Affinage

CNTNAP2

Contactin-associated protein-like 2 · UniProt Q9UHC6

Length
1331 aa
Mass
148.2 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CNTNAP2 (Caspr2) is a neurexin-superfamily transmembrane cell adhesion molecule that organizes axonal domains, regulates synaptic function, and controls cortical development. At myelinated axons, Caspr2 forms a complex with contactin-2/TAG-1 and, through its cytoplasmic protein 4.1B-binding domain, clusters Kv1 potassium channels at the juxtaparanodal region, thereby shaping axonal excitability and action potential waveform (PMID:12963709, PMID:20164332, PMID:29300891). At excitatory synapses, Caspr2 stabilizes newly formed dendritic spines, maintains synaptic AMPA receptor expression, and is required for homeostatic synaptic scaling; its intracellular domain, released by γ-secretase cleavage, translocates CASK to the nucleus to drive Necdin transcription and regulate social behavior (PMID:30843029, PMID:25951243, PMID:37271769). Loss of CNTNAP2 causes reduced cortical interneurons (particularly parvalbumin-positive), neuronal migration abnormalities, hyperactive Akt-mTOR signaling, decreased hypothalamic oxytocin, and increased neural progenitor proliferation, while patient autoantibodies against the Caspr2 ectodomain internalize surface Caspr2, disrupt contactin-2 binding, and reduce Kv1 channels and GluA1, causing autoimmune encephalitis and neuropathic pain (PMID:21962519, PMID:29028946, PMID:35253937, PMID:29429934).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2001 High

    Before Caspr2's function was known at the node of Ranvier, analysis of paranodal adhesion mutants established that the juxtaparanodal positioning of Caspr2 and Kv1.2 depends on intact paranodal barriers, revealing that axon-glia interactions gate Caspr2 localization.

    Evidence Immunostaining in CGT-/- and contactin-KO mice with developmental time-course

    PMID:11567047

    Open questions at the time
    • Mechanism by which paranodal barriers exclude Caspr2 not defined
    • Whether Caspr2 is actively transported or passively excluded was unknown
  2. 2003 High

    Gene-targeted deletion of Caspr2 established it as the essential organizer for juxtaparanodal Kv1 channel clustering and demonstrated that this function requires the Caspr2–TAG-1 interaction, defining the core adhesion complex at the juxtaparanode.

    Evidence Cntnap2 knockout mice with immunostaining and co-localization studies

    PMID:12963709

    Open questions at the time
    • Which Caspr2 domains mediate Kv1 recruitment was unknown
    • Trans vs. cis interaction with TAG-1 not resolved
  3. 2008 High

    Transgenic rescue with domain-deletion mutants resolved that the Caspr2 cytoplasmic domain (not the PDZ-binding motif) is essential for Kv1 clustering, and that PSD-93/PSD-95 accumulate at juxtaparanodes in a Caspr2-dependent manner, while PSD-93 independently clusters Kv1 at the AIS.

    Evidence Caspr2-null mice rescued with Caspr2ΔCT or Caspr2ΔPDZ transgenes; PSD-93 KO and RNAi

    PMID:18509034 PMID:19109503

    Open questions at the time
    • Precise scaffolding contacts between Caspr2 cytoplasmic domain and Kv1 subunits not identified
    • Role of individual MAGUK family members at juxtaparanode not dissected
  4. 2009 High

    The mechanism of Caspr2 axonal polarization was revealed to be selective somatodendritic endocytosis rather than directed axonal transport, requiring dynamin and a PKC-phosphorylatable residue (Thr1292) within the 4.1B-binding domain.

    Evidence HA-tagged Caspr2 in hippocampal neurons with dominant-negative dynamin, Dynasore, T1292 mutagenesis, and live-cell imaging

    PMID:19706678

    Open questions at the time
    • Identity of the PKC isoform phosphorylating T1292 not determined
    • Whether this mechanism operates in vivo during myelination not shown
  5. 2010 High

    The requirement for protein 4.1B in Caspr2 membrane retention was demonstrated: a Caspr2 transgene lacking the 4.1B-binding sequence and 4.1B-null mice both fail to accumulate Caspr2 and Kv1 at juxtaparanodes, establishing 4.1B as a critical cytoskeletal anchor.

