{"gene":"GABBR1","run_date":"2026-04-28T17:46:04","timeline":{"discoveries":[{"year":2022,"finding":"GABBR1 encodes a subunit of the obligatory GABAB heterodimeric receptor; de novo missense variants in GABBR1 (p.Glu368Asp, p.Ala397Val, p.Ala535Thr, p.Gly673Asp) reduce GABA potency and/or efficacy, with p.Gly673Asp in transmembrane domain 3 abolishing receptor activity by preventing the receptor from reaching the cell surface, and p.Glu368Asp located near the orthosteric binding site reducing GABA potency and efficacy.","method":"In vitro functional characterization in transfected HEK293 cells; active-site and transmembrane domain mutagenesis; cell-surface expression assay","journal":"American Journal of Human Genetics","confidence":"High","confidence_rationale":"Tier 1 — in vitro functional assay with multiple variant characterizations, active-site mutagenesis, and cell-surface trafficking assessment in a single rigorous study","pmids":["36103875"],"is_preprint":false},{"year":2026,"finding":"De novo missense variants in GABBR1 produce a spectrum of gain- and loss-of-function alterations including: (i) increased constitutive activity with decreased GABA efficacy, (ii) significant reduction in GABA potency, and (iii) reduced surface expression resulting in decreased GABA efficacy, demonstrating that functional characterization is necessary beyond computational predictions.","method":"In vitro functional characterization of receptor variants; surface expression assays; pharmacological receptor assays","journal":"NPJ Genomic Medicine","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with multiple orthogonal functional readouts for several variants","pmids":["41803176"],"is_preprint":false},{"year":2021,"finding":"GABBR1 is required for hematopoietic stem and progenitor cell (HSPC) proliferation and self-renewal; Gabbr1-knockout mice show significantly reduced HSPC numbers in bone marrow, diminished competitive reconstitution capacity, a slow/non-cycling state of HSPCs, and defects in B-cell lineage differentiation. Ex vivo GABBR1 agonist treatment of human cord blood HSPCs significantly increased long-term engraftment in immunodeficient mice.","method":"Constitutive Gabbr1 knockout mouse model; competitive transplantation assay; colony-forming unit assay; in vitro coculture differentiation; imaging mass spectrometry of GABA in bone marrow niche; ex vivo agonist/antagonist treatment prior to xenograft transplantation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype plus multiple orthogonal functional readouts and pharmacological validation","pmids":["32881992"],"is_preprint":false},{"year":2015,"finding":"In the paraventricular nucleus (PVN), angiotensin II acting via AT1R induces HoxD10, which upregulates miR-7b; miR-7b binds the 3'UTR of GABBR1 mRNA to inhibit its translation, thereby reducing GABBR1 protein levels and contributing to sympathoexcitation in chronic heart failure. This ANG II/AT1R/HoxD10/miR-7b/GABBR1 pathway was validated in vivo and in vitro.","method":"Luciferase reporter assay with GABBR1 3'UTR; targeted mutagenesis of miR-7b binding site; miR-7b antisense infusion in PVN; HoxD10 silencing/overexpression; AT1R knockdown in vivo; coronary artery ligation CHF rat model","journal":"Circulation: Heart Failure","confidence":"High","confidence_rationale":"Tier 1-2 — luciferase reporter with mutagenesis, multiple in vivo interventions, and consistent mechanistic pathway validated by multiple orthogonal approaches","pmids":["26699387"],"is_preprint":false},{"year":2016,"finding":"miR-106a/b, miR-20a/b, and miR-17 (miR-17-92 cluster members) promote colorectal cancer cell proliferation and invasion by directly binding the 3'UTR of GABBR1, reducing its expression; GABBR1 functions as a tumor suppressor in colorectal cancer, as its inhibition mimics miRNA overexpression and its overexpression blocks miRNA-promoted proliferation and invasion.","method":"Luciferase reporter assay with GABBR1 3'UTR; RT-PCR; western blotting; MTT/BrdU proliferation assays; Transwell invasion assay; forced expression and knockdown experiments in HCT116 and HT-29 cells","journal":"Cancer Medicine","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase reporter confirming direct miRNA-3'UTR binding plus functional rescue experiments, single lab","pmids":["27230463"],"is_preprint":false},{"year":2001,"finding":"Two alternatively spliced cDNA variants