic link connecting Caspr2 loss of function to hyperactive Akt-mTOR signaling and to the integration of its proteolytic/nuclear signaling arm with its membrane adhesion functions remains unresolved.
  • No direct signaling chain from Caspr2 to Akt-mTOR identified
  • Relative contributions of membrane adhesion versus CICD transcription to phenotypes not partitioned
  • Atomic structure of Caspr2-CNTN2 complex undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2 GO:0005856 cytoskeleton 2 GO:0005634 nucleus 1
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 2
Partners
ADAM22CASKCNTN2EPB41L3FOXP2GRIA1KCNA1LGI1
Complex memberships
Caspr2-CASK-GluA1 tripartite complexjuxtaparanodal Caspr2-Kv1-CNTN2 complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Caspr2's conserved intracellular juxtamembrane GNP motif binds proteins 4.1R and 4.1B; 4.1B co-immunoprecipitates with Caspr2 from brain homogenates and colocalizes with Caspr2 at juxtaparanodal regions of myelinated axons, linking Caspr2 to the actin-based cytoskeleton. Co-immunoprecipitation from brain homogenates, pull-down binding assays, immunostaining of developing CNS and PNS The European journal of neuroscience High 12542678
2009 Caspr2 is targeted to the axonal surface through PKC-dependent, dynamin-mediated endocytosis from the somatodendritic compartment. A short sequence within the 4.1B-binding domain containing a PKC substrate motif (Thr1292) is required; point mutation of Thr1292 or PKC inhibition prevents somatodendritic internalization, establishing polarized axonal expression. HA-tagged Caspr2 constructs in hippocampal neurons, dominant-negative Dynamin-1, Dynasore treatment, PKC inhibitor, site-directed mutagenesis (T1292A) Journal of cell science High 19706678
2010 Interaction of Caspr2 with protein 4.1B (via 4.1-binding sequence) is required for accumulation of Caspr2 and Kv1 channels at the juxtaparanodal region; transgenic Caspr2 lacking the 4.1-binding domain fails to cluster at juxtaparanodes, and Caspr2 and Kv1 channels are absent from juxtaparanodes in 4.1B-null mice. Transgenic rescue of Caspr2-null mice with Caspr2-d4.1 mutant, 4.1B knockout mice, immunofluorescence The Journal of neuroscience High 20164332
2011 Cntnap2 knockout mice display neuronal migration abnormalities, reduced number of interneurons, and abnormal neuronal network activity before seizure onset, demonstrating CNTNAP2 is required for normal cortical interneuron placement and brain network development. Cntnap2 constitutive knockout mouse model, neuropathological analysis, electrophysiology, behavioral testing Cell High 21962519
2012 Caspr2 autoantibodies from patients with encephalitis and peripheral nerve hyperexcitability target Caspr2 protein; immunoabsorption with Caspr2 abolishes reactivity, and antibodies are absent in tissues from Caspr2-null mice, confirming Caspr2 as the pathological autoantigen. Immunoprecipitation and mass spectrometry antigen identification, cell-based assay with Caspr2-expressing cells, immunoabsorption, comparative immunostaining of wild-type vs. Caspr2-null mouse tissues Annals of neurology High 21387375
2012 CNTNAP2 is a direct transcriptional target of FOXP2; FOXP2 binds the CNTNAP2 promoter and regulates its expression, placing CNTNAP2 downstream of FOXP2 in a language-related gene-regulatory pathway. Lentiviral FoxP2 knockdown in zebra finch Area X (in vivo), luciferase promoter assays (in vitro), quantitative RT-PCR showing reduced CNTNAP2 expression upon FoxP2 knockdown Genes, brain, and behavior Medium 28488276
2012 Several autism-associated CNTNAP2 missense mutations (e.g., D1129H) cause retention of CASPR2 in the endoplasmic reticulum, activate ER chaperones (BiP/Grp78, Calnexin, ERp57) and the ATF6 branch of the unfolded protein response, and promote proteasomal degradation; a frameshift mutation (1253*) produces a secreted soluble protein, losing membrane-tethered function. Immunofluorescence confocal microscopy, biochemical fractionation, Western blot in HEK-293 cells and hippocampal neurons Human molecular genetics Medium 22872700