    Evidence Transgenic rescue with Caspr2-Δ4.1 in Caspr2-null mice; 4.1B-null mice

    PMID:20164332

    Open questions at the time
    • Whether 4.1B links Caspr2 to spectrin-actin cytoskeleton directly or through intermediaries not resolved
    • Redundancy with other 4.1 family members not fully tested
  6. 2011 High

    Beyond its role at axonal domains, Cntnap2 knockout mice revealed a developmental function: reduced cortical interneurons, neuronal migration abnormalities, and abnormal network activity prior to seizure onset, establishing Caspr2 as a regulator of cortical circuit assembly.

    Evidence Cntnap2-/- mice with neuropathological analysis, EEG, behavioral testing

    PMID:21962519

    Open questions at the time
    • Cell-autonomous vs. non-autonomous mechanism of interneuron loss not determined at this stage
    • Molecular pathway linking Caspr2 to migration not identified
  7. 2012 High

    Autism-associated CNTNAP2 missense variants were shown to cause pathology through protein misfolding: D1129H is retained in the ER via chaperone interactions and activates the ATF6 UPR branch, while the 1253* frameshift produces a secreted, untethered protein, revealing loss-of-function mechanisms at the protein level.

    Evidence Confocal microscopy and co-immunoprecipitation in HEK-293 cells and hippocampal neurons

    PMID:22872700

    Open questions at the time
    • Whether ER-retained variants exert gain-of-function toxicity via chronic UPR activation not tested in vivo
    • Prevalence of trafficking-defective variants among all ASD-associated CNTNAP2 alleles unknown
  8. 2015 High

    Multiple studies converged to define Caspr2's synaptic and circuit-level roles: it stabilizes new dendritic spines, selectively supports perisomatic inhibition, and its interactome includes ADAM22/23, LGI family, Kv1 channels, and MAGUKs; separately, loss of Cntnap2 causes reduced hypothalamic oxytocin neurons and brain oxytocin, with oxytocin administration rescuing social deficits.

    Evidence In vivo two-photon spine imaging; hippocampal slice electrophysiology; interaction proteomics/co-IP; oxytocin immunostaining, ELISA, DREADD chemogenetics in Cntnap2-/- mice

    PMID:25609168 PMID:25707359 PMID:25951243 PMID:26511255

    Open questions at the time
    • How Caspr2 mechanistically stabilizes spines (signaling pathway) unknown
    • Whether oxytocin deficit is cell-autonomous or circuit-level consequence not resolved
    • Functional significance of ADAM22/LGI1 interaction for Caspr2 not tested
  9. 2015 High

    ASD-associated CNTNAP2 missense variants I869T and G731S (impaired TAG-1 binding) fail to rescue axon growth in haploinsufficient neurons, while R1119H exerts a dominant-negative effect through oligomerization with wild-type Caspr2, demonstrating dose-dependent and dominant-negative pathogenic mechanisms.

    Evidence Cortical neuron cultures from heterozygous Cntnap2+/- mouse embryos with variant rescue assays

    PMID:29788201

    Open questions at the time
    • Oligomerization interface enabling dominant-negative effect not structurally defined
    • In vivo consequences of heterozygous ASD variants not characterized
  10. 2016 High

    Structural characterization of the Caspr2 ectodomain by EM revealed a three-lobed architecture that binds contactin-2 with low-nanomolar affinity; autism-associated mutations are distributed throughout the ectodomain rather than clustering in one binding interface.

    Evidence Electron microscopy with epitope labeling; domain fragment binding assays

    PMID:27621318

    Open questions at the time
    • Atomic-resolution structure not available
    • Which ectodomain surface contacts contactin-2 not mapped
  11. 2018 High

    Caspr2 was shown to cell-autonomously regulate PV+ fast-spiking interneuron physiology but not somatostatin+ interneurons, and separately, passive transfer of patient CASPR2 autoantibodies into mice demonstrated that immune-mediated Caspr2 loss enhances DRG excitability and causes neuropathic pain through peripheral Kv1 channel dysregulation.

    Evidence MGE-derived interneuron transplantation into wild-type brain; passive transfer of patient IgG; Cntnap2-/- DRG electrophysiology

    PMID:29028946 PMID:29429934

    Open questions at the time
    • How Caspr2 controls PV+ interneuron maturation at the molecular level unknown
    • Whether peripheral and central autoantibody effects are mechanistically distinct not resolved
  12. 2018 High

    Caspr2 autoantibodies were shown to block the Caspr2–contactin-2 interaction at nanomolar sensitivity, identifying functional disruption of this adhesion complex as the primary pathogenic mechanism of IgG4 autoantibodies in encephalitis.