of murine GABBR1 were identified, both predominantly expressed in the CNS. The deduced protein structures are highly homologous to rat and human receptors. Alternative splicing occurs at the same position as in the human gene, though the mouse gene has an additional 5' exon. The Gabbr1 gene was mapped to mouse chromosome 17 in a region homologous to human 6p21.3.","method":"cDNA cloning; tissue distribution analysis; genomic structure comparison; radiation hybrid mapping","journal":"Cytogenetics and Cell Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct molecular cloning and mapping with structural characterization, single study","pmids":["11306808"],"is_preprint":false},{"year":2021,"finding":"ADSC-derived extracellular vesicles carry LINC00622 into neuroblastoma cells, where LINC00622 inhibits transcription factor AR (androgen receptor), leading to increased GABBR1 expression and suppression of neuroblastoma cell proliferation, invasion, and migration.","method":"PKH26-labeled EV coculture; gene knockdown/overexpression; CCK-8/invasion/migration assays; xenograft tumor experiment in nude mice; western blotting; RT-PCR","journal":"Journal of Leukocyte Biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple functional assays with in vivo validation, but pathway placement of LINC00622/AR→GABBR1 is single-lab with indirect evidence for AR regulation of GABBR1","pmids":["34448502"],"is_preprint":false},{"year":2024,"finding":"GABBR1 modulates p38 MAPK signaling in the context of rheumatoid arthritis; glucocorticoid treatment reduces GABBR1 expression in joint tissue and synovial fluid mononuclear cells, with concurrent reduction in p38 MAPK expression and joint inflammation.","method":"Collagen-induced arthritis mouse model; immunohistochemistry; western blotting; ex vivo and in vitro dexamethasone treatment of peripheral blood and synovial fluid mononuclear cells","journal":"Cellular and Molecular Biology","confidence":"Low","confidence_rationale":"Tier 3 — correlative western blot evidence for GABBR1/p38 MAPK linkage, no direct mechanistic demonstration of GABBR1 acting on MAPK","pmids":["38836679"],"is_preprint":false},{"year":2025,"finding":"GABBR1 regulates insulin resistance and liver injury through a GABBR1/miR-19b-3p/WNT2B axis; GABBR1 overexpression reduces miR-19b-3p levels, which in turn increases WNT2B expression, alleviating palmitic acid- and poly I:C-induced hepatocyte damage, inflammation, and insulin resistance in vitro and in a diabetic mouse model.","method":"miR-19b-3p and GABBR1 overexpression/knockdown in AML12 cells; CCK-8 assay; ELISA; immunofluorescence; western blot; diabetic mouse model with liver injury assessment","journal":"Cell Cycle","confidence":"Low","confidence_rationale":"Tier 3 — single lab, indirect axis (GABBR1 regulation of miRNA and downstream target), no direct binding or reconstitution evidence","pmids":["40999757"],"is_preprint":false},{"year":2025,"finding":"GABBR1 and GABBR2 heterodimerize to form a functional GABAB receptor; global knockout of either GABBR1 or GABBR2 in mice results in the same phenotype (spontaneous epileptiform activity, hyperlocomotor activity, hyperalgesia, impaired memory, premature death), consistent with obligatory heterodimerization for functional receptor formation.","method":"Germline knockout mouse models; CRISPR-generated conditional floxed Gabbr2 mice bred with Actin-Cre; phenotypic comparison of global knockouts","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis via dual knockout with identical phenotypes supports obligatory heterodimerization; foundational finding replicated in preprint context","pmids":[],"is_preprint":true}],"current_model":"GABBR1 encodes the subunit 1 of the obligatory heterodimeric GABAB G protein-coupled receptor, where it contributes the orthosteric GABA-binding site; pathogenic variants reduce GABA potency/efficacy or impair surface trafficking, and GABBR1 activity is regulated post-transcriptionally by miRNAs (miR-7b, miR-17/20/106 family) binding its 3'UTR, while receptor signaling controls neuronal excitability, sympathetic tone via a PVN ANG II/AT1R/HoxD10/miR-7b pathway, and hematopoietic stem cell proliferation in the bone marrow niche."