{"gene":"ARHGEF9","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2009,"finding":"The pleckstrin homology (PH) domain of collybistin (ARHGEF9) binds phosphatidylinositol-3-phosphate (PI3P/PtdIns-3-P), not PIP3 as previously suggested; expression of truncated collybistin proteins lacking the PH domain in cultured neurons interferes with synaptic localization of endogenous gephyrin and GABA-A receptors.","method":"PH domain lipid-binding assay; expression of truncated collybistin in cultured neurons with immunocytochemistry readout of gephyrin/GABA-A receptor localization","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vitro lipid-binding assay plus loss-of-function in neurons with defined molecular phenotype; replicated by subsequent studies","pmids":["18615734"],"is_preprint":false},{"year":2016,"finding":"The ARHGEF9 missense mutation R338W disrupts PI3P binding by the PH domain and abolishes the ability of collybistin to translocate EGFP-gephyrin to submembrane microaggregates in an in vitro clustering assay; molecular modeling showed R338W causes clashes with adjacent residues K363 and N335, disrupting local PH domain folding.","method":"Recombinant protein PI3P-binding assay; in vitro gephyrin clustering assay in transfected cells; molecular modeling","journal":"Frontiers in molecular neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (lipid binding, clustering assay, structural modeling) in a single study","pmids":["26834553"],"is_preprint":false},{"year":2015,"finding":"ARHGEF9 acts as a Cdc42-specific guanine nucleotide exchange factor downstream of the scaffold protein IQGAP1; the LAI-1-dependent signaling pathway inhibiting cell migration requires IQGAP1, Cdc42, and ARHGEF9, and LAI-1 treatment inactivates Cdc42 while causing IQGAP1 redistribution to the cell cortex.","method":"siRNA knockdown of ARHGEF9, IQGAP1, Cdc42 and other GTPase modulators; cell migration assay (forward migration index); Cdc42 activity measurement; immunofluorescence of IQGAP1 redistribution","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype and pathway placement, single lab","pmids":["26633832"],"is_preprint":false},{"year":2020,"finding":"Two missense variants in collybistin (p.I294T and p.R357I) disrupt CB-mediated accumulation of gephyrin in submembrane microclusters; a splicing variant (c.381+3A>G) leads to aberrant transcripts and a truncated protein product.","method":"In vitro gephyrin clustering assay in transfected cells; transcriptional/splicing analysis by RT-PCR","journal":"Journal of molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional clustering assay with multiple variants; single lab","pmids":["31942680"],"is_preprint":false},{"year":2022,"finding":"Collybistin directly interacts with the large intracellular loop of the GABA-A receptor α2 subunit; mutation of the Cb-binding motif in α2 (Gabra2-1 knock-in) causes strong downregulation of Cb expression particularly at cholecystokinin basket cell inhibitory synapses, producing working/recognition memory deficits, hyperactivity, anxiety, reduced social preference, spontaneous seizures, and sleep disturbance — phenocopying ARHGEF9 patient features.","method":"Knock-in mouse model (Gabra2-1); EEG recording; behavioral assays; immunohistochemistry of inhibitory synapses; protein expression analysis","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 1-2 — genetic knock-in with multiple orthogonal phenotypic readouts (electrophysiology, behavior, synaptic protein expression) in a rigorous single study","pmids":["35169261"],"is_preprint":false},{"year":2022,"finding":"ARHGEF9/collybistin is required for melanoma cell shape determination on both soft and stiff substrates and in 3D hydrogels; its depletion results in loss of tension at focal adhesions, decreased cell-wide contractility, inability to stabilize protrusions, loss of actin-rich filopodia, and impaired invasion of 3D matrices.","method":"Genetic screen with siRNA knockdown; single-cell quantitative morphological analysis; traction force microscopy; 3D invasion assay; fluorescence imaging of focal adhesions and actin","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal readouts (morphology, mechanics, invasion) with clean KD; single lab","pmids":["36039362"],"is_preprint":false},{"year":2024,"finding":"In a mouse model carrying a patient-derived ARHGEF9 variant, loss of ARHGEF9 function causes aggregation of postsynaptic proteins and loss of functional inhibitory synapses at the axon initial segment (AIS), altered axo-axonic synaptic inhibition, and disrupted action potential generation, revealing a role for ARHGEF9 in organizing inhibitory postsynaptic density at the AIS.","method":"Patient-derived variant knock-in mouse model; immunofluorescence/confocal microscopy of AIS synaptic proteins; electrophysiology (patch-clamp) of axo-axonic synaptic transmission and action potential generation; in vivo seizure recording","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (structural, electrophysiological, in vivo seizure) in a rigorous knock-in model","pmids":["39374387"],"is_preprint":false},{"year":2025,"finding":"Collybistin (ARHGEF9) regulates gephyrin phosphorylation in the medial prefrontal cortex; conditional knockout of Cb in mPFC reduces inhibitory synapse density, impairs GABAergic synaptic transmission, and reduces gephyrin phosphorylation. ASD-associated ARHGEF9 variant p.R290C promotes abnormal gephyrin clustering; p.G485S markedly decreases PI3P-binding activity; p.V374F and p.G485S induce defective inhibitory synaptic transmission. Mismatch between Cb