{"gene":"MDGA2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2016,"finding":"MDGA2 blocks neuroligin-1 (NLGN1) interaction with neurexins, thereby suppressing excitatory synapse development. Mdga2+/- mice show increased asymmetric synapse density, elevated mEPSC frequency and amplitude, and altered LTP with no change in inhibitory synapse measures, indicating MDGA2 is a suppressor of excitatory (not inhibitory) synapse formation acting through the NRXN-NLGN pathway.","method":"Genetic haploinsufficiency mouse model (Mdga2+/-), electrophysiology (mEPSC, LTP), synapse density quantification, behavioral assays, in vivo voltage-sensitive dye imaging","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional assays in vivo and in vitro, replicated across multiple orthogonal readouts (electrophysiology, morphology, behavior, imaging) in a single rigorous study","pmids":["27608760"],"is_preprint":false},{"year":2011,"finding":"MDGA2 supports rostral axonal growth of post-crossing commissural axons through homophilic MDGA2-MDGA2 interactions between ipsilateral axons and post-crossing commissural axons. RNAi knockdown or function-blocking antibodies against MDGA2 abolish longitudinal axon extension in chick spinal cord commissural interneurons.","method":"RNAi knockdown in ovo, function-blocking antibody experiments, binding studies in chick spinal cord commissural neurons","journal":"Neural development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal loss-of-function methods (RNAi and antibody blockade) plus binding studies, single lab","pmids":["21542908"],"is_preprint":false},{"year":2015,"finding":"MDGA2 directly stabilizes DMAP1 (DNA methyltransferase 1 associated protein 1) via protein-protein interaction, and this complex activates p53/p21 signaling cascades to cause G1-S cell cycle arrest and apoptosis in gastric cancer cells.","method":"Mass spectrometry identification of interacting protein, co-immunoprecipitation, reporter activity assays, PCR array, re-expression and knockdown experiments, xenograft mouse models","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP, functional rescue/knockdown with defined pathway readout, single lab","pmids":["26206665"],"is_preprint":false},{"year":2024,"finding":"MDGA2 selectively suppresses the density and function of excitatory (but not inhibitory) synapses on CA1 pyramidal neurons in the mature hippocampus. Conditional deletion of Mdga2 in CA1 pyramidal neurons upregulates mEPSCs, spontaneous EPSPs, vGluT1 intensity, AMPAR currents, and neuronal excitability, while leaving mIPSC properties and vGAT intensity unchanged, and impairs LTP, memory, and social behavior.","method":"Conditional knockout (Cre-lox) restricted to CA1 pyramidal neurons, electrophysiology (mEPSC, mIPSC, evoked synaptic transmission, AMPAR currents), immunofluorescence, behavioral assays (novel object recognition, contextual fear conditioning, social affiliation)","journal":"Neuroscience bulletin","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with multiple orthogonal electrophysiological, morphological, and behavioral readouts in a single rigorous study","pmids":["38321347"],"is_preprint":false},{"year":2025,"finding":"MDGA2 interacts with TrkB through its MAM (meprin/A5/mu) domain and competes with BDNF for binding to TrkB. Loss of MDGA2 or the ASD-associated MDGA2 V930I mutation promotes aberrant BDNF/TrkB signaling activation, which increases AMPA receptor-mediated excitatory synaptic activity. Inhibition of BDNF/TrkB signaling (by small molecule or MDGA2-derived peptide) rescues increased excitatory transmission and social deficits in Mdga2+/- mice.","method":"Co-immunoprecipitation, domain-deletion mapping (MAM domain), in vitro competition binding assay, electrophysiology (AMPA receptor-mediated EPSCs), pharmacological rescue, peptide rescue in Mdga2+/- mice","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — domain-mapped Co-IP, competitive binding assay, mutagenesis (V930I), pharmacological and peptide rescue with defined synaptic and behavioral readouts, single lab with multiple orthogonal methods","pmids":["40168357"],"is_preprint":false},{"year":2023,"finding":"Using epitope-tagged knock-in mice, endogenous