2014 Both Caspr and Caspr2 are required for the organization of the axolemma at the mesaxonal internodal line: in single mutants Kv1 channels cluster along the inner mesaxon and below Schmidt-Lanterman incisures, but in Caspr/Caspr2 double knockout mice these channels form dispersed aggregates, revealing compensatory roles. Double deletion also widens nodes of Ranvier. Caspr/Caspr2 double-knockout mouse generation, immunofluorescence, electron microscopy The Journal of neuroscience High 25378149
2015 CNTNAP2 is present in dendritic spines and is required for normal spine density and synaptic localization of GluA1 AMPA receptor subunits; Cntnap2 knockout neurons show reduced spine density, reduced spine GluA1 levels, and large cytoplasmic GluA1 aggregates, indicating a role for CNTNAP2 in GluA1 trafficking. Structured illumination super-resolution microscopy, immunofluorescence, Western blot in Cntnap2 KO cultured neurons and brain slices Proceedings of the National Academy of Sciences of the United States of America High 25918374
2015 New dendritic spines in Cntnap2 knockout mice form at normal rates but fail to stabilize in vivo, indicating a specific role for CNTNAP2 in new spine stabilization rather than spine formation or elimination. In vivo two-photon microscopy for longitudinal spine imaging in Cntnap2 KO mice PloS one Medium 25951243
2015 Interaction proteomics of Caspr2 identifies its binding partners including CNTN2 (TAG-1), Kv1 channel subunits (KCNAs), ADAM family members (ADAM22, ADAM23, ADAM11), LGI family proteins, and MAGUKs (DLGs, MPPs). Caspr2 is enriched in lipid rafts and synaptic membranes but depleted from the postsynaptic density. A short isoform lacking most extracellular domains still associates with ADAM22, LGI1, and Kv1. Affinity purification-mass spectrometry (interaction proteomics), subcellular fractionation, Western blot Biochimica et biophysica acta Medium 25707359
2015 Cntnap2 is expressed throughout all primary sensory organs and multiple sensory brain regions; Cntnap2 knockout mice exhibit abnormal olfactory responses and lack novelty preference, linking Caspr2 expression in sensory circuits to sensory behavior. Caspr2:tau-LacZ knock-in reporter line, X-gal staining for circuit mapping, olfaction-based behavioral tests Molecular and cellular neurosciences Medium 26647347
2016 Electron microscopy reveals that CNTNAP2 has a three-lobed architecture (large, medium, small lobes) distinct from neurexin-1α; domain assignment places F58C, L1, L2 in the large lobe, FBG and L3 in the middle lobe, and L4 in the small lobe. CNTNAP2 and CNTN2 ectodomains bind directly with low nanomolar affinity. Electron microscopy with epitope labeling, domain-deletion fragment binding assays, solid-phase binding assay The Journal of biological chemistry High 27621318
2016 4.1B is required for the proper targeting of Caspr2 to juxtaparanodes early during myelination; in 4.1B KO DRG-Schwann cell myelinating cultures, Caspr2 fails to target correctly while paranodal junctions (stability of Caspr at paranodes) are unaffected. Myelinating DRG neuron-Schwann cell co-cultures from 4.1B KO mice, adenoviral Caspr-GFP, FRAP Glia Medium 26840208
2018 CNTNAP2 stabilizes interneuron dendritic arbors through direct interaction of its C-terminus with CASK; yeast two-hybrid screening, proximity ligation assay, and super-resolution microscopy (SIM/STED) demonstrate CNTNAP2-CASK interaction at the membrane. Loss of Cntnap2 causes interneuron-specific dendritic simplification (not excitatory neuron), reduced cortical membrane CASK, and this phenotype is rescued by CASK expression. Yeast two-hybrid, biochemical co-IP, proximity ligation assay, SIM and STED super-resolution microscopy, shRNA knockdown, phenotype rescue Molecular psychiatry High 29610457