activity and gephyrin phosphorylation state is proposed as a pathomechanism for ASD.","method":"Conditional knockout mouse; electrophysiology (mEIPSC recording); proteomic phosphoproteomics of mPFC; in vitro gephyrin clustering assay in COS-7 cells; PI3P-binding assay; ultrasonic vocalization assay","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (proteomic, electrophysiological, biochemical, behavioral) across in vitro and in vivo systems in a single study","pmids":["41174051"],"is_preprint":false},{"year":2023,"finding":"In experimental autoimmune encephalomyelitis (EAE) mice, inflammation induces region-specific increase in inclusion of alternative exon 11a of Arhgef9 selectively in the CA3 and dentate gyrus hippocampal subfields, associated with downregulation of the splicing factor Sam68 that normally represses this splicing event.","method":"Laser microdissection of hippocampal subfields; RT-PCR-based alternative splicing analysis; immunohistochemistry for Sam68; EAE mouse model","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — direct regional splicing analysis linked to a specific splicing regulator (Sam68) with regional specificity; single lab","pmids":["36710925"],"is_preprint":false},{"year":2025,"finding":"ARHGEF9 expression increases during skeletal muscle regeneration post-injury and during C2C12 myoblast differentiation, co-localizing with actin filaments; inhibition of ARHGEF9 reduces myoblast migration rate, actin filament polymerization, migration-related protein expression, and differentiation capacity.","method":"Mouse muscle injury model with Western blot; siRNA knockdown in C2C12 cells; migration assay; immunofluorescence of actin and ARHGEF9; differentiation assay with myosin heavy chain staining","journal":"Journal of muscle research and cell motility","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with multiple cellular readouts (migration, actin, differentiation); single lab, single study","pmids":["39992578"],"is_preprint":false},{"year":2018,"finding":"ARHGEF9 (collybistin) is expressed in a tissue-dependent manner in mouse brain and shows developmental stage-dependent expression in cerebral cortex, hippocampus, and cerebellum; in cultured hippocampal neurons it exhibits partial localization at dendritic spines.","method":"Western blotting with specific polyclonal antibody; immunohistochemistry in mouse brain sections; immunofluorescence in cultured hippocampal neurons","journal":"Acta histochemica et cytochemica","confidence":"Medium","confidence_rationale":"Tier 3 — direct localization with validated antibody, no functional consequence established; single lab","pmids":["30083020"],"is_preprint":false}],"current_model":"ARHGEF9/collybistin is a neuronal Cdc42-specific guanine nucleotide exchange factor whose PH domain binds PI3P to facilitate membrane targeting; it is essential for clustering gephyrin and anchoring GABA-A and glycine receptors at inhibitory postsynaptic densities (including at the axon initial segment), directly interacts with the GABA-A receptor α2 subunit and neuroligin-2, regulates gephyrin phosphorylation, and also promotes actin-rich filopodia formation and cell migration/adhesion in non-neuronal contexts."},"narrative":{"teleology":[{"year":2009,"claim":"Identifying the lipid specificity of the collybistin PH domain resolved how the protein targets membranes: PI3P, not PIP3, is the cognate ligand, and loss of the PH domain disrupts gephyrin and GABA-A receptor synaptic localization in neurons.","evidence":"In vitro PH-domain lipid-binding assay combined with expression of truncated collybistin in cultured neurons and immunocytochemistry","pmids":["18615734"],"confidence":"High","gaps":["Structural basis for PI3P selectivity over other phosphoinositides not resolved","Whether PI3P binding is sufficient or merely necessary for membrane targeting in vivo"]},{"year":2016,"claim":"A patient-derived R338W mutation provided the first structure–function link between a specific PH-domain residue, PI3P binding, and the ability to cluster gephyrin at submembrane sites, establishing how point mutations cause disease.","evidence":"Recombinant protein PI3P-binding assay, gephyrin clustering assay in transfected cells, and molecular modeling of R338W","pmids":["26834553"],"confidence":"High","gaps":["Crystal structure of the PH domain bound to PI3P not available","Whether R338W also affects GEF catalytic activity toward Cdc42"]},{"year":2018,"claim":"Characterization of ARHGEF9 expression across brain regions and developmental stages established that the protein shows region- and age-dependent expression and partially localizes to dendritic spines in hippocampal neurons.","evidence":"Western blotting and immunohistochemistry in mouse brain with validated polyclonal antibody; immunofluorescence in cultured hippocampal neurons","pmids":["30083020"],"confidence":"Medium","gaps":["No functional consequence of dendritic spine localization established","Splice-isoform-specific expression patterns not resolved"]},{"year":2015,"claim":"Placing ARHGEF9 downstream of IQGAP1 in a Cdc42-dependent migration pathway demonstrated that collybistin functions as a GEF for Cdc42 in non-neuronal cell migration, broadening its known biological roles.","evidence":"siRNA knockdown of ARHGEF9, IQGAP1, and Cdc42 in cell migration assays with Cdc42 activity measurements","pmids":["26633832"],"confidence":"Medium","gaps":["Direct physical interaction between IQGAP1 and ARHGEF9 not demonstrated","Whether this pathway operates in neurons"]},{"year":2020,"claim":"Functional analysis of