CNTNAP2 encodes Caspr2, a single-pass neuronal membrane protein with a large extracellular adhesion domain and a short intracellular interaction tail. Caspr2 organizes contactin-associated Kv1 potassium-channel assemblies at juxtaparanodes of myelinated axons and also occupies context-dependent synaptic and intracellular trafficking pools. Its extracellular domain binds contactin family proteins under defined conditions, while its terminal peptide binds PDZ domains. These interactions support neuronal membrane organization and circuit maturation. Biallelic loss of CNTNAP2 causes severe neurodevelopmental disease with seizures and language impairment; broader common-variant associations have more limited causal resolution.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001964 startle response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the rat-supported startle phenotype as a contextual role. Reason: The exact rat donor has experimentally supported acoustic-startle phenotypes. Cntnap2-deficient rats show altered startle reactivity and auditory timing; this supports the conserved circuit-level context, without making startle behavior a separate molecular function. |
| GO:0002020 protease binding | IEA GO_REF:0000107 | ACCEPT | Summary: Accept the conserved carboxypeptidase interaction. Reason: The rat donor records identify protease binding. The original CPE study reports positive two-hybrid, GST pull-down and co-immunoprecipitation evidence for Caspr2βCPE association. CPE is a protease; no modulation of its catalytic activity or sequence-verified human construct is inferred from the available abstract. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MODIFY | Summary: Specify binding to a DNA-binding transcription factor. Reason: The exact positive HI-II-14 records join CNTNAP2 to MEOX2/P50222, including a validated two-hybrid record. Official MEOX2 identity establishes its homeodomain DNA-binding transcription-factor class. The refinement describes the partner class; the screen does not establish nuclear colocalization or a transcriptional role for CNTNAP2. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:26721881 Structural Characterization of the Extracellular Domain of C... | MODIFY | Summary: Specify directly measured cell adhesion molecule binding. Reason: Human CASPR2 ectodomain binds CNTN1 in biolayer interferometry, cell-surface and bead assays. CNTN1 is an authenticated cell adhesion molecule. The tested soluble domains and tagged full-length cell constructs support this binding class; they do not establish equivalent affinity for every contactin or every CNTNAP2 product. Proposed replacements: cell adhesion molecule binding Supporting Evidence: PMID:26721881 contactin 1 (CNTN1) specifically associates with the extracellular domain of CASPR2 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the positive POLR2G pair without a whole-polymerase inference. Reason: Three exact HuRI records support CNTNAP2βPOLR2G/P62487 association, including the validated pair. POLR2G is a polymerase subunit, but the isolated pair does not show binding to the assembled RNA polymerase II complex or a transcriptional mechanism. Supported generic binding is retained outside the core under the campaign policy. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Specify the independently mapped GORASP2 PDZ interaction. Reason: The original HuRI pair with GORASP2/Q9H8Y8 is positive but does not map an interface. Independent holdup records in PMID:36115835 directly test the CNTNAP2 terminal peptide against the GORASP2 PDZ domain. That same-pair domain evidence supports PDZ-domain binding without attributing a domain assay to HuRI or inferring a native Golgi mechanism. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:A4D2P6. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:O75970. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:P78352. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q02410. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q12959. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q14005. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q14160. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q5T2W1. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q68DX3. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q86UL8. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q86UT5. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q8N448. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q8NI35. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q8TBB1. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q92796. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q96QZ7. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q99767. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q9C0E4. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q9H8Y8. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q9P202. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Specify the experimentally tested PDZ-domain interaction. Reason: Exact positive holdup records pair the human CNTNAP2 C-terminal peptide, residues 1322β1331, with an isolated PDZ-domain construct of UniProtKB:Q9Y3R0. The assayed peptide/domain features, including tagged or substituted constructs where recorded, are preserved in the source index. This directly supports PDZ-domain binding, not a full-length cellular complex or a physiological function shared by every partner. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005769 early endosome | IDA PMID:19706678 Axonal targeting of Caspr2 in hippocampal neurons via select... | ACCEPT | Summary: Accept the experimentally observed early-endosomal pool. Reason: The original full text uses HA-tagged human Caspr2 in rat hippocampal neurons and follows selective somatodendritic internalization, including early-endosome colocalization. This trafficking pool is compatible with predominant axonal surface localization; it is not evidence that the whole protein is an endosomal resident. Supporting Evidence: |