2018 Either immune-mediated (patient autoantibody passive transfer) or genetic (Cntnap2-/-) ablation of CASPR2 enhances excitability of dorsal root ganglion neurons in a cell-autonomous manner through downregulation of Kv1 channel expression at the soma membrane, causing pain hypersensitivity. Human CASPR2 autoantibodies are peripherally restricted when injected into mice. Passive transfer of human autoantibodies into mice, Cntnap2 KO mice, DRG neuron electrophysiology, Kv1 immunostaining and Western blot Neuron High 29429934
2018 Caspr2 autoantibodies inhibit the interaction of Caspr2 with contactin-2 (nanomolar affinity interaction confirmed by solid-phase assay) but do not cause internalization of surface Caspr2 from primary hippocampal neurons or HEK cells. Solid-phase binding assay quantifying Caspr2-contactin-2 interaction, cell-surface biotinylation and Western blot of HEK cells, living neuron immunofluorescence Annals of neurology Medium 29244234
2018 Human ASD-associated CNTNAP2 missense variants (e.g., I869T, G731S) impair Contactin2/TAG-1 binding and fail to rescue axonal growth deficits in Cntnap2 heterozygous cortical neurons; variant R1119H is retained in ER and exerts a dominant-negative effect on axon growth via oligomerization with wild-type Caspr2. Loss of one Cntnap2 allele is sufficient to reduce axon growth in a dose-dependent manner. Cortical neuron cultures from mouse embryos, axon growth measurements, co-immunoprecipitation for oligomerization, binding assays for Contactin2, immunofluorescence for ER retention Human molecular genetics Medium 29788201
2018 Mouse and human ASD CNTNAP2 missense mutations cell-autonomously impair the physiology of parvalbumin-positive (PV+) fast-spiking cortical interneurons in a transplantation assay; Cntnap2 null constitutive mutants have reduced PV+ CINs but normal total MGE-derived CIN numbers. Somatostatin+ CINs show no phenotype. MGE cell transplantation assay (cell-autonomous testing), constitutive Cntnap2 null mice, whole-cell patch clamp, immunofluorescence Cerebral cortex High 29028946
2019 CNTNAP2 loss causes dramatic reduction in excitatory and inhibitory synaptic inputs onto L2/3 pyramidal neurons of medial prefrontal cortex, along with reduced spines and synapses despite normal dendritic complexity and intrinsic excitability; in vivo mPFC recordings show increased inhibitory neuron activity and disrupted phase-locking to delta/theta oscillations. Laser-scanning photostimulation, whole-cell recordings, electron microscopy, in vivo LFP and unit recording in Cntnap2 KO mice Cell reports High 31141683
2019 Caspr2 loss of function (genetic knockdown or knockout) decreases synaptic AMPA receptor expression and amplitude of AMPA receptor-mediated currents in cortex, blocks synaptic scaling in vitro, and impairs experience-dependent homeostatic synaptic plasticity in vivo; patient CASPR2 antibodies decrease dendritic Caspr2 levels and synaptic AMPA receptor trafficking. In vitro shRNA knockdown, Cntnap2 KO, in vivo visual cortex monocular deprivation, whole-cell recordings, immunofluorescence; patient antibody application to neurons Cerebral cortex High 30843029
2019 CNTNAP2, CASK, and GluA1 form a tripartite complex in interneurons (confirmed by SIM super-resolution microscopy and biochemical co-IP in mouse brain); individual knockdown of either CNTNAP2 or CASK similarly alters GluA1 levels and localization in interneurons. Co-immunoprecipitation from mouse brain, structured illumination microscopy, shRNA knockdown Neuroscience letters Medium 30779956
2019 Hyperactive Akt-mTOR signaling is present in the hippocampus and DRG of Cntnap2-/- mice; pharmacological inhibition with Akt inhibitor (LY294002) or mTOR inhibitor (rapamycin) rescues social deficits and pain hypersensitivity, and reduces DRG neuronal hyperexcitability. RNA sequencing followed by biochemical validation (Western blot for phospho-Akt/mTOR), pharmacological rescue in Cntnap2 KO mice, patch-clamp electrophysiology of DRG neurons Scientific reports / Neuropharmacology Medium 30816216 31874168