multiple patient variants (I294T, R357I, splicing variant) confirmed that diverse ARHGEF9 mutations converge on defective gephyrin clustering, reinforcing gephyrin recruitment as the central functional readout.","evidence":"In vitro gephyrin clustering assay and RT-PCR splicing analysis of patient-derived variants","pmids":["31942680"],"confidence":"Medium","gaps":["Effects on endogenous inhibitory synapses in neurons not tested","Whether truncated splicing products exert dominant-negative effects"]},{"year":2022,"claim":"Discovery that collybistin directly binds the GABA-A receptor α2 subunit intracellular loop, and that disrupting this interaction in a knock-in mouse phenocopies ARHGEF9 patient features, established a receptor-level anchoring mechanism for collybistin at inhibitory synapses.","evidence":"Gabra2-1 knock-in mouse with EEG, behavioral assays, immunohistochemistry, and protein expression analysis","pmids":["35169261"],"confidence":"High","gaps":["Binding interface between collybistin and α2 not structurally resolved","Whether collybistin binds other GABA-A receptor subunit isoforms"]},{"year":2022,"claim":"A non-neuronal role for ARHGEF9 in cell shape, focal adhesion tension, and 3D invasion was established in melanoma cells, demonstrating that the actin-regulatory function of collybistin extends to mechanotransduction and motility.","evidence":"siRNA knockdown in melanoma cells with traction force microscopy, morphological analysis, and 3D invasion assay","pmids":["36039362"],"confidence":"Medium","gaps":["Whether Cdc42 GEF activity is required for the mechanical phenotype","Relevance to melanoma progression in vivo"]},{"year":2023,"claim":"Inflammation-driven alternative splicing of Arhgef9 exon 11a in hippocampal subfields, regulated by Sam68, revealed a mechanism by which neuroinflammation could alter collybistin isoform composition and potentially inhibitory synapse function.","evidence":"Laser microdissection of hippocampal subfields with RT-PCR splicing analysis and Sam68 immunohistochemistry in EAE mouse model","pmids":["36710925"],"confidence":"Medium","gaps":["Functional consequence of exon 11a inclusion on collybistin activity not determined","Whether Sam68 directly or indirectly regulates this splicing event"]},{"year":2024,"claim":"A patient-derived variant knock-in mouse revealed that ARHGEF9 is essential for organizing inhibitory postsynaptic density at the axon initial segment, with loss of function causing protein aggregation, disrupted axo-axonic inhibition, and aberrant action potential generation.","evidence":"Knock-in mouse with confocal imaging of AIS synaptic proteins, patch-clamp electrophysiology, and in vivo seizure recording","pmids":["39374387"],"confidence":"High","gaps":["Mechanism by which collybistin loss causes protein aggregation rather than dispersal at the AIS","Whether AIS-specific phenotype involves distinct collybistin-binding partners"]},{"year":2025,"claim":"Conditional knockout in medial prefrontal cortex linked collybistin to gephyrin phosphorylation regulation and showed that ASD-associated variants produce variant-specific defects in PI3P binding and gephyrin clustering, implicating a mismatch between GEF activity and gephyrin phosphorylation in ASD pathogenesis.","evidence":"Conditional knockout mouse with electrophysiology, phosphoproteomics of mPFC, PI3P-binding and gephyrin clustering assays, and behavioral analysis","pmids":["41174051"],"confidence":"High","gaps":["Which kinase or phosphatase mediates collybistin-dependent gephyrin phosphorylation","Whether gephyrin phosphorylation changes are a direct or indirect consequence of collybistin loss"]},{"year":2025,"claim":"ARHGEF9 was shown to promote myoblast migration and differentiation via actin filament polymerization, extending its non-neuronal roles to skeletal muscle regeneration.","evidence":"Mouse muscle injury model with Western blot; siRNA knockdown in C2C12 cells with migration, actin, and differentiation assays","pmids":["39992578"],"confidence":"Medium","gaps":["Whether Cdc42 mediates the myoblast effects","Relevance to human muscle regeneration"]},{"year":null,"claim":"The structural basis for collybistin's interactions with PI3P, gephyrin, and the GABA-A receptor α2 subunit remains unresolved at atomic resolution, and the kinase/phosphatase linking collybistin activity to gephyrin phosphorylation is unknown.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of collybistin in complex with any partner","Identity of the kinase/phosphatase that transduces collybistin activity into gephyrin phosphorylation changes","How collybistin splice isoforms differentially regulate inhibitory synapse subtypes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,3,7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,1,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[5,9]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,4,6,7]}],"complexes":[],"partners":["GPHN","CDC42","GABRA2","IQGAP1"],"other_free_text":[]},"mechanistic_narrative":"ARHGEF9 (collybistin) is a Cdc42-specific guanine nucleotide exchange factor that organizes inhibitory postsynaptic scaffolds by clustering gephyrin at GABAergic and glycinergic synapses in the brain. Its PH domain binds phosphatidylinositol-3-phosphate (PI3P) to drive membrane targeting, and disease-associated mutations that disrupt PI3P binding abolish gephyrin submembrane clustering and impair inhibitory synaptic transmission, including at the axon initial segment where loss of ARHGEF9 function causes aggregation of postsynaptic proteins, disrupted axo-axonic