| GO:0005794 Golgi apparatus | IDA PMID:19166515 Contactin-associated protein (Caspr) 2 interacts with carbox... | KEEP AS NON CORE | Summary: Retain the reported Golgi pool as trafficking context. Reason: The complete available abstract explicitly reports Caspr2 and CPE colocalization in neuronal Golgi/ER and in cotransfected COS-7 cells. This positive compartment evidence is retained, with the uninspected full assay and exact Caspr2 construct species left unresolved. The Golgi pool is outside the principal axonal scaffold location. Supporting Evidence: |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Accept plasma-membrane activity. Reason: Direct human surface-targeting and ectodomain-interaction experiments independently support the target location. Current target and ortholog records corroborate the PAINT assertion. Target self-inclusion is legitimate experimental grounding; the supplied neurexin-family donors are not all CNTNAP2 orthologs, and no historical IBD placement is reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002309037 UNRESOLVED The historical tree, alignment and IBD placement have not been inspected. Positive target adjudication and current experimental premises below do not reconstruct this ancestral node. FB:FBgn0013997 SUPPORTS TRANSFER Current exact same-term experimental records are present for UniProtKB:Q94887. Their literal qualifiers and source references are preserved in the source index; these are current premises, not proof of historical IBD placement. MGI:MGI:2153093 SUPPORTS TRANSFER Current exact same-term experimental records are present for UniProtKB:Q8VHY0. Their literal qualifiers and source references are preserved in the source index; these are current premises, not proof of historical IBD placement. MGI:MGI:2183572 SUPPORTS TRANSFER Current exact same-term experimental records are present for UniProtKB:Q99P47. Their literal qualifiers and source references are preserved in the source index; these are current premises, not proof of historical IBD placement. MGI:MGI:87961 SUPPORTS TRANSFER Current exact same-term experimental records are present for UniProtKB:A2ASQ1. Their literal qualifiers and source references are preserved in the source index; these are current premises, not proof of historical IBD placement. RGD:2067 SUPPORTS TRANSFER Current exact same-term experimental records are present for UniProtKB:P25304. Their literal qualifiers and source references are preserved in the source index; these are current premises, not proof of historical IBD placement. RGD:619942 SUPPORTS TRANSFER Current exact same-term experimental records are present for UniProtKB:Q00657. Their literal qualifiers and source references are preserved in the source index; these are current premises, not proof of historical IBD placement. RGD:628659 SUPPORTS TRANSFER Current exact same-term experimental records are present for UniProtKB:Q63372. Their literal qualifiers and source references are preserved in the source index; these are current premises, not proof of historical IBD placement. UniProtKB:P31696 SUPPORTS TRANSFER Current exact same-term experimental records are present for UniProtKB:P31696. Their literal qualifiers and source references are preserved in the source index; these are current premises, not proof of historical IBD placement. |
| GO:0007165 signal transduction | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain inherited signaling participation as a broad context. Reason: The actual broad signal-transduction definition includes participation in a receptor-triggered cellular response; it does not require intrinsic receptor catalysis. In mouse DRG cultures, Caspr2 antibody blockade altered the CD24-dependent neurite response in the appropriate TAG-1/contactin genetic backgrounds. The Caspr2 knockout was not tested, and cerebellar neurons gave a different, Caspr2-independent result. These source-specific findings support non-core signaling participation through a neuronal surface assembly. The heterogeneous donor list neither reconstructs nor refutes historical PAINT node placement, which remains unresolved separately from this target evidence. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002309037 UNRESOLVED The historical tree, alignment and IBD placement have not been inspected. Positive target adjudication and current experimental premises below do not reconstruct this ancestral node. MGI:MGI:1096362 SUPPORTS TRANSFER Current exact same-term experimental records are present for UniProtKB:E9Q7X7. Their literal qualifiers and source references are preserved in the source index; these are current premises, not proof of historical IBD placement. MGI:MGI:1096391 SUPPORTS TRANSFER Current exact same-term experimental records are present for UniProtKB:P0DI97. Their literal qualifiers and source references are preserved in the source index; these are current premises, not proof of historical IBD placement. RGD:628659 SUPPORTS TRANSFER Current exact same-term experimental records are present for UniProtKB:Q63373. Their literal qualifiers and source references are preserved in the source index; these are current premises, not proof of historical IBD placement. |