    Evidence Solid-phase binding assay; cell-surface biotinylation in hippocampal neurons and HEK cells

    PMID:29244234

    Open questions at the time
    • Whether different epitope specificities of patient antibodies produce different clinical phenotypes not tested
    • Complement-independent vs. complement-dependent pathology not dissected
  13. 2019 High

    Caspr2's synaptic role was extended to excitatory synapses: knockdown reduces synaptic AMPA receptor expression and blocks homeostatic synaptic scaling both in vitro and in visual cortex in vivo; patient antibodies phenocopy this by internalizing dendritic Caspr2 and reducing AMPA receptor trafficking.

    Evidence siRNA knockdown in vitro and in vivo; whole-cell electrophysiology; AMPA receptor trafficking assays; patient antibody treatment

    PMID:30843029

    Open questions at the time
    • Molecular mechanism linking Caspr2 to AMPA receptor insertion/retention unknown
    • Whether Caspr2-dependent homeostatic plasticity operates at all cortical synapses or is layer-specific not determined
  14. 2019 High

    Loss of Cntnap2 profoundly reduces both excitatory and inhibitory synaptic inputs onto mPFC L2/3 pyramidal neurons despite normal dendritic morphology and intrinsic excitability, and disrupts cortical myelination timing and axonal action potential waveform, revealing convergent circuit-level consequences.

    Evidence Laser-scanning photostimulation, in vivo electrophysiology, EM in Cntnap2-/- mice; developmental myelination analysis

    PMID:29300891 PMID:31141683

    Open questions at the time
    • Whether myelination delay is secondary to altered neuronal activity or a direct glial effect of Caspr2 loss unknown
    • Relationship between mPFC circuit changes and behavioral phenotypes not causally tested
  15. 2021 High

    Patient-derived forebrain organoids with homozygous CNTNAP2 truncation revealed increased neural progenitor proliferation and organoid overgrowth, rescued by CRISPR correction, identifying a human-relevant role for CNTNAP2 in controlling progenitor expansion in PFC-excitatory neuron lineages.

    Evidence iPSC-derived forebrain organoids; scRNA-seq; CRISPR-Cas9 isogenic correction

    PMID:34471112

    Open questions at the time
    • Signaling pathway by which Caspr2 restrains progenitor proliferation not identified
    • Whether this phenotype occurs in heterozygous patient cells not tested
  16. 2022 High

    In vivo infusion of patient anti-CASPR2 IgG confirmed a unified autoimmune mechanism: antibodies internalize surface Caspr2, disrupt Caspr2/TAG-1 co-localization (by STED), and reduce both Kv1.1 and GluA1, with full reversibility upon IgG removal, establishing the downstream molecular cascade of autoantibody-mediated encephalitis.

    Evidence Intracerebroventricular IgG infusion; STED super-resolution microscopy; behavioral testing; cultured neuron internalization assay

    PMID:35253937

    Open questions at the time
    • Whether antibody-induced internalization proceeds via the same PKC/dynamin pathway as physiological somatodendritic endocytosis unknown
    • Long-term irreversible synaptic damage thresholds not defined
  17. 2023 Medium

    A non-canonical signaling function was discovered: γ-secretase cleavage of Caspr2 releases an intracellular domain (CICD) that translocates CASK to the nucleus to activate Necdin transcription, with viral CICD or Necdin delivery to mPFC rescuing social deficits in Cntnap2-/- mice.