2019 Anti-CASPR2 patient antibodies alter Caspr2 distribution at the cell membrane (promoting cluster formation), impede CASPR2/TAG-1 interaction, and introduction of Caspr2 into HEK cells induces increased Kv1.2 surface expression; patient antibodies increase Kv1.2 expression in both HEK and hippocampal neuron models. Cell-based assays (HEK cells expressing Caspr2), primary hippocampal neuron cultures, immunofluorescence, domain-deletion constructs identifying CASPR2-TAG1 interaction domains Journal of autoimmunity Medium 31176559
2022 Patient IgG infused into mouse cerebroventricular system causes reversible memory impairment, reduces surface CASPR2 clusters, decreases CASPR2/TAG-1 colocalization (super-resolution STED), selectively internalizes CASPR2 (not TAG-1) in cultured neurons, and decreases hippocampal Kv1.1 and GluA1 levels; all effects reverse upon IgG removal. Intracerebroventricular IgG infusion in mice, STED super-resolution microscopy, confocal quantification of Kv1.1 and GluA1, behavioral memory testing, cultured neuron internalization assay Annals of neurology High 35253937
2023 CNTNAP2 is cleaved by γ-secretase to produce a CNTNAP2 intracellular domain (CICD); viral delivery of CICD to the medial prefrontal cortex of Cntnap2-/- mice rescues social and repetitive behavior deficits. CICD promotes nuclear translocation of CASK to regulate transcription of Necdin; Necdin deficiency reduces social interaction, and Necdin viral expression in mPFC rescues social preference in Cntnap2-/- mice. Biochemical γ-secretase cleavage assay, viral delivery of CICD/Necdin, behavioral rescue in Cntnap2 KO mice, nuclear fractionation showing CASK translocation Signal transduction and targeted therapy Medium 37271769
2024 CNTNAP2 undergoes sequential proteolytic processing: furin cleavage, then ADAM10/17-dependent α-secretase cleavage at residues I79 (ADAM10) and L96 (ADAM17) generating fragment C79, which is required for subsequent γ-secretase cleavage to produce CICD. ASD-associated CNTNAP2 mutations impair α-cleavage; inhibiting α-cleavage in Cntnap2-I1254T knock-in mice produces autism-like social and repetitive behaviors. Exogenous C79 rescues these phenotypes in both knock-in and knockout mice. In vitro cleavage assays with ADAM10/17, γ-secretase inhibitors, mass spectrometry of cleavage sites, Cntnap2-I1254T knock-in mouse generation, behavioral phenotyping, viral C79 delivery Signal transduction and targeted therapy High 38424048

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 860 21962519
2008 Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. American journal of human genetics 620 18179893
2011 Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia. Annals of neurology 333 21387375
2016 The clinical spectrum of Caspr2 antibody-associated disease. Neurology 317 27371488
2015 Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism. Science translational medicine 312 25609168
2009 CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. American journal of human genetics 269 19896112
2007 CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Molecular psychiatry 234 17646849
2013 Shining a light on CNTNAP2: complex functions to complex disorders. European journal of human genetics : EJHG 208 23714751
2016 Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2. Neuron 165 26833134
2017 LGI1, CASPR2 and related antibodies: a molecular evolution of the phenotypes. Journal of neurology, neurosurgery, and psychiatry 161 29055902
2018 Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability. Neuron 148 29429934
2013 Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA neurology 148 23407760
2012 What does CNTNAP2 reveal about autism spectrum disorder? Trends in molecular medicine 137 22365836
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
2015 Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein-like 2/Caspr2 knockout neurons. Proceedings of the National Academy of Sciences of the United States of America 120 25918374