| GO:0007399 nervous system development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain nervous-system development outside the molecular core. Reason: Target rescue and ortholog experiments show effects on interneuron maturation and projection responses, with a membrane-organizing role rather than only regional expression. These support the broad inherited developmental context. They do not establish each specific regional-development annotation or reconstruct the PAINT node. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000804946 UNRESOLVED The historical tree, alignment and IBD placement have not been inspected. Positive target adjudication and current experimental premises below do not reconstruct this ancestral node. |
| GO:0007417 central nervous system development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Retain the broad central nervous system developmental context. Reason: The live ARBA rule is genuinely retrieved, but its historical assignment path is not reconstructed. Actual human-CNTNAP2 rescue in mouse interneuron experiments and ortholog neuronal organization evidence independently support a contextual CNS role. The broad rule output does not establish proliferation or a particular brain-region developmental mechanism. |
| GO:0007420 brain development | TAS PMID:10624965 Caspr2, a new member of the neurexin superfamily, is localiz... | KEEP AS NON CORE | Summary: Retain brain-development context with the original proposal distinguished. Reason: The original characterization proposes developmental roles from a neuronal adhesion/complex protein. Later human-CNTNAP2 rescue in mouse interneurons demonstrates a contribution to maturation and physiology, independently supporting a broad developmental context. The original paper is not presented as a direct regional-development perturbation assay. |
| GO:0007612 learning | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain inherited learning context. Reason: The PAINT source includes legitimate target clinical evidence and current experimental mouse learning annotations. CNTNAP2 organizes neuronal complexes and has documented neurodevelopmental effects; the behavioral association is retained outside the molecular core. Current donor records do not reconstruct which historical learning experiment seeded the ancestral node. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002687838 UNRESOLVED The historical tree, alignment and IBD placement have not been inspected. Positive target adjudication and current experimental premises below do not reconstruct this ancestral node. MGI:MGI:1914047 SUPPORTS TRANSFER Current exact same-term experimental records are present for UniProtKB:Q9CPW0. Their literal qualifiers and source references are preserved in the source index; these are current premises, not proof of historical IBD placement. UniProtKB:Q9UHC6 SUPPORTS TRANSFER Current exact same-term experimental records are present for UniProtKB:Q9UHC6. Their literal qualifiers and source references are preserved in the source index; these are current premises, not proof of historical IBD placement. |
| GO:0007612 learning | IMP PMID:18179893 Linkage, association, and gene-expression analyses identify ... | KEEP AS NON CORE | Summary: Retain the clinically observed learning context. Reason: The study links CNTNAP2 variation to language-related phenotypes and discusses recessive childhood regression with learning impairment. These observations support the curated broad clinical context, rather than a defined learning computation or a second molecular function. The common-variant association is not equivalent to a demonstrated causal allele mechanism. Supporting Evidence: |
| GO:0008038 neuron recognition | NAS PMID:10624965 Caspr2, a new member of the neurexin superfamily, is localiz... | UNDECIDED | Summary: Leave the original neuron-recognition proposal unresolved. Reason: The actual original characterization establishes localization and channel-associated complexes, but recognition is proposed rather than tested as neuronal interpretation of surroundings. Later contactin binding demonstrates a molecular interaction, not by itself the entire recognition process. The source-specific NAS assertion remains uncertain without declaring the paper miscited. |