MDGA2 was found to selectively depress NMDA receptor-mediated transmission and enhance inhibitory transmission; MDGA2 knockdown/knockout selectively impaired NMDAR-mediated synaptic responses and enhanced GABAergic transmission, contrasting with MDGA1 which supports AMPAR-mediated excitatory transmission.","method":"Epitope-tagged MDGA2 knock-in mice (endogenous localization), shRNA knockdown, CRISPR/Cas9 knockout, electrophysiology (NMDAR- and AMPAR-mediated currents, GABAergic transmission)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in endogenous tagging plus two loss-of-function approaches (shRNA and CRISPR KO) with electrophysiological readouts, single lab, preprint","pmids":["37720016"],"is_preprint":true},{"year":2025,"finding":"MDGA2 is degraded via a SORT1-mediated lysosomal degradation pathway. RPS23RG1 competes with SORT1 for MDGA2 binding, thereby protecting MDGA2 from lysosomal degradation. Both RPS23RG1 and SORT1 were confirmed to interact with MDGA2 by co-immunoprecipitation and mass spectrometry.","method":"LC-MS/MS interactome of MDGA2 extracellular domain, co-immunoprecipitation, siRNA knockdown of SORT1 and RPS23RG1, lysosome isolation, immunoblotting, immunostaining, behavioral rescue in KO mice","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interactions confirmed by Co-IP, lysosome fractionation, siRNA loss-of-function, and in vivo rescue, single lab","pmids":["39816685"],"is_preprint":false},{"year":2025,"finding":"MDGA2 binds EphB2 receptor tyrosine kinase via its first three Ig domains (cis-binding to the EphB2 ligand-binding domain), competing with Ephrin-B1 for EphB2 binding. EphB2 forms a complex with MDGA2 and GluN2B-containing NMDARs in mouse brain. MDGA2 must bind EphB2 to suppress spontaneous synaptic transmission and NMDAR-mediated (but not AMPAR-mediated) postsynaptic responses at excitatory synapses. MDGA2 deletion promotes EphB2/Ephrin-B1 complex formation but does not alter surface expression or Ephrin-stimulated EphB2 activation.","method":"Co-immunoprecipitation (EphB2, MDGA2, GluN2B in mouse brain), domain-deletion mapping (Ig1-3 of MDGA2), competition binding assay (Ephrin-B1 vs MDGA2), AlphaFold-based molecular replacement, electrophysiology in cultured neurons (NMDAR- and AMPAR-mediated currents, spontaneous transmission), cell surface expression assays","journal":"Progress in neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapped Co-IP in mouse brain tissue, competition binding, structural modeling, electrophysiological functional validation, single lab","pmids":["40316130"],"is_preprint":false},{"year":2025,"finding":"Homozygous loss-of-function variants in MDGA2 impair MDGA2 membrane trafficking, disrupt Nlgn1 (neuroligin-1) interaction, and perturb MDGA2-mediated excitatory synaptic functions in mammalian expression systems and cultured hippocampal neurons.","method":"Mammalian expression of nonsense variants, membrane trafficking assay, co-immunoprecipitation (MDGA2-Nlgn1 interaction), electrophysiology in cultured hippocampal neurons","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional studies of three variants with multiple orthogonal assays (trafficking, interaction, electrophysiology), single lab","pmids":["41570816"],"is_preprint":false}],"current_model":"MDGA2 is a GPI-anchored IgCAM superfamily protein that acts as a synaptic suppressor primarily by blocking neuroligin-1 interaction with neurexins (thereby restraining excitatory synapse development), competing with BDNF for TrkB binding via its MAM domain to limit BDNF/TrkB signaling, and cis-binding EphB2 via its Ig1-3 domains to suppress NMDAR-mediated excitatory transmission; MDGA2 protein stability is regulated through SORT1-mediated lysosomal degradation, which is antagonized by RPS23RG1, and homophilic MDGA2 interactions support commissural axon growth along the longitudinal axis in the spinal cord."