inhibition, and seizures [PMID:18615734, PMID:26834553, PMID:39374387]. ARHGEF9 directly interacts with the GABA-A receptor α2 subunit, and disruption of this interaction downregulates collybistin at inhibitory synapses and produces behavioral phenotypes—hyperactivity, seizures, memory deficits, and reduced social preference—that recapitulate features of X-linked intellectual disability caused by ARHGEF9 mutations [PMID:35169261]. In the medial prefrontal cortex, conditional knockout reduces inhibitory synapse density and gephyrin phosphorylation, linking collybistin activity to regulation of gephyrin post-translational modification and autism spectrum disorder-associated synaptic dysfunction; outside the nervous system, ARHGEF9 promotes Cdc42-dependent actin dynamics, cell migration, and focal adhesion contractility [PMID:41174051, PMID:36039362, PMID:39992578]."},"prefetch_data":{"uniprot":{"accession":"O43307","full_name":"Rho guanine nucleotide exchange factor 9","aliases":["Collybistin","PEM-2 homolog","Rac/Cdc42 guanine nucleotide exchange factor 9"],"length_aa":516,"mass_kda":61.0,"function":"Acts as a guanine nucleotide exchange factor (GEF) for CDC42. Promotes formation of GPHN clusters (By similarity)","subcellular_location":"Cytoplasm; Postsynaptic density","url":"https://www.uniprot.org/uniprotkb/O43307/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARHGEF9","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ARHGEF9","total_profiled":1310},"omim":[{"mim_id":"613324","title":"SPERMATOGENESIS-ASSOCIATED PROTEIN 13; SPATA13","url":"https://www.omim.org/entry/613324"},{"mim_id":"613039","title":"CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 1-LIKE; CHD1L","url":"https://www.omim.org/entry/613039"},{"mim_id":"605216","title":"RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR 4; ARHGEF4","url":"https://www.omim.org/entry/605216"},{"mim_id":"308350","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 1; DEE1","url":"https://www.omim.org/entry/308350"},{"mim_id":"300607","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 8; DEE8","url":"https://www.omim.org/entry/300607"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":68.4},{"tissue":"retina","ntpm":81.7}],"url":"https://www.proteinatlas.org/search/ARHGEF9"},"hgnc":{"alias_symbol":["KIAA0424","PEM-2"],"prev_symbol":[]},"alphafold":{"accession":"O43307","domains":[{"cath_id":"2.30.30.40","chopping":"10-63","consensus_level":"high","plddt":83.3983,"start":10,"end":63},{"cath_id":"1.20.900.10","chopping":"100-294","consensus_level":"high","plddt":94.5782,"start":100,"end":294},{"cath_id":"2.30.29.30","chopping":"311-450","consensus_level":"high","plddt":93.4884,"start":311,"end":450}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43307","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43307-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43307-F1-predicted_aligned_error_v6.png","plddt_mean":80.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARHGEF9","jax_strain_url":"https://www.jax.org/strain/search?query=ARHGEF9"},"sequence":{"accession":"O43307","fasta_url":"https://rest.uniprot.org/uniprotkb/O43307.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43307/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43307"}},"corpus_meta":[{"pmid":"18615734","id":"PMC_18615734","title":"A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation.","date":"2009","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/18615734","citation_count":115,"is_preprint":false},{"pmid":"9441682","id":"PMC_9441682","title":"Posterior end mark 2 (pem-2), pem-4, pem-5, and pem-6: maternal genes with localized mRNA in the ascidian embryo.","date":"1997","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/9441682","citation_count":72,"is_preprint":false},{"pmid":"17893116","id":"PMC_17893116","title":"ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal.","date":"2007","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17893116","citation_count":57,"is_preprint":false},{"pmid":"29130122","id":"PMC_29130122","title":"ARHGEF9 mutations in epileptic encephalopathy/intellectual disability: toward understanding the mechanism underlying phenotypic variation.","date":"2017","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/29130122","citation_count":47,"is_preprint":false},{"pmid":"26633832","id":"PMC_26633832","title":"Inter-kingdom Signaling by the Legionella Quorum Sensing Molecule LAI-1 Modulates Cell Migration through an IQGAP1-Cdc42-ARHGEF9-Dependent Pathway.","date":"2015","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/26633832","citation_count":41,"is_preprint":false},{"pmid":"21626670","id":"PMC_21626670","title":"De novo Xq11.11 microdeletion including ARHGEF9 in a boy with mental retardation, epilepsy, macrosomia, and dysmorphic features.","date":"2011","source":"American journal of medical genetics. 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et cytochemica","url":"https://pubmed.ncbi.nlm.nih.gov/30083020","citation_count":7,"is_preprint":false},{"pmid":"36039362","id":"PMC_36039362","title":"ARHGEF9 regulates melanoma morphogenesis in environments with diverse geometry and elasticity by promoting filopodial-driven adhesion.","date":"2022","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/36039362","citation_count":6,"is_preprint":false},{"pmid":"36710925","id":"PMC_36710925","title":"Regionally restricted modulation of Sam68 expression and Arhgef9 alternative splicing in the hippocampus of a murine model of multiple sclerosis.","date":"2023","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36710925","citation_count":6,"is_preprint":false},{"pmid":"38680425","id":"PMC_38680425","title":"Association analysis of polymorphisms in SLK, ARHGEF9, WWC2, GAB3, and FSHR genes with reproductive traits in different sheep breeds.