    Evidence Biochemical γ-secretase cleavage assay; viral CICD and Necdin rescue in mPFC of Cntnap2-/- mice; nuclear translocation assays

    PMID:37271769

    Open questions at the time
    • γ-secretase cleavage regulation and stimulus-dependence not characterized
    • Independent replication of CICD nuclear signaling pathway needed
    • Whether CICD signaling operates at juxtaparanodes or only at synapses unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic-resolution structure of the Caspr2–contactin-2 complex, the signaling pathway by which Caspr2 controls neural progenitor proliferation and interneuron migration, the precise mechanism linking Caspr2 to AMPA receptor synaptic retention, and whether the γ-secretase/CICD/CASK/Necdin pathway is broadly operative across brain regions.
  • No atomic-resolution structure of Caspr2 or Caspr2–CNTN2 complex
  • Signaling cascade from Caspr2 to progenitor proliferation control not identified
  • Mechanism of AMPA receptor stabilization by Caspr2 at the molecular level unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098631 cell adhesion mediator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 6 R-HSA-1266738 Developmental Biology 3 R-HSA-1500931 Cell-Cell communication 3 R-HSA-162582 Signal Transduction 2
Partners
ADAM22CASKCNTN2DLG1EPB41L3LGI1MPDZMPP2
Complex memberships
Caspr2/ADAM22/LGI1 complexCaspr2/GPR37/MUPP1 complexCaspr2/TAG-1(CNTN2)/Kv1 juxtaparanodal complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Caspr2 (CNTNAP2) is required to maintain Kv1 (Shaker-like K+) channels at the juxtaparanodal region of myelinated axons, and this clustering depends on the interaction of Caspr2 with TAG-1 (an immunoglobulin-like cell adhesion molecule that binds Caspr2), forming a scaffold that organizes ion channels in the axonal membrane through axon-glia interactions. Gene-targeted knockout mice, immunostaining, co-localization studies The Journal of cell biology High 12963709
2001 Caspr2 localization to the juxtaparanodal region depends on axon-glia interactions and the formation of paranodal barriers; in the absence of paranodal adhesion (CGT-/- or contactin KO mice), Caspr2 and Kv1.2 fail to relocate to juxtaparanodes and instead remain at paranodes, demonstrating that Caspr-containing barriers control the positioning of Caspr2. Analysis of mutant mice (CGT-/- and contactin KO) with immunostaining and developmental time-course experiments The Journal of neuroscience High 11567047
2008 Caspr2 clusters Kv1 channels at the juxtaparanodal region via its cytoplasmic domain but not via its carboxy-terminal PDZ-binding motif; PSD-93 and PSD-95 accumulate at the juxtaparanode in a Caspr2- and TAG-1-dependent manner; Caspr2 interacts with distinct scaffolding proteins through both PDZ- and protein 4.1-binding sequences as revealed by proteomics. Transgenic rescue experiments with deletion mutants (Caspr2dCT, Caspr2dPDZ) in Caspr2-null mice; co-immunoprecipitation; proteomic analysis The Journal of neuroscience High 19109503
2008 PSD-93, but not Caspr2, is required for clustering Kv1 channels at the axon initial segment (AIS); Caspr2 mediates Kv1 channel clustering at the juxtaparanode through a distinct mechanism independent of PSD-93. PSD-93 knockdown by RNAi in hippocampal neurons; PSD-93-/- knockout mice; comparison with Caspr2-null mice The Journal of neuroscience High 18509034
2010 The interaction of Caspr2 with protein 4.1B is required for the accumulation of Caspr2 and Kv1 channels at the juxtaparanodal axonal membrane; a Caspr2 transgene lacking the 4.1B-binding sequence (Caspr2-d4.1) does not accumulate at the juxtaparanode, and Kv1 channels are not clustered at the juxtaparanode in 4.1B-null mice. Transgenic rescue experiments with 4.1-binding domain deletion mutants in Caspr2-null mice; analysis of 4.1B-null mice The Journal of neuroscience High 20164332
2009 Caspr2 is targeted to the axonal surface through selective somatodendritic endocytosis; internalization from dendrites and cell body is dynamin-dependent and requires a PKC substrate motif at Thr1292 within the 4.1B-binding domain, as mutation of this residue or PKC inhibition prevents somatodendritic internalization. HA-tagged Caspr2 in hippocampal neurons, dominant-negative dynamin-1 or Dynasore treatment, site-directed mutagenesis (T1292 mutant), live-cell imaging Journal of cell science High 19706678