},"narrative":{"mechanistic_narrative":"MDGA2 is a cell-surface IgCAM-superfamily protein that functions as a selective suppressor of excitatory synapse development and function in the mammalian brain [PMID:27608760, PMID:38321347]. Its canonical mechanism is to block neuroligin-1 (NLGN1) engagement of neurexins, restraining excitatory synaptogenesis: Mdga2 haploinsufficient mice and CA1-restricted conditional knockouts show increased asymmetric synapse density, elevated mEPSCs, enhanced AMPAR currents, and impaired LTP, memory, and social behavior, with inhibitory synapse measures left unchanged [PMID:27608760, PMID:38321347]. MDGA2 enforces excitatory restraint through multiple parallel cis interactions: it competes with BDNF for TrkB binding via its MAM domain to limit BDNF/TrkB-driven AMPAR-mediated transmission [PMID:40168357], and it binds EphB2 via its first three Ig domains, competing with Ephrin-B1 and forming a complex with GluN2B-containing NMDARs to suppress NMDAR-mediated postsynaptic responses [PMID:40316130]. MDGA2 protein abundance is set by a SORT1-mediated lysosomal degradation pathway that is antagonized by RPS23RG1, both of which bind the MDGA2 extracellular domain [PMID:39816685]. Homozygous loss-of-function variants impair MDGA2 membrane trafficking and disrupt its NLGN1 interaction, linking the gene to disease through perturbed excitatory synaptic function, consistent with an ASD-associated V930I mutation that drives aberrant BDNF/TrkB signaling [PMID:40168357, PMID:41570816]. Beyond the synaptic role, MDGA2 supports rostral longitudinal growth of post-crossing commissural axons through homophilic MDGA2-MDGA2 interactions [PMID:21542908], and a separate report links it to DMAP1 stabilization and p53/p21-mediated cell cycle arrest in gastric cancer cells [PMID:26206665].","teleology":[{"year":2011,"claim":"Established an early non-synaptic role for MDGA2 in axon guidance, showing it acts through homophilic adhesion to steer post-crossing commissural axons.","evidence":"RNAi knockdown and function-blocking antibodies in chick spinal cord commissural neurons with binding studies","pmids":["21542908"],"confidence":"Medium","gaps":["Mechanism downstream of homophilic binding unresolved","Relationship to later synaptic functions not addressed","Single lab, ortholog system"]},{"year":2015,"claim":"Identified an unexpected intracellular tumor-suppressive function, showing MDGA2 stabilizes DMAP1 to activate p53/p21 and trigger cell cycle arrest in gastric cancer.","evidence":"Mass spectrometry, Co-IP, reporter assays, knockdown/re-expression, and xenografts in gastric cancer cells","pmids":["26206665"],"confidence":"Medium","gaps":["How a cell-surface IgCAM accesses nuclear DMAP1 is unexplained","Not connected to neuronal functions","Single lab"]},{"year":2016,"claim":"Defined the core synaptic mechanism, showing MDGA2 selectively suppresses excitatory synapse development by blocking the NLGN1-neurexin interaction.","evidence":"Mdga2+/- mouse model with electrophysiology, synapse density, behavior, and voltage-sensitive dye imaging","pmids":["27608760"],"confidence":"High","gaps":["Domain basis of NLGN1 binding not mapped here","Mechanism of excitatory vs inhibitory selectivity unresolved"]},{"year":2023,"claim":"Distinguished MDGA2 from MDGA1 functionally, showing endogenous MDGA2 selectively depresses NMDAR-mediated transmission while enhancing inhibitory transmission.","evidence":"Epitope-tagged knock-in mice, shRNA knockdown, CRISPR knockout, and electrophysiology (preprint)","pmids":["37720016"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Molecular partner mediating NMDAR depression not identified in this study","Apparent contrast with prior excitatory-suppression data needs reconciliation"]},{"year":2024,"claim":"Confirmed cell-autonomous excitatory suppression in the mature circuit, showing CA1-specific Mdga2 deletion elevates excitatory transmission and impairs LTP, memory, and social behavior.","evidence":"Cre-lox conditional knockout in CA1 pyramidal neurons with electrophysiology, immunofluorescence, and behavioral assays","pmids":["38321347"],"confidence":"High","gaps":["Molecular effector at the postsynapse not dissected here","Adult vs developmental requirement not separated"]},{"year":2025,"claim":"Identified domain-resolved receptor interactions explaining excitatory suppression, showing MDGA2 competes with BDNF at TrkB via its MAM domain and with Ephrin-B1 at EphB2 via its Ig1-3 domains.","evidence":"Domain-deletion