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38680425","citation_count":5,"is_preprint":false},{"pmid":"37379702","id":"PMC_37379702","title":"Increased delivery and cytotoxicity of doxorubicin in HeLa cells using the synthetic cationic peptide pEM-2 functionalized liposomes.","date":"2023","source":"Colloids and surfaces. B, Biointerfaces","url":"https://pubmed.ncbi.nlm.nih.gov/37379702","citation_count":5,"is_preprint":false},{"pmid":"21731583","id":"PMC_21731583","title":"ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal.","date":"2009","source":"BMJ case reports","url":"https://pubmed.ncbi.nlm.nih.gov/21731583","citation_count":4,"is_preprint":false},{"pmid":"39374387","id":"PMC_39374387","title":"Impaired axon initial segment structure and function in a model of ARHGEF9 developmental and epileptic encephalopathy.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39374387","citation_count":3,"is_preprint":false},{"pmid":"34851771","id":"PMC_34851771","title":"A novel de novo hemizygous ARHGEF9 mutation associated with severe intellectual disability and epilepsy: a case report.","date":"2021","source":"The Journal of international medical research","url":"https://pubmed.ncbi.nlm.nih.gov/34851771","citation_count":2,"is_preprint":false},{"pmid":"33600053","id":"PMC_33600053","title":"Loss-of-function variants in ARHGEF9 are associated with an X-linked intellectual disability dominant disorder.","date":"2021","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/33600053","citation_count":2,"is_preprint":false},{"pmid":"36852158","id":"PMC_36852158","title":"Peptide ARHGEF9 Inhibits Glioma Progression via PI3K/AKT/mTOR Pathway.","date":"2023","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/36852158","citation_count":1,"is_preprint":false},{"pmid":"41174051","id":"PMC_41174051","title":"Autism-associated ARHGEF9 variants impair GABAergic synapses and ultrasonic communication by reducing gephyrin phosphorylation.","date":"2025","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/41174051","citation_count":1,"is_preprint":false},{"pmid":"39992578","id":"PMC_39992578","title":"The influences of ARHGEF9 on myoblasts migration and differentiation.","date":"2025","source":"Journal of muscle research and cell motility","url":"https://pubmed.ncbi.nlm.nih.gov/39992578","citation_count":0,"is_preprint":false},{"pmid":"31907904","id":"PMC_31907904","title":"[Patients with ARHGEF9-mutation: a case report and implications of genetic disorders in child psychiatry].","date":"2019","source":"Tijdschrift voor psychiatrie","url":"https://pubmed.ncbi.nlm.nih.gov/31907904","citation_count":0,"is_preprint":false},{"pmid":"36184101","id":"PMC_36184101","title":"[Clinical analysis of early-onset infantile epileptic encephalopathy associated with synonymous variant of the ARHGEF9 gene].","date":"2022","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36184101","citation_count":0,"is_preprint":false},{"pmid":"37593569","id":"PMC_37593569","title":"Retracted: Peptide ARHGEF9 Inhibits Glioma Progression via PI3K/AKT/mTOR Pathway.","date":"2023","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/37593569","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16389,"output_tokens":2930,"usd":0.046559},"stage2":{"model":"claude-opus-4-6","input_tokens":6269,"output_tokens":2951,"usd":0.15768},"total_usd":0.204239,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"The pleckstrin homology (PH) domain of collybistin (ARHGEF9) binds phosphatidylinositol-3-phosphate (PI3P/PtdIns-3-P), not PIP3 as previously suggested; expression of truncated collybistin proteins lacking the PH domain in cultured neurons interferes with synaptic localization of endogenous gephyrin and GABA-A receptors.\",\n      \"method\": \"PH domain lipid-binding assay; expression of truncated collybistin in cultured neurons with immunocytochemistry readout of gephyrin/GABA-A receptor localization\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro lipid-binding assay plus loss-of-function in neurons with defined molecular phenotype; replicated by subsequent studies\",\n      \"pmids\": [\"18615734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The ARHGEF9 missense mutation R338W disrupts PI3P binding by the PH domain and abolishes the ability of collybistin to translocate EGFP-gephyrin to submembrane microaggregates in an in vitro clustering assay; molecular modeling showed R338W causes clashes with adjacent residues K363 and N335, disrupting local PH domain folding.\",\n      \"method\": \"Recombinant protein PI3P-binding assay; in vitro gephyrin clustering assay in transfected cells; molecular modeling\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (lipid binding, clustering assay, structural modeling) in a single study\",\n      \"pmids\": [\"26834553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ARHGEF9 acts as a Cdc42-specific guanine nucleotide exchange factor downstream of the scaffold protein IQGAP1; the LAI-1-dependent signaling pathway inhibiting cell migration requires IQGAP1, Cdc42, and ARHGEF9, and LAI-1 treatment inactivates Cdc42 while causing IQGAP1 redistribution to the cell cortex.