2014 Both Caspr and Caspr2 together are required for the radial (mesaxonal line) and longitudinal organization of Kv1 channels along myelinated peripheral axons; in Caspr/Caspr2 double-null mice, Kv1 channels are dispersed along the axolemma rather than confined to the internodal line, and nodes of Ranvier are widened, revealing compensatory functions between the two proteins. Double knockout mice (caspr-/-/caspr2-/-), immunostaining, comparison with single mutants The Journal of neuroscience High 25378149
2011 Cntnap2 knockout mice show neuronal migration abnormalities, reduced number of cortical interneurons, and abnormal neuronal network activity prior to seizure onset, establishing a functional role for CNTNAP2 in brain development including interneuron positioning. Cntnap2-/- knockout mouse characterization; neuropathological analysis, EEG recording, behavioral testing Cell High 21962519
2012 Autism-associated CNTNAP2 missense variants cause aberrant protein trafficking; the D1129H mutant is retained in the endoplasmic reticulum through interaction with ER chaperones (BiP/Grp78, Calnexin, ERp57) and activates the ATF6 branch of the unfolded protein response and proteasomal degradation; the 1253* frameshift mutation produces a secreted soluble protein lacking membrane anchorage. Immunofluorescence confocal microscopy and biochemical analysis in HEK-293 cells and hippocampal neurons; co-immunoprecipitation with ER chaperones; UPR pathway analysis Human molecular genetics High 22872700
2016 The ectodomain of CNTNAP2 consists of three lobes (large, medium, small) with distinct domain assignments, and binds directly and specifically to contactin 2 (CNTN2) with low nanomolar affinity; autism-associated mutations are distributed throughout the entire ectodomain rather than clustering in a single region. Electron microscopy of CNTNAP2 protein with epitope labeling, domain fragment analysis, direct binding assays The Journal of biological chemistry High 27621318
2015 CNTNAP2 plays a dose-dependent role in axon growth; loss of one Cntnap2 allele is sufficient to reduce axonal growth in cortical neurons; ASD missense variants I869T and G731S (with impaired TAG-1/Contactin2 binding) do not rescue axonal growth deficits; R1119H (which causes ER retention) has a dominant-negative effect via oligomerization with wild-type Caspr2; N407S also exerts a dominant-negative effect on axon growth despite normal membrane localization. Cortical neuron cultures from mouse embryos; heterozygous genetic background rescue assays; ASD missense variant functional analysis Human molecular genetics High 29788201
2018 Caspr2 autoantibodies inhibit the interaction of Caspr2 with contactin-2 (nanomolar affinity interaction confirmed by solid-phase binding assay) but do not cause internalization of surface Caspr2 in hippocampal neurons or transfected HEK cells; functional blocking of this cell adhesion molecule interaction is proposed as the pathogenic mechanism of IgG4 autoantibodies. Solid-phase binding assay, cell-based assay, cell-surface biotinylation, Western blot, live neuron cultures Annals of neurology High 29244234
2018 Either immune- or genetic-mediated loss of CASPR2 enhances primary afferent excitability through regulation of Kv1 channel expression at the DRG soma membrane; passive transfer of patient CASPR2 autoantibodies into mice causes mechanical pain hypersensitivity in a peripherally restricted manner without neural injury; Cntnap2-/- mice show increased DRG neuron excitability and enhanced nociceptive transmission in dorsal horn. Passive transfer of human autoantibodies into mice; Cntnap2-/- KO mice; in vivo and ex vivo electrophysiology; Kv1 channel quantification Neuron High 29429934
2019 Caspr2 is expressed at excitatory synapses in the cortex; knockdown of Caspr2 in vitro or in vivo decreases synaptic expression of AMPA receptors and amplitude of AMPA receptor-mediated currents, and blocks both synaptic scaling in vitro and experience-dependent homeostatic synaptic plasticity in visual cortex; patient CASPR2 antibodies decrease dendritic Caspr2 levels and synaptic AMPA receptor trafficking. In vitro siRNA knockdown; in vivo knockdown; whole-cell electrophysiology; AMPA receptor trafficking assays; patient antibody treatment of neurons Cerebral cortex High 30843029
2015 New dendritic spines in Cntnap2-/- mice are formed at normal rates but fail to stabilize, while rates of spine elimination are unaltered, revealing a specific role for CNTNAP2 in stabilizing new synaptic contacts in vivo. In vivo two-photon spine imaging in Cntnap2-/- knockout mice PloS one Medium 25951243