},"narrative":{"teleology":[{"year":2001,"claim":"Cloning of murine Gabbr1 established the gene's conserved structure, CNS-predominant expression, and alternative splicing pattern shared with the human orthologue, providing the molecular framework for subsequent functional studies.","evidence":"cDNA cloning, tissue distribution analysis, and radiation hybrid mapping in mouse","pmids":["11306808"],"confidence":"Medium","gaps":["No functional assay performed—expression pattern only","Protein-level validation of splice variants not demonstrated"]},{"year":2015,"claim":"Identification of a complete ANG II/AT1R/HoxD10/miR-7b pathway that post-transcriptionally silences GABBR1 in the hypothalamic PVN revealed how GABBR1 levels are dynamically regulated to modulate sympathetic outflow in heart failure.","evidence":"Luciferase reporter with 3′-UTR mutagenesis, miR-7b antisense PVN infusion, AT1R knockdown, and coronary-artery-ligation CHF rat model","pmids":["26699387"],"confidence":"High","gaps":["Whether this pathway operates in PVN neurons of species other than rat is untested","Direct electrophysiological consequences of miR-7b-mediated GABBR1 reduction in PVN neurons not measured"]},{"year":2016,"claim":"Demonstration that miR-17/20/106 family members directly target the GABBR1 3′-UTR to suppress its expression broadened the post-transcriptional regulatory landscape of GABBR1 and implicated its loss in colorectal cancer proliferation and invasion.","evidence":"Luciferase reporter assay, forced expression/knockdown rescue in HCT116 and HT-29 cells, proliferation and invasion assays","pmids":["27230463"],"confidence":"Medium","gaps":["Tumor-suppressive role of GABBR1 demonstrated only in cell lines, not validated in patient-derived models or in vivo","Downstream signaling pathway by which GABBR1 suppresses proliferation/invasion not identified"]},{"year":2021,"claim":"Gabbr1 knockout mice revealed a non-neuronal role for GABBR1 in hematopoietic stem cell self-renewal, proliferation, and B-cell differentiation, establishing the bone marrow niche as a GABA-responsive compartment.","evidence":"Constitutive Gabbr1 KO mice, competitive transplantation, colony-forming assays, imaging mass spectrometry of GABA in bone marrow, ex vivo agonist treatment of human cord blood HSPCs followed by xenograft","pmids":["32881992"],"confidence":"High","gaps":["Cell-intrinsic versus niche-mediated contributions not fully dissected","Downstream G-protein signaling cascade mediating HSPC self-renewal not characterized"]},{"year":2022,"claim":"Functional characterization of de novo GABBR1 missense variants established that the orthosteric binding site and transmembrane domains are critical determinants of receptor activity and surface trafficking, linking GABBR1 variants to a neurodevelopmental disorder.","evidence":"In vitro GABA dose-response curves, cell-surface expression assays, and active-site mutagenesis in transfected HEK293 cells","pmids":["36103875"],"confidence":"High","gaps":["Structural basis for how each variant disrupts function not resolved at atomic level","Patient phenotype–genotype correlation limited by small cohort size"]},{"year":2026,"claim":"Expanded variant characterization demonstrated that GABBR1 pathogenic variants produce both gain- and loss-of-function effects—including increased constitutive activity—establishing a bidirectional disease mechanism that cannot be predicted computationally.","evidence":"In vitro pharmacological receptor assays and surface expression measurements for multiple novel variants","pmids":["41803176"],"confidence":"High","gaps":["Whether gain-of-function variants respond differently to baclofen or other GABAB modulators is untested","In vivo neurophysiological consequences of constitutively active variants not modeled"]},{"year":null,"claim":"The structural basis of GABBR1-GABBR2 heterodimer assembly, the full downstream signaling cascade in non-neuronal tissues (bone marrow, liver), and variant-specific therapeutic strategies remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of disease-associated GABBR1 variant heterodimers","Signaling intermediates between GABBR1 activation and HSPC self-renewal unknown","Pharmacological rescue strategies for trafficking-deficient variants not explored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1,3]}],"complexes":["GABAB receptor heterodimer (GABBR1-GABBR2)"],"partners":["GABBR2"],"other_free_text":[]},"mechanistic_narrative":"GABBR1 encodes the ligand-binding subunit of the obligatory GABAB heterodimeric G protein-coupled receptor, which requires heterodimerization