| GO:0008076 voltage-gated potassium channel complex | IDA PMID:10624965 Caspr2, a new member of the neurexin superfamily, is localiz... | ACCEPT | Summary: Accept membership in the potassium-channel-associated complex. Reason: Original rat brain co-immunoprecipitation positively places Caspr2 with Kv1.2 and KvΞ²2, with Kv2.1 and preimmune controls; later rat brain experiments also co-precipitate TAG-1, Caspr2 and Kv1.2. The failure to reconstitute a stable association from the tested Caspr2/channel combinations in transfected cells limits direct-contact and minimal-composition claims, but does not negate the native channel-associated complex. Retain the original complex-membership assertion without assigning potassium conductance or a defined channel-subunit stoichiometry to CNTNAP2. |
| GO:0008076 voltage-gated potassium channel complex | NAS PMID:10624965 Caspr2, a new member of the neurexin superfamily, is localiz... | ACCEPT | Summary: Accept membership in the potassium-channel-associated complex. Reason: Original rat brain co-immunoprecipitation positively places Caspr2 with Kv1.2 and KvΞ²2, with Kv2.1 and preimmune controls; later rat brain experiments also co-precipitate TAG-1, Caspr2 and Kv1.2. The failure to reconstitute a stable association from the tested Caspr2/channel combinations in transfected cells limits direct-contact and minimal-composition claims, but does not negate the native channel-associated complex. Retain the original complex-membership assertion without assigning potassium conductance or a defined channel-subunit stoichiometry to CNTNAP2. |
| GO:0008283 cell population proliferation | IDA PMID:29028946 Mouse Cntnap2 and Human CNTNAP2 ASD Alleles Cell Autonomousl... | MARK AS OVER ANNOTATED | Summary: Do not equate altered PV expression with cell proliferation. Reason: The source reports unchanged MGE proliferation/survival and normal numbers of fate-mapped interneurons, while PV expression, maturation and physiology change and human CNTNAP2 rescues PV expression. The population-proliferation annotation overstates this specific assay. This does not exclude proliferation roles in another experimental context or negate the positive maturation findings. Supporting Evidence: PMID:29028946 but did not observe any changes (data not shown) |
| GO:0009986 cell surface | IDA PMID:19706678 Axonal targeting of Caspr2 in hippocampal neurons via select... | ACCEPT | Summary: Accept directly assayed human Caspr2 surface localization. Reason: Tagged human Caspr2 is detected at the cell surface in rat hippocampal neurons, and selective somatodendritic endocytosis contributes to its axonal polarization. Construct and host species are distinguished. Supporting Evidence: |
| GO:0016020 membrane | IDA PMID:10624965 Caspr2, a new member of the neurexin superfamily, is localiz... | ACCEPT | Summary: Accept the membrane location. Reason: Original localization, single-pass topology and human surface-targeting experiments establish membrane association. The broad term remains correct across axonal surface and intracellular trafficking pools; it is not narrowed to one compartment solely to remove ontology redundancy. |
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Accept the membrane location. Reason: Original localization, single-pass topology and human surface-targeting experiments establish membrane association. The broad term remains correct across axonal surface and intracellular trafficking pools; it is not narrowed to one compartment solely to remove ontology redundancy. |
| GO:0016020 membrane | NAS PMID:11352571 The human contactin-associated protein-like 2 gene (CNTNAP2)... | ACCEPT | Summary: Accept the membrane location. Reason: Original localization, single-pass topology and human surface-targeting experiments establish membrane association. The broad term remains correct across axonal surface and intracellular trafficking pools; it is not narrowed to one compartment solely to remove ontology redundancy. |
| GO:0019226 transmission of nerve impulse | NAS PMID:11352571 The human contactin-associated protein-like 2 gene (CNTNAP2)... | UNDECIDED | Summary: Leave the original nerve-impulse assertion unresolved at source scope. Reason: The available original PMID:11352571 is a human gene-organization abstract; its exact NAS premise for impulse transmission remains unverified because the full source was not recovered. Later mouse Caspr2-null experiments measured conduction velocity and refractory period without a significant change, and reported no apparent nerve-conduction or tested excitability defect despite channel redistribution. Those results remove channel clustering as positive proof of this transmission claim. They are bounded negative observations in the tested nerves, ages and conditions, not evidence that CNTNAP2 can never influence electrical signaling. UNDECIDED rests on the unresolved original NAS source. |
| GO:0019899 enzyme binding | IPI PMID:19166515 Contactin-associated protein (Caspr) 2 interacts with carbox... | MODIFY | Summary: Specify the positive protease interaction. Reason: The original complete abstract reports Caspr2 binding to carboxypeptidase E by two-hybrid, GST pull-down and co-immunoprecipitation. Authenticated P16870 is CPE, a protease; protease binding is more informative than enzyme binding. No effect on CPE catalysis or exact human construct verification is claimed from the abstract. Proposed replacements: protease binding Supporting Evidence: PMID:19166515 immunoprecipitation analyses indicated that Caspr2 was associated with CPE |