2003 Protein 4.1B associates with both Caspr/paranodin and Caspr2 at paranodes and juxtaparanodes of myelinated fibres. The European journal of neuroscience 114 12542678
2011 Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1. BMC medical genetics 101 21827697
2019 Reduced Prefrontal Synaptic Connectivity and Disturbed Oscillatory Population Dynamics in the CNTNAP2 Model of Autism. Cell reports 99 31141683
2010 Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B. The Journal of neuroscience : the official journal of the Society for Neuroscience 94 20164332
2018 Mechanisms of Caspr2 antibodies in autoimmune encephalitis and neuromyotonia. Annals of neurology 93 29244234
2015 Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders. Molecular syndromology 84 25852443
2021 Cortical overgrowth in a preclinical forebrain organoid model of CNTNAP2-associated autism spectrum disorder. Nature communications 83 34471112
2018 Homozygous Loss of Autism-Risk Gene CNTNAP2 Results in Reduced Local and Long-Range Prefrontal Functional Connectivity. Cerebral cortex (New York, N.Y. : 1991) 83 28184409
2020 Systematic review of the clinical spectrum of CASPR2 antibody syndrome. Journal of neurology 78 31912210
2020 Anti-CASPR2 clinical phenotypes correlate with HLA and immunological features. Journal of neurology, neurosurgery, and psychiatry 78 32651251
2018 Mouse Cntnap2 and Human CNTNAP2 ASD Alleles Cell Autonomously Regulate PV+ Cortical Interneurons. Cerebral cortex (New York, N.Y. : 1991) 76 29028946
2015 The Autism Related Protein Contactin-Associated Protein-Like 2 (CNTNAP2) Stabilizes New Spines: An In Vivo Mouse Study. PloS one 74 25951243
2018 Dysregulation of Parvalbumin Expression in the Cntnap2-/- Mouse Model of Autism Spectrum Disorder. Frontiers in molecular neuroscience 68 30116174
2017 Autoimmune episodic ataxia in patients with anti-CASPR2 antibody-associated encephalitis. Neurology(R) neuroimmunology & neuroinflammation 61 28638854
2010 Caspr2 antibodies in patients with thymomas. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 60 20859119
2009 Axonal targeting of Caspr2 in hippocampal neurons via selective somatodendritic endocytosis. Journal of cell science 58 19706678
2012 CNTNAP2 is significantly associated with schizophrenia and major depression in the Han Chinese population. Psychiatry research 57 23123147
2019 Suppression of Akt-mTOR pathway rescued the social behavior in Cntnap2-deficient mice. Scientific reports 56 30816216
2019 Daratumumab treatment for therapy-refractory anti-CASPR2 encephalitis. Journal of neurology 56 31630242
2015 Expression of Cntnap2 (Caspr2) in multiple levels of sensory systems. Molecular and cellular neurosciences 56 26647347
2017 Cntnap2 Knockout Rats and Mice Exhibit Epileptiform Activity and Abnormal Sleep-Wake Physiology. Sleep 52 28364455
2020 Anti-LGI1, anti-GABABR, and Anti-CASPR2 encephalitides in Asia: A systematic review. Brain and behavior 51 32783406
2019 Disrupted AMPA Receptor Function upon Genetic- or Antibody-Mediated Loss of Autism-Associated CASPR2. Cerebral cortex (New York, N.Y. : 1991) 51 30843029
2018 Altered Auditory Processing, Filtering, and Reactivity in the Cntnap2 Knock-Out Rat Model for Neurodevelopmental Disorders. The Journal of neuroscience : the official journal of the Society for Neuroscience 49 30126973
2018 LGI1 and CASPR2 neurological autoimmunity in children. Annals of neurology 48 30076629
2018 Genetic variants in autism-related CNTNAP2 impair axonal growth of cortical neurons. Human molecular genetics 47 29788201
2016 Molecular Architecture of Contactin-associated Protein-like 2 (CNTNAP2) and Its Interaction with Contactin 2 (CNTN2). The Journal of biological chemistry 47 27621318
2015 Clinical manifestations of patients with CASPR2 antibodies. Journal of neuroimmunology 47 25867463
2021 Clinical Character of CASPR2 Autoimmune Encephalitis: A Multiple Center Retrospective Study. Frontiers in immunology 43 34054814