2015 Cntnap2-/- mice show selective reduction in perisomatic (but not dendritic) evoked IPSCs onto CA1 pyramidal cells, with normal excitatory transmission and normal miniature IPSC frequency and amplitude but increased spontaneous action potential-driven IPSCs, indicating Cntnap2 deletion selectively impairs perisomatic hippocampal inhibition. Whole-cell electrophysiology in acute hippocampal slices from Cntnap2-/- mice The Journal of neuroscience Medium 26511255
2019 Cntnap2 knockout mice show a dramatic decrease in excitatory and inhibitory synaptic inputs onto L2/3 pyramidal neurons of the medial prefrontal cortex, with reduced spines and synapses, increased activity in inhibitory neurons in vivo, and reduced phase-locking to delta and theta oscillations despite normal dendritic complexity and intrinsic excitability. Laser-scanning photostimulation, whole-cell recordings, electron microscopy, in vivo local field potential and unit recording Cell reports High 31141683
2019 Loss of Cntnap2 causes profound deficiency in clustering of Kv1-family potassium channels at juxtaparanodes of brain myelinated axons, alters axonal action potential waveform, increases postsynaptic excitatory responses, and delays the normal process of cortical myelination. Cntnap2-/- mouse electrophysiology, immunostaining of myelinated axons, developmental myelination analysis Cerebral cortex High 29300891
2018 Cntnap2 cell-autonomously regulates the physiology of parvalbumin (PV)+, fast-spiking cortical interneurons; human ASD missense mutations in CNTNAP2 impair PV+ interneuron development; somatostatin+ regular-spiking interneurons are not affected. Transplantation assay of MGE-derived interneurons into wild-type brain; constitutive Cntnap2 null mice; in vivo testing of human ASD missense alleles Cerebral cortex High 29028946
2015 Interaction proteomics reveals the Caspr2 interactome includes CNTN2, Kv1 channels (KCNAs), ADAM family members (ADAM22, ADAM23, ADAM11), LGI family members, and MAGUKs (DLGs, MPPs); a short isoform of Caspr2 lacking most extracellular domains still associates with ADAM22, LGI1, and Kv1 channels; Caspr2 is enriched in lipid rafts and synaptic membrane but depleted from the postsynaptic density. Co-immunoprecipitation/interaction proteomics; subcellular fractionation; Western blot Biochimica et biophysica acta Medium 25707359
2015 CASPR2 forms a tripartite complex with GPR37 and MUPP1 in the mouse brain; CASPR2 interacts with the PDZ3 domain of MUPP1, and GPR37 interacts with the PDZ11 domain; the ASD-related GPR37(R558Q) mutation impairs binding to MUPP1 and prevents cell-surface transport by MUPP1, causing ER retention and loss of synaptic co-localization with CASPR2 and MUPP1 in hippocampal neurons. Co-immunoprecipitation from mouse brain; cell-based assay; immunofluorescence in primary hippocampal neurons; domain-deletion and point-mutation analysis Journal of neurochemistry Medium 25977097
2019 Cntnap2-/- mice show hyperactive Akt-mTOR signaling in the hippocampus; treatment with Akt inhibitor LY294002 or mTOR inhibitor rapamycin rescues social deficits (but not hyperactivity or repetitive behaviors) in Cntnap2-/- mice, identifying dysregulated Akt-mTOR as a pathway downstream of CNTNAP2 loss. RNA sequencing, biochemical pathway analysis, pharmacological rescue in Cntnap2-/- mice Scientific reports Medium 30816216
2023 CNTNAP2 is cleaved by γ-secretase to produce a CNTNAP2 intracellular domain (CICD); CICD promotes nuclear translocation of CASK to regulate transcription of Necdin; viral delivery of CICD to the mPFC of Cntnap2-/- mice rescues social and repetitive behavior deficits; Necdin deficiency reduces social interaction, and viral Necdin expression in mPFC rescues social preference in Cntnap2-/- mice, defining a CNTNAP2-CASK-Necdin signaling pathway. Biochemical γ-secretase cleavage assay; viral CICD delivery; nuclear translocation assays; behavioral rescue; Necdin rescue in mPFC Signal transduction and targeted therapy Medium 37271769
2012 STOX1A, a forkhead-related transcription factor, directly downregulates CNTNAP2 as identified by chromatin immunoprecipitation coupled to shotgun cloning. Chromatin immunoprecipitation (ChIP) with shotgun cloning; gene expression analysis Journal of Alzheimer's disease Low 22728895
2017 Experimental downregulation of FoxP2 in zebra finch Area X using lentiviral vectors reduces Cntnap2 expression; FoxP2 binds to and activates the avian CNTNAP2 promoter in vitro; natural downregulation of FoxP2 by age or singing also downregulates Cntnap2, establishing CNTNAP2 as a direct transcriptional target of FOXP2. Lentiviral FoxP2 knockdown in vivo; luciferase promoter assay in vitro; in situ hybridization; qPCR Genes, brain, and behavior Medium 28488276