| GO:0021756 striatum development | IEP PMID:18179893 Linkage, association, and gene-expression analyses identify ... | MARK AS OVER ANNOTATED | Summary: Separate regional fetal expression from a performed developmental role. Reason: The source maps CNTNAP2 RNA in developing human brain and reports genetic associations. Expression in the named region does not establish that CNTNAP2 performs that regionβs developmental process. The positive expression pattern is preserved; this source-specific judgment does not deny the broader neuronal developmental role. |
| GO:0021761 limbic system development | IEP PMID:18179895 Molecular cytogenetic analysis and resequencing of contactin... | MARK AS OVER ANNOTATED | Summary: Preserve limbic expression without inferring limbic development. Reason: The original Methods/Results describe mouse limbic expression, separate from human temporal-cortex expression and autism-associated variation. These observations do not directly establish CNTNAP2 participation in limbic-system development. The source is not falsely labeled unrelated to CNTNAP2 or its ortholog. Supporting Evidence: |
| GO:0021794 thalamus development | IEP PMID:18179893 Linkage, association, and gene-expression analyses identify ... | MARK AS OVER ANNOTATED | Summary: Separate regional fetal expression from a performed developmental role. Reason: The source maps CNTNAP2 RNA in developing human brain and reports genetic associations. Expression in the named region does not establish that CNTNAP2 performs that regionβs developmental process. The positive expression pattern is preserved; this source-specific judgment does not deny the broader neuronal developmental role. |
| GO:0021987 cerebral cortex development | IEP PMID:18179893 Linkage, association, and gene-expression analyses identify ... | MARK AS OVER ANNOTATED | Summary: Separate regional fetal expression from a performed developmental role. Reason: The source maps CNTNAP2 RNA in developing human brain and reports genetic associations. Expression in the named region does not establish that CNTNAP2 performs that regionβs developmental process. The positive expression pattern is preserved; this source-specific judgment does not deny the broader neuronal developmental role. |
| GO:0021987 cerebral cortex development | IEP PMID:18987363 A functional genetic link between distinct developmental lan... | MARK AS OVER ANNOTATED | Summary: Distinguish FOXP2 regulation and cortical expression from cortical development. Reason: The source demonstrates FOXP2 occupancy/regulation of CNTNAP2 in human neuronal cells and complementary fetal cortical expression. FOXP2 performs the assayed transcriptional-regulatory step; the data do not directly establish a CNTNAP2-performed cortex-development step. Language association and real expression remain intact. Supporting Evidence: |
| GO:0030424 axon | IEA GO_REF:0000044 | ACCEPT | Summary: Accept axonal localization. Reason: The UniProt location mapping agrees with direct human construct targeting in rat neurons and endogenous rodent axonal localization. The location is not limited to one experimental expression system. |
| GO:0030424 axon | NAS PMID:19706678 Axonal targeting of Caspr2 in hippocampal neurons via select... | ACCEPT | Summary: Accept the original axonal-targeting conclusion. Reason: The full original Methods identify human Caspr2 constructs in rat hippocampal cultures. Surface labeling, internalization and tail-mutant experiments establish preferential axonal surface targeting, with an intracellular somatodendritic pool distinguished. Supporting Evidence: |
| GO:0030425 dendrite | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain somatodendritic localization as contextual. Reason: The rat donor/original localization and subsequent targeting experiments identify somatodendritic protein pools, including endocytosed material and context-dependent neuronal expression. This is compatible with predominant axonal surface enrichment, not a reason to treat dendritic evidence as a paralog error. |
| GO:0030425 dendrite | NAS PMID:10624965 Caspr2, a new member of the neurexin superfamily, is localiz... | KEEP AS NON CORE | Summary: Retain somatodendritic localization as contextual. Reason: The rat donor/original localization and subsequent targeting experiments identify somatodendritic protein pools, including endocytosed material and context-dependent neuronal expression. This is compatible with predominant axonal surface enrichment, not a reason to treat dendritic evidence as a paralog error. |
| GO:0030534 adult behavior | IMP PMID:18179893 Linkage, association, and gene-expression analyses identify ... | MARK AS OVER ANNOTATED | Summary: Do not broaden childhood clinical observations to adult behavior. Reason: The source directly analyzes childrenβs age at first word and discusses childhood regression. The official adult-behavior term requires a mature organism; this source does not establish that age scope. Preserve the clinical phenotype without asserting that CNTNAP2 can never affect adult behavior. Supporting Evidence: |