Co-IP, competition binding assays, V930I mutagenesis, AlphaFold modeling, electrophysiology, and pharmacological/peptide rescue in Mdga2+/- mice","pmids":["40168357","40316130"],"confidence":"High","gaps":["How TrkB and EphB2 pathways are integrated with NLGN1 blockade is unclear","Stoichiometry of MDGA2-EphB2-GluN2B complex not resolved","Whether one MDGA2 molecule engages multiple receptors unknown"]},{"year":2025,"claim":"Defined how MDGA2 protein levels are controlled, showing SORT1 routes MDGA2 to lysosomal degradation and RPS23RG1 protects it by competitive binding.","evidence":"LC-MS/MS interactome of MDGA2 ectodomain, Co-IP, siRNA knockdown, lysosome fractionation, and in vivo rescue","pmids":["39816685"],"confidence":"Medium","gaps":["Signals regulating the SORT1/RPS23RG1 balance unknown","Whether degradation tunes synaptic strength dynamically not shown","Single lab"]},{"year":2025,"claim":"Provided a direct disease link, showing homozygous loss-of-function MDGA2 variants impair membrane trafficking and disrupt NLGN1 interaction and excitatory synaptic function.","evidence":"Expression of nonsense variants in mammalian systems with trafficking assays, Co-IP, and electrophysiology in cultured hippocampal neurons","pmids":["41570816"],"confidence":"Medium","gaps":["Named clinical syndrome and inheritance breadth not detailed here","In vivo consequences of trafficking loss not modeled"]},{"year":null,"claim":"How MDGA2's multiple parallel mechanisms (NLGN1 blockade, TrkB competition, EphB2/NMDAR suppression, homophilic adhesion) are coordinated within a single neuron, and how degradation control gates them, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model linking the distinct receptor interactions","Relative contribution of each pathway to behavior not quantified","Connection between the non-neuronal DMAP1/p53 role and synaptic functions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4,7]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,7,8]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,3,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1]}],"complexes":[],"partners":["NLGN1","TRKB","EPHB2","GLUN2B","SORT1","RPS23RG1","DMAP1","MDGA2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z553","full_name":"MAM domain-containing glycosylphosphatidylinositol anchor protein 2","aliases":["MAM domain-containing protein 1"],"length_aa":956,"mass_kda":107.4,"function":"May be involved in cell-cell interactions","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q7Z553/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MDGA2","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MDGA2","total_profiled":1310},"omim":[{"mim_id":"611128","title":"MAM DOMAIN-CONTAINING GLYCOSYLPHOSPHATIDYLINOSITOL ANCHOR 2; MDGA2","url":"https://www.omim.org/entry/611128"},{"mim_id":"606167","title":"G PROTEIN-COUPLED RECEPTOR 132; GPR132","url":"https://www.omim.org/entry/606167"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":3.4},{"tissue":"retina","ntpm":4.1},{"tissue":"testis","ntpm":3.5}],"url":"https://www.proteinatlas.org/search/MDGA2"},"hgnc":{"alias_symbol":[],"prev_symbol":["MAMDC1"]},"alphafold":{"accession":"Q7Z553","domains":[{"cath_id":"2.60.40.10","chopping":"26-131","consensus_level":"high","plddt":79.0243,"start":26,"end":131},{"cath_id":"2.60.40.10","chopping":"136-235","consensus_level":"high","plddt":87.1065,"start":136,"end":235},{"cath_id":"2.60.40.10","chopping":"244-329","consensus_level":"high","plddt":92.4828,"start":244,"end":329},{"cath_id":"2.60.40.10","chopping":"331-439","consensus_level":"high","plddt":91.062,"start":331,"end":439},{"cath_id":"2.60.40.10","chopping":"442-538","consensus_level":"high","plddt":91.4887,"start":442,"end":538},{"cath_id":"2.60.40.10","chopping":"542-628","consensus_level":"high","plddt":91.3974,"start":542,"end":628},{"cath_id":"2.60.40.10","chopping":"634-735","consensus_level":"high","plddt":88.7238,"start":634,"end":735},{"cath_id":"2.60.120.200","chopping":"740-917","consensus_level":"high","plddt":84.3852,"start":740,"end":917}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z553","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z553-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z553-F1-predicted_aligned_error_v6.png","plddt_mean":84.