\",\n      \"method\": \"siRNA knockdown of ARHGEF9, IQGAP1, Cdc42 and other GTPase modulators; cell migration assay (forward migration index); Cdc42 activity measurement; immunofluorescence of IQGAP1 redistribution\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype and pathway placement, single lab\",\n      \"pmids\": [\"26633832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Two missense variants in collybistin (p.I294T and p.R357I) disrupt CB-mediated accumulation of gephyrin in submembrane microclusters; a splicing variant (c.381+3A>G) leads to aberrant transcripts and a truncated protein product.\",\n      \"method\": \"In vitro gephyrin clustering assay in transfected cells; transcriptional/splicing analysis by RT-PCR\",\n      \"journal\": \"Journal of molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional clustering assay with multiple variants; single lab\",\n      \"pmids\": [\"31942680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Collybistin directly interacts with the large intracellular loop of the GABA-A receptor α2 subunit; mutation of the Cb-binding motif in α2 (Gabra2-1 knock-in) causes strong downregulation of Cb expression particularly at cholecystokinin basket cell inhibitory synapses, producing working/recognition memory deficits, hyperactivity, anxiety, reduced social preference, spontaneous seizures, and sleep disturbance — phenocopying ARHGEF9 patient features.\",\n      \"method\": \"Knock-in mouse model (Gabra2-1); EEG recording; behavioral assays; immunohistochemistry of inhibitory synapses; protein expression analysis\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic knock-in with multiple orthogonal phenotypic readouts (electrophysiology, behavior, synaptic protein expression) in a rigorous single study\",\n      \"pmids\": [\"35169261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ARHGEF9/collybistin is required for melanoma cell shape determination on both soft and stiff substrates and in 3D hydrogels; its depletion results in loss of tension at focal adhesions, decreased cell-wide contractility, inability to stabilize protrusions, loss of actin-rich filopodia, and impaired invasion of 3D matrices.\",\n      \"method\": \"Genetic screen with siRNA knockdown; single-cell quantitative morphological analysis; traction force microscopy; 3D invasion assay; fluorescence imaging of focal adhesions and actin\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal readouts (morphology, mechanics, invasion) with clean KD; single lab\",\n      \"pmids\": [\"36039362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In a mouse model carrying a patient-derived ARHGEF9 variant, loss of ARHGEF9 function causes aggregation of postsynaptic proteins and loss of functional inhibitory synapses at the axon initial segment (AIS), altered axo-axonic synaptic inhibition, and disrupted action potential generation, revealing a role for ARHGEF9 in organizing inhibitory postsynaptic density at the AIS.\",\n      \"method\": \"Patient-derived variant knock-in mouse model; immunofluorescence/confocal microscopy of AIS synaptic proteins; electrophysiology (patch-clamp) of axo-axonic synaptic transmission and action potential generation; in vivo seizure recording\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (structural, electrophysiological, in vivo seizure) in a rigorous knock-in model\",\n      \"pmids\": [\"39374387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Collybistin (ARHGEF9) regulates gephyrin phosphorylation in the medial prefrontal cortex; conditional knockout of Cb in mPFC reduces inhibitory synapse density, impairs GABAergic synaptic transmission, and reduces gephyrin phosphorylation. ASD-associated ARHGEF9 variant p.R290C promotes abnormal gephyrin clustering; p.G485S markedly decreases PI3P-binding activity; p.V374F and p.G485S induce defective inhibitory synaptic transmission. Mismatch between Cb activity and gephyrin phosphorylation state is proposed as a pathomechanism for ASD.\",\n      \"method\": \"Conditional knockout mouse; electrophysiology (mEIPSC recording); proteomic phosphoproteomics of mPFC; in vitro gephyrin clustering assay in COS-7 cells; PI3P-binding assay; ultrasonic vocalization assay\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (proteomic, electrophysiological, biochemical, behavioral) across in vitro and in vivo systems in a single study\",\n      \"pmids\": [\"41174051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In experimental autoimmune encephalomyelitis (EAE) mice, inflammation induces region-specific increase in inclusion of alternative exon 11a of Arhgef9 selectively in the CA3 and dentate gyrus hippocampal subfields, associated with downregulation of the splicing factor Sam68 that normally represses this splicing event.\",\n      \"method\": \"Laser microdissection of hippocampal subfields; RT-PCR-based alternative splicing analysis; immunohistochemistry for Sam68; EAE mouse model\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct regional splicing analysis linked to a specific splicing regulator (Sam68) with regional specificity; single lab\",\n      \"pmids\": [\"36710925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ARHGEF9 expression increases during skeletal muscle regeneration post-injury and during C2C12 myoblast differentiation, co-localizing with actin filaments; inhibition of ARHGEF9 reduces myoblast migration rate, actin filament polymerization, migration-related protein expression, and differentiation capacity.