| GO:0030673 axolemma | IDA PMID:19706678 Axonal targeting of Caspr2 in hippocampal neurons via select... | ACCEPT | Summary: Accept activity at the axonal plasma membrane. Reason: Direct human Caspr2 surface-targeting experiments in rat neurons and endogenous rodent localization support axolemmal residence. Intracellular and somatodendritic pools do not contradict the axonal surface component. |
| GO:0030673 axolemma | IEA GO_REF:0000107 | ACCEPT | Summary: Accept activity at the axonal plasma membrane. Reason: Direct human Caspr2 surface-targeting experiments in rat neurons and endogenous rodent localization support axolemmal residence. Intracellular and somatodendritic pools do not contradict the axonal surface component. |
| GO:0031175 neuron projection development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain source-supported projection development as context. Reason: The exact mouse ortholog has curated experimental projection-development evidence. In the inspected DRG system, Caspr2 antibody blockade and contactin/TAG-1 genetic backgrounds identify a contribution to CD24-dependent neurite responses. The paperβs Caspr knockout experiments concern Caspr1 and are not relabeled as Caspr2 knockouts. |
| GO:0033010 paranodal junction | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Retain contextual paranodal localization. Reason: The original ultrastructural account describes predominant juxtaparanodal labeling plus occasional outermost glial paranodal loops. This is not the principal mature axonal scaffold compartment, but it makes categorical removal of the broad paranodal-junction location inappropriate. Glial-loop signal is not relabeled axonal signal. |
| GO:0033270 paranode region of axon | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the context-dependent axonal paranodal pool. Reason: The rat-source annotation is preserved separately from glial-loop staining. Developmental overlap and mouse Caspr-deficient axons demonstrate that Caspr2 can occupy paranodal regions outside its normal mature juxtaparanodal specialization. The sourceβs exact historical localization mapping is not reconstructed, and no universal mature-paranode role is asserted. |
| GO:0035176 social behavior | IMP PMID:18179893 Linkage, association, and gene-expression analyses identify ... | KEEP AS NON CORE | Summary: Retain social-behavior clinical context. Reason: Autism-related ascertainment and reported recessive regression support the curated social-behavior context. The source does not isolate a particular social circuit or prove the functional effect of each common variant; those limitations do not erase the observed human phenotype. Supporting Evidence: |
| GO:0035176 social behavior | IMP PMID:19896112 CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Ho... | KEEP AS NON CORE | Summary: Retain the recessive clinical social-behavior context. Reason: The source reports severe human CNTNAP2 loss-of-function phenotypes with variable autistic features. Human clinical findings are distinguished from the separate Drosophila neurexin-IV synaptic experiments. This is a contextual organismal consequence, not a distinct molecular activity. Supporting Evidence: |
| GO:0042297 vocal learning | IMP PMID:19896112 CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Ho... | MARK AS OVER ANNOTATED | Summary: Distinguish speech impairment from vocal imitation learning. Reason: The patients have absent or limited speech, but the official vocal-learning process specifically concerns modification of vocalizations by imitating others. No imitation-learning task or corresponding performed step is established here. The positive speech phenotype remains supported without inferring this narrower process. Supporting Evidence: |
| GO:0042734 presynaptic membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Accept the presynaptic membrane location. Reason: The rat donor has direct localization evidence. Inspected neuronal surface-labeling experiments place endogenous Caspr2 at GAD65- and vGLUT1-associated presynaptic sites, with knockdown effects on inhibitory contacts. The original is_active_in qualifier remains unchanged. |
| GO:0043025 neuronal cell body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain neuronal cell-body localization as context. Reason: Original localization and the CPE study report somatic Caspr2 pools, including intracellular trafficking compartments. These are compatible with a predominantly axonal surface function. Perikaryon and neuronal-cell-body source terms are preserved, without manufacturing separate core locations. |
| GO:0043025 neuronal cell body | NAS PMID:10624965 Caspr2, a new member of the neurexin superfamily, is localiz... | KEEP AS NON CORE | Summary: Retain neuronal cell-body localization as context. Reason: Original localization and the CPE study report somatic Caspr2 pools, including intracellular trafficking compartments. These are compatible with a predominantly axonal surface function. Perikaryon and neuronal-cell-body source terms are preserved, without manufacturing separate core locations. |