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MDGA2","jax_strain_url":"https://www.jax.org/strain/search?query=MDGA2"},"sequence":{"accession":"Q7Z553","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z553.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z553/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z553"}},"corpus_meta":[{"pmid":"27608760","id":"PMC_27608760","title":"Altered Cortical Dynamics and Cognitive Function upon Haploinsufficiency of the Autism-Linked Excitatory Synaptic Suppressor MDGA2.","date":"2016","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/27608760","citation_count":90,"is_preprint":false},{"pmid":"26206665","id":"PMC_26206665","title":"MDGA2 is a novel tumour suppressor cooperating with DMAP1 in gastric cancer and is associated with disease outcome.","date":"2015","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/26206665","citation_count":63,"is_preprint":false},{"pmid":"21542908","id":"PMC_21542908","title":"Rostral growth of commissural axons requires the cell adhesion molecule MDGA2.","date":"2011","source":"Neural development","url":"https://pubmed.ncbi.nlm.nih.gov/21542908","citation_count":28,"is_preprint":false},{"pmid":"19997561","id":"PMC_19997561","title":"Identification of MAMDC1 as a candidate susceptibility gene for systemic lupus erythematosus (SLE).","date":"2009","source":"PloS 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Mdga2+/- mice show increased asymmetric synapse density, elevated mEPSC frequency and amplitude, and altered LTP with no change in inhibitory synapse measures, indicating MDGA2 is a suppressor of excitatory (not inhibitory) synapse formation acting through the NRXN-NLGN pathway.\",\n      \"method\": \"Genetic haploinsufficiency mouse model (Mdga2+/-), electrophysiology (mEPSC, LTP), synapse density quantification, behavioral assays, in vivo voltage-sensitive dye imaging\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional assays in vivo and in vitro, replicated across multiple orthogonal readouts (electrophysiology, morphology, behavior, imaging) in a single rigorous study\",\n      \"pmids\": [\"27608760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MDGA2 supports rostral axonal growth of post-crossing commissural axons through homophilic MDGA2-MDGA2 interactions between ipsilateral axons and post-crossing commissural axons. RNAi knockdown or function-blocking antibodies against MDGA2 abolish longitudinal axon extension in chick spinal cord commissural interneurons.\",\n      \"method\": \"RNAi knockdown in ovo, function-blocking antibody experiments, binding studies in chick spinal cord commissural neurons\",\n      \"journal\": \"Neural development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal loss-of-function methods (RNAi and antibody blockade) plus binding studies, single lab\",\n      \"pmids\": [\"21542908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MDGA2 directly stabilizes DMAP1 (DNA methyltransferase 1 associated protein 1) via protein-protein interaction, and this complex activates p53/p21 signaling cascades to cause G1-S cell cycle arrest and apoptosis in gastric cancer cells.\",\n      \"method\": \"Mass spectrometry identification of interacting protein, co-immunoprecipitation, reporter activity assays, PCR array, re-expression and knockdown experiments, xenograft mouse models\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed by Co-IP, functional rescue/knockdown with defined pathway readout, single lab\",\n      \"pmids\": [\"26206665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MDGA2 selectively suppresses the density and function of excitatory (but not inhibitory) synapses on CA1 pyramidal neurons in the mature hippocampus. Conditional deletion of Mdga2 in CA1 pyramidal neurons upregulates mEPSCs, spontaneous EPSPs, vGluT1 intensity, AMPAR currents, and neuronal excitability, while leaving mIPSC properties and vGAT intensity unchanged, and impairs LTP, memory, and social behavior.