2022 Infusion of patients' IgG (anti-CASPR2 encephalitis) into mouse cerebroventricles causes memory impairment, reduces surface CASPR2 clusters, decreases CASPR2/TAG-1 co-localization (demonstrated by STED super-resolution microscopy), and lowers hippocampal Kv1.1 and GluA1 levels; in cultured neurons, patients' IgG selectively internalizes CASPR2 without affecting TAG-1; all effects are reversible upon IgG removal. Intracerebroventricular IgG infusion mouse model; STED super-resolution microscopy; confocal quantification of Kv1.1 and GluA1; behavioral tests; cultured neuron internalization assay Annals of neurology High 35253937
2016 In cultured hippocampal neurons, the LNG2-EGF1 modules in the Caspr2 ectodomain and the cytoplasmic PDZ-binding site regulate axonal positioning; deletion of LNG2-EGF1 promotes AIS localization and association with TAG-1; the PDZ-binding site can elicit AIS enrichment and recruit MPP2; Caspr2 and TAG-1 are co-sorted in axonal transport vesicles. Live-cell imaging; deletion construct analysis; co-transport vesicle imaging in hippocampal neurons Journal of cell science Medium 28533267
2015 Caspr2 autoantibodies from limbic encephalitis patients are directed against the N-terminal Discoidin and LamininG1 modules; in live hippocampal neuron cultures, these antibodies selectively target inhibitory interneurons (GAD65-positive axons and VGAT-positive presynaptic contacts), and may induce alteration of Gephyrin clusters at inhibitory synapses; Caspr2-Fc chimera binding to hippocampal neurons requires TAG-1 as a receptor. Domain-deletion mapping; live immunolabeling of hippocampal neurons; Caspr2-Fc chimera binding assay; comparison with TAG-1-deficient mouse neurons Frontiers in cellular neuroscience Medium 26217189
2016 Assembly of juxtaparanodal Kv1/Caspr2 complex during myelination requires protein 4.1B: in 4.1B KO myelinating DRG cultures and sciatic nerves, Caspr2 fails to be properly targeted early during myelination; Caspr2 and Kv1 channels transiently accumulate at the nodal region before relocalizing to juxtaparanodes; Kv1 channels display asymmetric enrichment at distal juxtaparanodes. Myelinating DRG/Schwann cell co-cultures; 4.1B KO mice; photobleaching (FRAP) of paranodal Caspr; adenoviral Caspr-GFP expression Glia Medium 26840208
2017 Disorganization of axonal domains in Caspr2 single mutants (and Caspr1/Caspr2 double mutants) in peripheral myelinated axons disrupts neuromuscular junction integrity, leading to NMJ denervation, reduced postsynaptic endplate areas, and muscle fiber degeneration with mitochondrial dysfunction in double mutants. Single and double Caspr1/Caspr2 knockout mice; NMJ immunostaining; muscle histology; electron microscopy Journal of neuroscience research Medium 28370195
2015 Cntnap2 is expressed in all primary sensory organs and in distinct brain regions involved in different sensory modalities; Cntnap2-/- mice exhibit abnormal sensory responses, including lack of preference for novel odors in olfaction-based tasks, linking Caspr2 loss throughout the sensory system to sensory manifestations. Caspr2:tau-LacZ knock-in reporter mouse; behavioral olfactory testing of Cntnap2-/- mice Molecular and cellular neurosciences Medium 26647347
2015 Cntnap2-/- mice exhibit a decrease in oxytocin immunoreactive neurons in the paraventricular nucleus of the hypothalamus and overall decreased brain oxytocin levels; acute oxytocin administration or activation of endogenous oxytocin neurons via DREADD rescues social deficits; chronic early postnatal oxytocin treatment leads to more lasting behavioral recovery and restores oxytocin immunoreactivity in the PVN. Oxytocin immunostaining, ELISA for brain oxytocin; pharmacological rescue; DREADD-based chemogenetic activation of PVN oxytocin neurons in Cntnap2-/- mice Science translational medicine High 25609168
2021 Patient-derived forebrain organoids with homozygous CNTNAP2 protein-truncating mutation display increased volume and cell number driven by increased neural progenitor proliferation; PFC-excitatory neurons are the key CNTNAP2-expressing cell type; organoid overgrowth phenotype is rescued by CRISPR-Cas9 correction of the mutation. iPSC-derived forebrain organoids; single-cell RNA sequencing; CRISPR-Cas9 correction; cell proliferation assays Nature communications High 34471112