\",\n      \"method\": \"Mouse muscle injury model with Western blot; siRNA knockdown in C2C12 cells; migration assay; immunofluorescence of actin and ARHGEF9; differentiation assay with myosin heavy chain staining\",\n      \"journal\": \"Journal of muscle research and cell motility\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with multiple cellular readouts (migration, actin, differentiation); single lab, single study\",\n      \"pmids\": [\"39992578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ARHGEF9 (collybistin) is expressed in a tissue-dependent manner in mouse brain and shows developmental stage-dependent expression in cerebral cortex, hippocampus, and cerebellum; in cultured hippocampal neurons it exhibits partial localization at dendritic spines.\",\n      \"method\": \"Western blotting with specific polyclonal antibody; immunohistochemistry in mouse brain sections; immunofluorescence in cultured hippocampal neurons\",\n      \"journal\": \"Acta histochemica et cytochemica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization with validated antibody, no functional consequence established; single lab\",\n      \"pmids\": [\"30083020\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARHGEF9/collybistin is a neuronal Cdc42-specific guanine nucleotide exchange factor whose PH domain binds PI3P to facilitate membrane targeting; it is essential for clustering gephyrin and anchoring GABA-A and glycine receptors at inhibitory postsynaptic densities (including at the axon initial segment), directly interacts with the GABA-A receptor α2 subunit and neuroligin-2, regulates gephyrin phosphorylation, and also promotes actin-rich filopodia formation and cell migration/adhesion in non-neuronal contexts.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ARHGEF9 (collybistin) is a Cdc42-specific guanine nucleotide exchange factor that organizes inhibitory postsynaptic scaffolds by clustering gephyrin at GABAergic and glycinergic synapses in the brain. Its PH domain binds phosphatidylinositol-3-phosphate (PI3P) to drive membrane targeting, and disease-associated mutations that disrupt PI3P binding abolish gephyrin submembrane clustering and impair inhibitory synaptic transmission, including at the axon initial segment where loss of ARHGEF9 function causes aggregation of postsynaptic proteins, disrupted axo-axonic inhibition, and seizures [PMID:18615734, PMID:26834553, PMID:39374387]. ARHGEF9 directly interacts with the GABA-A receptor α2 subunit, and disruption of this interaction downregulates collybistin at inhibitory synapses and produces behavioral phenotypes—hyperactivity, seizures, memory deficits, and reduced social preference—that recapitulate features of X-linked intellectual disability caused by ARHGEF9 mutations [PMID:35169261]. In the medial prefrontal cortex, conditional knockout reduces inhibitory synapse density and gephyrin phosphorylation, linking collybistin activity to regulation of gephyrin post-translational modification and autism spectrum disorder-associated synaptic dysfunction; outside the nervous system, ARHGEF9 promotes Cdc42-dependent actin dynamics, cell migration, and focal adhesion contractility [PMID:41174051, PMID:36039362, PMID:39992578].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying the lipid specificity of the collybistin PH domain resolved how the protein targets membranes: PI3P, not PIP3, is the cognate ligand, and loss of the PH domain disrupts gephyrin and GABA-A receptor synaptic localization in neurons.\",\n      \"evidence\": \"In vitro PH-domain lipid-binding assay combined with expression of truncated collybistin in cultured neurons and immunocytochemistry\",\n      \"pmids\": [\"18615734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for PI3P selectivity over other phosphoinositides not resolved\",\n        \"Whether PI3P binding is sufficient or merely necessary for membrane targeting in vivo\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A patient-derived R338W mutation provided the first structure–function link between a specific PH-domain residue, PI3P binding, and the ability to cluster gephyrin at submembrane sites, establishing how point mutations cause disease.\",\n      \"evidence\": \"Recombinant protein PI3P-binding assay, gephyrin clustering assay in transfected cells, and molecular modeling of R338W\",\n      \"pmids\": [\"26834553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Crystal structure of the PH domain bound to PI3P not available\",\n        \"Whether R338W also affects GEF catalytic activity toward Cdc42\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Characterization of ARHGEF9 expression across brain regions and developmental stages established that the protein shows region- and age-dependent expression and partially localizes to dendritic spines in hippocampal neurons.\",\n      \"evidence\": \"Western blotting and immunohistochemistry in mouse brain with validated polyclonal antibody; immunofluorescence in cultured hippocampal neurons\",\n      \"pmids\": [\"30083020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional consequence of dendritic spine localization established\",\n        \"Splice-isoform-specific expression patterns not resolved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placing ARHGEF9 downstream of IQGAP1 in a Cdc42-dependent migration pathway demonstrated that collybistin functions as a GEF for Cdc42 in non-neuronal cell migration, broadening its known biological roles.\",\n      \"evidence\": \"siRNA knockdown of ARHGEF9, IQGAP1, and Cdc42 in cell migration assays with Cdc42 activity measurements\",\n      \"pmids\": [\"26633832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical interaction between IQGAP1 and ARHGEF9 not demonstrated\",\n        \"Whether this pathway operates in neurons\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Functional analysis of multiple patient variants (I294T, R357I, splicing variant) confirmed that diverse ARHGEF9 mutations converge on defective gephyrin clustering, reinforcing gephyrin recruitment as the central functional readout.