\",\n      \"method\": \"Conditional knockout (Cre-lox) restricted to CA1 pyramidal neurons, electrophysiology (mEPSC, mIPSC, evoked synaptic transmission, AMPAR currents), immunofluorescence, behavioral assays (novel object recognition, contextual fear conditioning, social affiliation)\",\n      \"journal\": \"Neuroscience bulletin\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with multiple orthogonal electrophysiological, morphological, and behavioral readouts in a single rigorous study\",\n      \"pmids\": [\"38321347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MDGA2 interacts with TrkB through its MAM (meprin/A5/mu) domain and competes with BDNF for binding to TrkB. Loss of MDGA2 or the ASD-associated MDGA2 V930I mutation promotes aberrant BDNF/TrkB signaling activation, which increases AMPA receptor-mediated excitatory synaptic activity. Inhibition of BDNF/TrkB signaling (by small molecule or MDGA2-derived peptide) rescues increased excitatory transmission and social deficits in Mdga2+/- mice.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion mapping (MAM domain), in vitro competition binding assay, electrophysiology (AMPA receptor-mediated EPSCs), pharmacological rescue, peptide rescue in Mdga2+/- mice\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — domain-mapped Co-IP, competitive binding assay, mutagenesis (V930I), pharmacological and peptide rescue with defined synaptic and behavioral readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40168357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Using epitope-tagged knock-in mice, endogenous MDGA2 was found to selectively depress NMDA receptor-mediated transmission and enhance inhibitory transmission; MDGA2 knockdown/knockout selectively impaired NMDAR-mediated synaptic responses and enhanced GABAergic transmission, contrasting with MDGA1 which supports AMPAR-mediated excitatory transmission.\",\n      \"method\": \"Epitope-tagged MDGA2 knock-in mice (endogenous localization), shRNA knockdown, CRISPR/Cas9 knockout, electrophysiology (NMDAR- and AMPAR-mediated currents, GABAergic transmission)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in endogenous tagging plus two loss-of-function approaches (shRNA and CRISPR KO) with electrophysiological readouts, single lab, preprint\",\n      \"pmids\": [\"37720016\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MDGA2 is degraded via a SORT1-mediated lysosomal degradation pathway. RPS23RG1 competes with SORT1 for MDGA2 binding, thereby protecting MDGA2 from lysosomal degradation. Both RPS23RG1 and SORT1 were confirmed to interact with MDGA2 by co-immunoprecipitation and mass spectrometry.\",\n      \"method\": \"LC-MS/MS interactome of MDGA2 extracellular domain, co-immunoprecipitation, siRNA knockdown of SORT1 and RPS23RG1, lysosome isolation, immunoblotting, immunostaining, behavioral rescue in KO mice\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interactions confirmed by Co-IP, lysosome fractionation, siRNA loss-of-function, and in vivo rescue, single lab\",\n      \"pmids\": [\"39816685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MDGA2 binds EphB2 receptor tyrosine kinase via its first three Ig domains (cis-binding to the EphB2 ligand-binding domain), competing with Ephrin-B1 for EphB2 binding. EphB2 forms a complex with MDGA2 and GluN2B-containing NMDARs in mouse brain. MDGA2 must bind EphB2 to suppress spontaneous synaptic transmission and NMDAR-mediated (but not AMPAR-mediated) postsynaptic responses at excitatory synapses. MDGA2 deletion promotes EphB2/Ephrin-B1 complex formation but does not alter surface expression or Ephrin-stimulated EphB2 activation.\",\n      \"method\": \"Co-immunoprecipitation (EphB2, MDGA2, GluN2B in mouse brain), domain-deletion mapping (Ig1-3 of MDGA2), competition binding assay (Ephrin-B1 vs MDGA2), AlphaFold-based molecular replacement, electrophysiology in cultured neurons (NMDAR- and AMPAR-mediated currents, spontaneous transmission), cell surface expression assays\",\n      \"journal\": \"Progress in neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapped Co-IP in mouse brain tissue, competition binding, structural modeling, electrophysiological functional validation, single lab\",\n      \"pmids\": [\"40316130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Homozygous loss-of-function variants in MDGA2 impair MDGA2 membrane trafficking, disrupt Nlgn1 (neuroligin-1) interaction, and perturb MDGA2-mediated excitatory synaptic functions in mammalian expression systems and cultured hippocampal neurons.