2020 Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2. Practical neurology 43 32595134
2018 CNTNAP2 stabilizes interneuron dendritic arbors through CASK. Molecular psychiatry 42 29610457
2022 Cntnap2-dependent molecular networks in autism spectrum disorder revealed through an integrative multi-omics analysis. Molecular psychiatry 41 36253443
2012 Inherited genetic variants in autism-related CNTNAP2 show perturbed trafficking and ATF6 activation. Human molecular genetics 41 22872700
2019 LGI1 and CASPR2 autoimmunity in children: Systematic literature review and report of a young girl with Morvan syndrome. Journal of neuroimmunology 39 31352183
2015 Caspr2 autoantibodies target multiple epitopes. Neurology(R) neuroimmunology & neuroinflammation 38 26185774
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
2014 Caspr and caspr2 are required for both radial and longitudinal organization of myelinated axons. The Journal of neuroscience : the official journal of the Society for Neuroscience 37 25378149
2017 Intragenic CNTNAP2 Deletions: A Bridge Too Far? Molecular syndromology 36 28588433
2013 CNTNAP2 polymorphisms and structural brain connectivity: a diffusion-tensor imaging study. Journal of psychiatric research 35 23871450
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
2022 Human CASPR2 Antibodies Reversibly Alter Memory and the CASPR2 Protein Complex. Annals of neurology 34 35253937
2015 Auditory processing and morphological anomalies in medial geniculate nucleus of Cntnap2 mutant mice. Behavioral neuroscience 32 26501174
2019 Impact of anti-CASPR2 autoantibodies from patients with autoimmune encephalitis on CASPR2/TAG-1 interaction and Kv1 expression. Journal of autoimmunity 31 31176559
2015 Interaction proteomics of canonical Caspr2 (CNTNAP2) reveals the presence of two Caspr2 isoforms with overlapping interactomes. Biochimica et biophysica acta 31 25707359
2012 The juxtaparanodal proteins CNTNAP2 and TAG1 regulate diet-induced obesity. Mammalian genome : official journal of the International Mammalian Genome Society 31 22752552
2010 The CASPR2 cell adhesion molecule functions as a tumor suppressor gene in glioma. Oncogene 31 20711234
2017 Developmental Disruption of GABAAR-Meditated Inhibition in Cntnap2 KO Mice. eNeuro 30 28966979
2017 Expanding spectrum of contactin-associated protein 2 (CASPR2) autoimmunity-syndrome of parkinsonism and ataxia. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 30 29264691
2022 Contemporary advances in antibody-mediated encephalitis: anti-LGI1 and anti-Caspr2 antibody (Ab)-mediated encephalitides. Autoimmunity reviews 29 35247644
2017 Protein-Protein Interaction Among the FoxP Family Members and their Regulation of Two Target Genes, VLDLR and CNTNAP2 in the Zebra Finch Song System. Frontiers in molecular neuroscience 28 28507505
2022 CASPR2-IgG-associated autoimmune seizures. Epilepsia 27 35032032
2022 Seizure underreporting in LGI1 and CASPR2 antibody encephalitis. Epilepsia 27 35735209
2021 GABAB Receptor Agonist R-Baclofen Reverses Altered Auditory Reactivity and Filtering in the Cntnap2 Knock-Out Rat. Frontiers in integrative neuroscience 26 34489651
2020 CASPR2 autoimmunity in children expanding to mild encephalopathy with hypertension. Neurology 26 32424051
2019 Cross-species models of attention-deficit/hyperactivity disorder and autism spectrum disorder: lessons from CNTNAP2, ADGRL3, and PARK2. Psychiatric genetics 25 30376466
2022 Somatosensory cortex hyperconnectivity and impaired whisker-dependent responses in Cntnap2-/- mice. Neurobiology of disease 24 35483565
2023 CNTNAP2 intracellular domain (CICD) generated by γ-secretase cleavage improves autism-related behaviors. Signal transduction and targeted therapy 23 37271769
2021 CASPR2-Related Morvan Syndrome: Autonomic, Polysomnographic, and Neuropsychological Observations. Neurology. Clinical practice 23 34484901