\",\n      \"evidence\": \"In vitro gephyrin clustering assay and RT-PCR splicing analysis of patient-derived variants\",\n      \"pmids\": [\"31942680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Effects on endogenous inhibitory synapses in neurons not tested\",\n        \"Whether truncated splicing products exert dominant-negative effects\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery that collybistin directly binds the GABA-A receptor α2 subunit intracellular loop, and that disrupting this interaction in a knock-in mouse phenocopies ARHGEF9 patient features, established a receptor-level anchoring mechanism for collybistin at inhibitory synapses.\",\n      \"evidence\": \"Gabra2-1 knock-in mouse with EEG, behavioral assays, immunohistochemistry, and protein expression analysis\",\n      \"pmids\": [\"35169261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Binding interface between collybistin and α2 not structurally resolved\",\n        \"Whether collybistin binds other GABA-A receptor subunit isoforms\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A non-neuronal role for ARHGEF9 in cell shape, focal adhesion tension, and 3D invasion was established in melanoma cells, demonstrating that the actin-regulatory function of collybistin extends to mechanotransduction and motility.\",\n      \"evidence\": \"siRNA knockdown in melanoma cells with traction force microscopy, morphological analysis, and 3D invasion assay\",\n      \"pmids\": [\"36039362\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether Cdc42 GEF activity is required for the mechanical phenotype\",\n        \"Relevance to melanoma progression in vivo\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Inflammation-driven alternative splicing of Arhgef9 exon 11a in hippocampal subfields, regulated by Sam68, revealed a mechanism by which neuroinflammation could alter collybistin isoform composition and potentially inhibitory synapse function.\",\n      \"evidence\": \"Laser microdissection of hippocampal subfields with RT-PCR splicing analysis and Sam68 immunohistochemistry in EAE mouse model\",\n      \"pmids\": [\"36710925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of exon 11a inclusion on collybistin activity not determined\",\n        \"Whether Sam68 directly or indirectly regulates this splicing event\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A patient-derived variant knock-in mouse revealed that ARHGEF9 is essential for organizing inhibitory postsynaptic density at the axon initial segment, with loss of function causing protein aggregation, disrupted axo-axonic inhibition, and aberrant action potential generation.\",\n      \"evidence\": \"Knock-in mouse with confocal imaging of AIS synaptic proteins, patch-clamp electrophysiology, and in vivo seizure recording\",\n      \"pmids\": [\"39374387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which collybistin loss causes protein aggregation rather than dispersal at the AIS\",\n        \"Whether AIS-specific phenotype involves distinct collybistin-binding partners\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Conditional knockout in medial prefrontal cortex linked collybistin to gephyrin phosphorylation regulation and showed that ASD-associated variants produce variant-specific defects in PI3P binding and gephyrin clustering, implicating a mismatch between GEF activity and gephyrin phosphorylation in ASD pathogenesis.\",\n      \"evidence\": \"Conditional knockout mouse with electrophysiology, phosphoproteomics of mPFC, PI3P-binding and gephyrin clustering assays, and behavioral analysis\",\n      \"pmids\": [\"41174051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which kinase or phosphatase mediates collybistin-dependent gephyrin phosphorylation\",\n        \"Whether gephyrin phosphorylation changes are a direct or indirect consequence of collybistin loss\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ARHGEF9 was shown to promote myoblast migration and differentiation via actin filament polymerization, extending its non-neuronal roles to skeletal muscle regeneration.\",\n      \"evidence\": \"Mouse muscle injury model with Western blot; siRNA knockdown in C2C12 cells with migration, actin, and differentiation assays\",\n      \"pmids\": [\"39992578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether Cdc42 mediates the myoblast effects\",\n        \"Relevance to human muscle regeneration\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for collybistin's interactions with PI3P, gephyrin, and the GABA-A receptor α2 subunit remains unresolved at atomic resolution, and the kinase/phosphatase linking collybistin activity to gephyrin phosphorylation is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of collybistin in complex with any partner\",\n        \"Identity of the kinase/phosphatase that transduces collybistin activity into gephyrin phosphorylation changes\",\n        \"How collybistin splice isoforms differentially regulate inhibitory synapse subtypes\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 3, 7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 4, 6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"GPHN\",\n      \"CDC42\",\n      \"GABRA2\",\n      \"IQGAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}