\",\n      \"method\": \"Mammalian expression of nonsense variants, membrane trafficking assay, co-immunoprecipitation (MDGA2-Nlgn1 interaction), electrophysiology in cultured hippocampal neurons\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional studies of three variants with multiple orthogonal assays (trafficking, interaction, electrophysiology), single lab\",\n      \"pmids\": [\"41570816\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MDGA2 is a GPI-anchored IgCAM superfamily protein that acts as a synaptic suppressor primarily by blocking neuroligin-1 interaction with neurexins (thereby restraining excitatory synapse development), competing with BDNF for TrkB binding via its MAM domain to limit BDNF/TrkB signaling, and cis-binding EphB2 via its Ig1-3 domains to suppress NMDAR-mediated excitatory transmission; MDGA2 protein stability is regulated through SORT1-mediated lysosomal degradation, which is antagonized by RPS23RG1, and homophilic MDGA2 interactions support commissural axon growth along the longitudinal axis in the spinal cord.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MDGA2 is a cell-surface IgCAM-superfamily protein that functions as a selective suppressor of excitatory synapse development and function in the mammalian brain [#0, #3]. Its canonical mechanism is to block neuroligin-1 (NLGN1) engagement of neurexins, restraining excitatory synaptogenesis: Mdga2 haploinsufficient mice and CA1-restricted conditional knockouts show increased asymmetric synapse density, elevated mEPSCs, enhanced AMPAR currents, and impaired LTP, memory, and social behavior, with inhibitory synapse measures left unchanged [#0, #3]. MDGA2 enforces excitatory restraint through multiple parallel cis interactions: it competes with BDNF for TrkB binding via its MAM domain to limit BDNF/TrkB-driven AMPAR-mediated transmission [#4], and it binds EphB2 via its first three Ig domains, competing with Ephrin-B1 and forming a complex with GluN2B-containing NMDARs to suppress NMDAR-mediated postsynaptic responses [#7]. MDGA2 protein abundance is set by a SORT1-mediated lysosomal degradation pathway that is antagonized by RPS23RG1, both of which bind the MDGA2 extracellular domain [#6]. Homozygous loss-of-function variants impair MDGA2 membrane trafficking and disrupt its NLGN1 interaction, linking the gene to disease through perturbed excitatory synaptic function, consistent with an ASD-associated V930I mutation that drives aberrant BDNF/TrkB signaling [#4, #8]. Beyond the synaptic role, MDGA2 supports rostral longitudinal growth of post-crossing commissural axons through homophilic MDGA2-MDGA2 interactions [#1], and a separate report links it to DMAP1 stabilization and p53/p21-mediated cell cycle arrest in gastric cancer cells [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established an early non-synaptic role for MDGA2 in axon guidance, showing it acts through homophilic adhesion to steer post-crossing commissural axons.\",\n      \"evidence\": \"RNAi knockdown and function-blocking antibodies in chick spinal cord commissural neurons with binding studies\",\n      \"pmids\": [\"21542908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism downstream of homophilic binding unresolved\", \"Relationship to later synaptic functions not addressed\", \"Single lab, ortholog system\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified an unexpected intracellular tumor-suppressive function, showing MDGA2 stabilizes DMAP1 to activate p53/p21 and trigger cell cycle arrest in gastric cancer.\",\n      \"evidence\": \"Mass spectrometry, Co-IP, reporter assays, knockdown/re-expression, and xenografts in gastric cancer cells\",\n      \"pmids\": [\"26206665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a cell-surface IgCAM accesses nuclear DMAP1 is unexplained\", \"Not connected to neuronal functions\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the core synaptic mechanism, showing MDGA2 selectively suppresses excitatory synapse development by blocking the NLGN1-neurexin interaction.