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 852 21962519
2003 Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1. The Journal of cell biology 467 12963709
2011 Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia. Annals of neurology 331 21387375
2016 The clinical spectrum of Caspr2 antibody-associated disease. Neurology 312 27371488
2015 Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism. Science translational medicine 309 25609168
2007 CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Molecular psychiatry 233 17646849
2013 Shining a light on CNTNAP2: complex functions to complex disorders. European journal of human genetics : EJHG 205 23714751
2016 Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2. Neuron 158 26833134
2017 LGI1, CASPR2 and related antibodies: a molecular evolution of the phenotypes. Journal of neurology, neurosurgery, and psychiatry 156 29055902
2013 Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA neurology 148 23407760
2018 Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability. Neuron 144 29429934
2012 What does CNTNAP2 reveal about autism spectrum disorder? Trends in molecular medicine 135 22365836
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
2001 Localization of Caspr2 in myelinated nerves depends on axon-glia interactions and the generation of barriers along the axon. The Journal of neuroscience : the official journal of the Society for Neuroscience 113 11567047
2008 Postsynaptic density-93 clusters Kv1 channels at axon initial segments independently of Caspr2. The Journal of neuroscience : the official journal of the Society for Neuroscience 112 18509034
2011 Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1. BMC medical genetics 100 21827697
2009 Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder. Neurogenetics 100 19582487
2008 Multiple molecular interactions determine the clustering of Caspr2 and Kv1 channels in myelinated axons. The Journal of neuroscience : the official journal of the Society for Neuroscience 98 19109503
2019 Reduced Prefrontal Synaptic Connectivity and Disturbed Oscillatory Population Dynamics in the CNTNAP2 Model of Autism. Cell reports 96 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 93 20164332
2018 Mechanisms of Caspr2 antibodies in autoimmune encephalitis and neuromyotonia. Annals of neurology 89 29244234
2015 Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders. Molecular syndromology 84 25852443
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) 82 28184409
2021 Cortical overgrowth in a preclinical forebrain organoid model of CNTNAP2-associated autism spectrum disorder. Nature communications 80 34471112
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2018 Mouse Cntnap2 and Human CNTNAP2 ASD Alleles Cell Autonomously Regulate PV+ Cortical Interneurons. Cerebral cortex (New York, N.Y. : 1991) 75 29028946
2015 The Autism Related Protein Contactin-Associated Protein-Like 2 (CNTNAP2) Stabilizes New Spines: An In Vivo Mouse Study. PloS one 74 25951243
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2012 CNTNAP2 is significantly associated with schizophrenia and major depression in the Han Chinese population. Psychiatry research 56 23123147
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2015 Inhibitory axons are targeted in hippocampal cell culture by anti-Caspr2 autoantibodies associated with limbic encephalitis. Frontiers in cellular neuroscience 53 26217189
2017 Cntnap2 Knockout Rats and Mice Exhibit Epileptiform Activity and Abnormal Sleep-Wake Physiology. Sleep 52 28364455
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2015 Characterization of molecular and cellular phenotypes associated with a heterozygous CNTNAP2 deletion using patient-derived hiPSC neural cells. NPJ schizophrenia 44 26985448
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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
2010 Language-related Cntnap2 gene is differentially expressed in sexually dimorphic song nuclei essential for vocal learning in songbirds. The Journal of comparative neurology 37 20394055
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2012 Direct downregulation of CNTNAP2 by STOX1A is associated with Alzheimer's disease. Journal of Alzheimer's disease : JAD 33 22728895
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2012 The juxtaparanodal proteins CNTNAP2 and TAG1 regulate diet-induced obesity. Mammalian genome : official journal of the International Mammalian Genome Society 31 22752552
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