| GO:0043204 perikaryon | NAS PMID:19166515 Contactin-associated protein (Caspr) 2 interacts with carbox... | KEEP AS NON CORE | Summary: Retain neuronal cell-body localization as context. Reason: Original localization and the CPE study report somatic Caspr2 pools, including intracellular trafficking compartments. These are compatible with a predominantly axonal surface function. Perikaryon and neuronal-cell-body source terms are preserved, without manufacturing separate core locations. |
| GO:0044224 juxtaparanode region of axon | IEA GO_REF:0000107 | ACCEPT | Summary: Accept juxtaparanodal axonal localization. Reason: Rat localization and mouse ortholog experiments directly establish the normal juxtaparanodal Caspr2 pool. The channel-organizing scaffold is concentrated at this compartment; occasional developmental or mutant-context paranodal locations do not negate it. |
| GO:0044224 juxtaparanode region of axon | ISS GO_REF:0000024 | ACCEPT | Summary: Accept juxtaparanodal axonal localization. Reason: Rat localization and mouse ortholog experiments directly establish the normal juxtaparanodal Caspr2 pool. The channel-organizing scaffold is concentrated at this compartment; occasional developmental or mutant-context paranodal locations do not negate it. |
| GO:0044325 transmembrane transporter binding | IEA GO_REF:0000107 | ACCEPT | Summary: Accept transporter-complex binding with indirect-association limits. Reason: The rat donor is supported by native Caspr2 association with Kv1.2/KvΞ²2. The original study did not reconstitute a stable complex with these proteins alone, so the binding assertion is retained at native assembly scope rather than as demonstrated isolated binary channel contact. |
| GO:0045163 clustering of voltage-gated potassium channels | ISS GO_REF:0000024 | ACCEPT | Summary: Accept the performed channel-clustering role. Reason: In mouse nerves, Caspr2 loss redistributes Kv1 channels without reducing total Kv1.2, and biochemical cis association with TAG-1 identifies a structural assembly role. This supports clustering participation rather than necessity alone, while initial recruitment and maintenance are not fully separated. |
| GO:0045202 synapse | IBA GO_REF:0000033 | ACCEPT | Summary: Accept synaptic activity with current source scope explicit. Reason: The PAINT sources include target-ortholog and other neurexin-family synaptic evidence. Actual rat synaptic fractionation and neuronal surface localization independently support Caspr2 at synapses; this does not reconstruct the historical IBD or transfer every donorβs detailed synaptic mechanism. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000013648 UNRESOLVED The historical tree, alignment and IBD placement have not been inspected. Positive target adjudication and current experimental premises below do not reconstruct this ancestral node. FB:FBgn0013997 SUPPORTS TRANSFER Current exact same-term experimental records are present for UniProtKB:Q94887. Their literal qualifiers and source references are preserved in the source index; these are current premises, not proof of historical IBD placement. MGI:MGI:1914047 SUPPORTS TRANSFER Current exact same-term experimental records are present for UniProtKB:Q9CPW0. Their literal qualifiers and source references are preserved in the source index; these are current premises, not proof of historical IBD placement. |
| GO:0048812 neuron projection morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain ortholog-supported projection morphology as context. Reason: The mouse source includes axonal domain-organization experiments, with Caspr/Caspr2 double-mutant effects distinguished from single-target effects. This supports a contextual structural contribution to neuronal projection morphology, not an additional enzymatic activity. The selected original abstract limits detailed attribution of individual panels. |
| GO:0060134 prepulse inhibition | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the experimentally supported sensorimotor-gating context. Reason: The rat donor has progressive prepulse-inhibition abnormalities measured alongside startle reactivity and auditory timing. This supports a circuit-level contextual phenotype without identifying an independent molecular gating activity of CNTNAP2. |
| GO:0071109 superior temporal gyrus development | IEP PMID:18179893 Linkage, association, and gene-expression analyses identify ... | MARK AS OVER ANNOTATED | Summary: Separate regional fetal expression from a performed developmental role. Reason: The source maps CNTNAP2 RNA in developing human brain and reports genetic associations. Expression in the named region does not establish that CNTNAP2 performs that regionβs developmental process. The positive expression pattern is preserved; this source-specific judgment does not deny the broader neuronal developmental role. |
| GO:0071205 protein localization to juxtaparanode region of axon | ISS GO_REF:0000024 | ACCEPT | Summary: Accept performed localization of the juxtaparanodal complex. Reason: Mouse Caspr2 and TAG-1 loss, together with physical complex evidence and redistribution without reduced total Kv1.2, support a structural contribution to maintaining or recruiting proteins at the juxtaparanode. The exact original mouse source is retained; the PDZ-tail deletion study also shows that the terminal PDZ motif is not universally required for this localization. |