\",\n      \"evidence\": \"Mdga2+/- mouse model with electrophysiology, synapse density, behavior, and voltage-sensitive dye imaging\",\n      \"pmids\": [\"27608760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain basis of NLGN1 binding not mapped here\", \"Mechanism of excitatory vs inhibitory selectivity unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Distinguished MDGA2 from MDGA1 functionally, showing endogenous MDGA2 selectively depresses NMDAR-mediated transmission while enhancing inhibitory transmission.\",\n      \"evidence\": \"Epitope-tagged knock-in mice, shRNA knockdown, CRISPR knockout, and electrophysiology (preprint)\",\n      \"pmids\": [\"37720016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Molecular partner mediating NMDAR depression not identified in this study\", \"Apparent contrast with prior excitatory-suppression data needs reconciliation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirmed cell-autonomous excitatory suppression in the mature circuit, showing CA1-specific Mdga2 deletion elevates excitatory transmission and impairs LTP, memory, and social behavior.\",\n      \"evidence\": \"Cre-lox conditional knockout in CA1 pyramidal neurons with electrophysiology, immunofluorescence, and behavioral assays\",\n      \"pmids\": [\"38321347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular effector at the postsynapse not dissected here\", \"Adult vs developmental requirement not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified domain-resolved receptor interactions explaining excitatory suppression, showing MDGA2 competes with BDNF at TrkB via its MAM domain and with Ephrin-B1 at EphB2 via its Ig1-3 domains.\",\n      \"evidence\": \"Domain-deletion Co-IP, competition binding assays, V930I mutagenesis, AlphaFold modeling, electrophysiology, and pharmacological/peptide rescue in Mdga2+/- mice\",\n      \"pmids\": [\"40168357\", \"40316130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TrkB and EphB2 pathways are integrated with NLGN1 blockade is unclear\", \"Stoichiometry of MDGA2-EphB2-GluN2B complex not resolved\", \"Whether one MDGA2 molecule engages multiple receptors unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined how MDGA2 protein levels are controlled, showing SORT1 routes MDGA2 to lysosomal degradation and RPS23RG1 protects it by competitive binding.\",\n      \"evidence\": \"LC-MS/MS interactome of MDGA2 ectodomain, Co-IP, siRNA knockdown, lysosome fractionation, and in vivo rescue\",\n      \"pmids\": [\"39816685\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals regulating the SORT1/RPS23RG1 balance unknown\", \"Whether degradation tunes synaptic strength dynamically not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided a direct disease link, showing homozygous loss-of-function MDGA2 variants impair membrane trafficking and disrupt NLGN1 interaction and excitatory synaptic function.\",\n      \"evidence\": \"Expression of nonsense variants in mammalian systems with trafficking assays, Co-IP, and electrophysiology in cultured hippocampal neurons\",\n      \"pmids\": [\"41570816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Named clinical syndrome and inheritance breadth not detailed here\", \"In vivo consequences of trafficking loss not modeled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MDGA2's multiple parallel mechanisms (NLGN1 blockade, TrkB competition, EphB2/NMDAR suppression, homophilic adhesion) are coordinated within a single neuron, and how degradation control gates them, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model linking the distinct receptor interactions\", \"Relative contribution of each pathway to behavior not quantified\", \"Connection between the non-neuronal DMAP1/p53 role and synaptic functions unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 7]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 7, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 3, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NLGN1\", \"TrkB\", \"EphB2\", \"GluN2B\", \"SORT1\", \"RPS23RG1\", \"DMAP1\", \"MDGA2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}