2019 Hyperactive Akt-mTOR pathway as a therapeutic target for pain hypersensitivity in Cntnap2-deficient mice. Neuropharmacology 23 31874168
2018 Genetic variants in the CNTNAP2 gene are associated with gender differences among dyslexic children in China. EBioMedicine 23 30017804
2023 Loss of CNTNAP2 Alters Human Cortical Excitatory Neuron Differentiation and Neural Network Development. Biological psychiatry 22 37001843
2020 Coexistent MOG, NMDAR, CASPR2 antibody positivity: Triumph over the triumvirate. Multiple sclerosis and related disorders 22 32906000
2019 Acquired neuromyotonia in children with CASPR2 and LGI1 antibodies. Developmental medicine and child neurology 22 30724344
2016 Assembly of juxtaparanodes in myelinating DRG culture: Differential clustering of the Kv1/Caspr2 complex and scaffolding protein 4.1B. Glia 21 26840208
2016 Single nucleotide polymorphisms in the CNTNAP2 gene in Brazilian patients with autistic spectrum disorder. Genetics and molecular research : GMR 21 26909962
2014 Distribution of language-related Cntnap2 protein in neural circuits critical for vocal learning. The Journal of comparative neurology 21 23818387
2014 Widespread differences in cortex DNA methylation of the "language gene" CNTNAP2 between humans and chimpanzees. Epigenetics 21 24434791
2021 Altered cingulate structures and the associations with social awareness deficits and CNTNAP2 gene in autism spectrum disorder. NeuroImage. Clinical 20 34271514
2020 Serum and CSF cytokine levels mirror different neuroimmunological mechanisms in patients with LGI1 and Caspr2 encephalitis. Cytokine 20 32799011
2017 CNTNAP2 is a direct FoxP2 target in vitro and in vivo in zebra finches: complex regulation by age and activity. Genes, brain, and behavior 20 28488276
2023 Genotype-phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder. Human genetics 19 37183190
2022 Objective sleep profile in LGI1/CASPR2 autoimmunity. Sleep 19 34953167
2014 Caspr2 antibody limbic encephalitis is associated with Hashimoto thyroiditis and thymoma. Journal of the neurological sciences 19 24726720
2022 Hyperexcitable and immature-like neuronal activity in the auditory cortex of adult rats lacking the language-linked CNTNAP2 gene. Cerebral cortex (New York, N.Y. : 1991) 18 35106542
2017 The association of CNTNAP2 rs7794745 gene polymorphism and autism in Iranian population. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 18 28284582
2017 Axonal domain disorganization in Caspr1 and Caspr2 mutant myelinated axons affects neuromuscular junction integrity, leading to muscle atrophy. Journal of neuroscience research 18 28370195
2019 The CNTNAP2-CASK complex modulates GluA1 subcellular distribution in interneurons. Neuroscience letters 17 30779956
2011 Cntnap2 expression in the cerebellum of Foxp2(R552H) mice, with a mutation related to speech-language disorder. Neuroscience letters 16 22133810
2025 The interplay between oxidative stress and inflammation supports autistic-related behaviors in Cntnap2 knockout mice. Brain, behavior, and immunity 15 40023202
2024 Contactin-associated protein-like 2 (CNTNAP2) mutations impair the essential α-secretase cleavages, leading to autism-like phenotypes. Signal transduction and targeted therapy 15 38424048
2023 Neuroanatomical Alterations in the CNTNAP2 Mouse Model of Autism Spectrum Disorder. Brain sciences 15 37371370
2015 CNTNAP2 gene in high functioning autism: no association according to family and meta-analysis approaches. Journal of neural transmission (Vienna, Austria : 1996) 15 26559825
2021 Altered Cerebellar Response to Somatosensory Stimuli in the Cntnap2 Mouse Model of Autism. eNeuro 14 34593517
2019 Association between CNTNAP2 polymorphisms and autism: A family-based study in the chinese han population and a meta-analysis combined with GWAS data of psychiatric genomics consortium. Autism research : official journal of the International Society for Autism Research 14 30681286

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