| GO:0071625 vocalization behavior | IMP PMID:18179893 Linkage, association, and gene-expression analyses identify ... | KEEP AS NON CORE | Summary: Retain broad vocalization behavior as clinical context. Reason: The human source reports language/speech impairment associated with CNTNAP2 variation or recessive loss. This supports the curated broad vocal-behavior context outside the molecular core, while the narrower imitation-learning process and an adult-specific age scope are not inferred. Supporting Evidence: |
| GO:0071625 vocalization behavior | IMP PMID:19896112 CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Ho... | KEEP AS NON CORE | Summary: Retain broad vocalization behavior as clinical context. Reason: The human source reports language/speech impairment associated with CNTNAP2 variation or recessive loss. This supports the curated broad vocal-behavior context outside the molecular core, while the narrower imitation-learning process and an adult-specific age scope are not inferred. Supporting Evidence: |
| GO:0097060 synaptic membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Accept synaptic membrane localization. Reason: The exact rat donor derives from inspected fractionation of P9 rat brain: CNTNAP2 and CNTN2 are enriched in synaptic plasma-membrane fractions. Mouse/human regional-expression experiments elsewhere in the paper are kept separate. |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | ACCEPT | Summary: Accept localization at the assayed synapse class. Reason: The exact rat donor is grounded in neuronal Caspr2 labeling relative to vGLUT1 and GAD65/gephyrin synaptic markers. The inspected study distinguishes inhibitory-contact effects and human Fc/TAG-1 constructs from endogenous rat synaptic localization. No neurotransmitter synthesis or receptor activity is assigned to CNTNAP2. |
| GO:0098982 GABA-ergic synapse | IEA GO_REF:0000107 | ACCEPT | Summary: Accept localization at the assayed synapse class. Reason: The exact rat donor is grounded in neuronal Caspr2 labeling relative to vGLUT1 and GAD65/gephyrin synaptic markers. The inspected study distinguishes inhibitory-contact effects and human Fc/TAG-1 constructs from endogenous rat synaptic localization. No neurotransmitter synthesis or receptor activity is assigned to CNTNAP2. |
| GO:1903598 positive regulation of gap junction assembly | IMP PMID:33238150 NLR-1/CASPR Anchors F-Actin to Promote Gap Junction Formatio... | KEEP AS NON CORE | Summary: Retain the human-transgene gap-junction assembly contribution. Reason: Actual human CNTNAP2 expression rescues junction morphology and locomotion in nlr-1-deficient worms and restores ectopic Cx43-based junction formation. This is genuine human-product complementation, not a worm-only observation. Direct actin-binding assays on worm NLR-1 are not transferred into a human actin-binding MF, and native human gap-junction physiology remains untested. Supporting Evidence: PMID:33238150 human CNTNAP2 restored the formation of Cx43-based gap junctions |
| GO:0140378 protein complex scaffold activity | ISS PMID:12963709 Juxtaparanodal clustering of Shaker-like K+ channels in myel... | NEW | Summary: Add the ortholog-supported channel-complex scaffold activity. Reason: Mouse Caspr2 supports juxtaparanodal Kv1/TAG-1 assembly, with physical complex association and channel redistribution despite unchanged total Kv1.2. These observations identify performed structural organization. Transfer to human CNTNAP2 is explicitly ISS, not a human IDA claim. The full-length membrane product is the supported architectural counterpart; the short product is not assigned the activity. Typed ontology checks show no ancestor/descendant overlap with the original terms or final replacements, and no NEW process is proposed. Supporting Evidence: PMID:12963709 form a scaffold that is essential for the clustering of K+ channels |
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Download this section (compressed HTML)Q: Which components physically bridge the Caspr2 cytoplasmic tail to Kv1 channels, and which steps establish versus maintain the juxtaparanodal assembly?
Q: What functions and membrane topology does the 108-residue human product have in native cells?
Q: Which neuronal functions explain the clinical learning, social and speech phenotypes without treating regional expression as direct developmental participation?
Q: How do construct presentation and cis versus trans geometry explain the different reported contactin-binding outcomes?
Experiment: Reconstitute sequence-verified human full-length Caspr2, CNTN2 and Kv1 complexes with candidate cytoplasmic adaptors, and compare assembly and channel localization after targeted interface disruption while measuring total channel abundance.
Hypothesis: Caspr2 contributes a defined structural linkage rather than autonomous channel activity.
Type: Complex reconstitution and neuronal targeting
Experiment: Compare native expression, topology and PDZ-domain binding of both sequence-verified human products, then test rescue of juxtaparanodal assembly at matched expression levels.
Hypothesis: The short human product retains a subset of tail interactions but not the full extracellular scaffold function.
Type: Product-resolved localization and rescue
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