with GABBR2 for surface expression and function. The GABBR1 subunit harbors the orthosteric GABA-binding site in its Venus flytrap domain, and de novo missense variants at or near this site reduce GABA potency and efficacy, while transmembrane-domain variants can abolish receptor activity by preventing cell-surface trafficking; additional variants produce gain-of-function constitutive activity, demonstrating a bidirectional spectrum of pathogenic mechanisms [PMID:36103875, PMID:41803176]. Beyond its canonical role in neuronal inhibition and control of sympathetic tone—where its expression is regulated post-transcriptionally by miR-7b downstream of an angiotensin II/AT1R/HoxD10 pathway in the paraventricular nucleus [PMID:26699387]—GABBR1 is required for hematopoietic stem and progenitor cell proliferation, self-renewal, and B-cell differentiation, as demonstrated by reduced bone-marrow HSPC numbers and competitive reconstitution failure in Gabbr1-knockout mice [PMID:32881992]. GABBR1 expression is also regulated by miR-17/20/106 family members via direct 3′-UTR binding, and its downregulation promotes colorectal cancer cell proliferation and invasion, consistent with a tumor-suppressive role in that context [PMID:27230463]."},"prefetch_data":{"uniprot":{"accession":"Q9UBS5","full_name":"Gamma-aminobutyric acid type B receptor subunit 1","aliases":[],"length_aa":961,"mass_kda":108.3,"function":"Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2 (PubMed:15617512, PubMed:18165688, PubMed:22660477, PubMed:24305054, PubMed:36103875, PubMed:9872316, PubMed:9872744). Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins (PubMed:18165688). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase (PubMed:10075644, PubMed:10773016, PubMed:10906333, PubMed:24305054, PubMed:9872744). Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis (PubMed:10075644). Calcium is required for high affinity binding to GABA (By similarity). Plays a critical role in the fine-tuning of inhibitory synaptic transmission (PubMed:9844003). Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials (PubMed:10075644, PubMed:22660477, PubMed:9844003, PubMed:9872316, PubMed:9872744). Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception (Probable). Activated by (-)-baclofen, cgp27492 and blocked by phaclofen (PubMed:24305054, PubMed:9844003, PubMed:9872316) Isoform 1E may regulate the formation of functional GABBR1/GABBR2 heterodimers by competing for GABBR2 binding. This could explain the observation that certain small molecule ligands exhibit differential affinity for central versus peripheral sites","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9UBS5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GABBR1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GABBR1","total_profiled":1310},"omim":[{"mim_id":"620502","title":"NEURODEVELOPMENTAL DISORDER WITH LANGUAGE DELAY AND VARIABLE COGNITIVE ABNORMALITIES; NEDLC","url":"https://www.omim.org/entry/620502"},{"mim_id":"611195","title":"JANUS KINASE AND MICROTUBULE-INTERACTING PROTEIN 1; JAKMIP1","url":"https://www.omim.org/entry/611195"},{"mim_id":"610464","title":"G PROTEIN-COUPLED RECEPTOR 156; GPR156","url":"https://www.omim.org/entry/610464"},{"mim_id":"609327","title":"MICRO RNA 124-1; MIR124-1","url":"https://www.omim.org/entry/609327"},{"mim_id":"608645","title":"DEAFNESS, AUTOSOMAL DOMINANT 31; DFNA31","url":"https://www.omim.org/entry/608645"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Primary cilium tip","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":224.4}],"url":"https://www.proteinatlas.org/search/GABBR1"},"hgnc":{"alias_symbol":["hGB1a","GPRC3A"],"prev_symbol":[]},"alphafold":{"accession":"Q9UBS5","domains":[{"cath_id":"2.10.70.10","chopping":"29-97","consensus_level":"high","plddt":82.4271,"start":29,"end":97},{"cath_id":"2.10.70.10","chopping":"101-158","consensus_level":"high","plddt":82.8509,"start":101,"end":158},{"cath_id":"3.40.50.2300","chopping":"187-287_431-521","consensus_level":"high","plddt":91.8152,"start":187,"end":521},{"cath_id":"3.40.50.2300","chopping":"289-428_537-577","consensus_level":"high","plddt":94.8313,"start":289,"end":577},{"cath_id":"1.20.1070.10","chopping":"587-694_705-737_764-861","consensus_level":"high","plddt":89.434,"start":587,"end":861}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBS5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBS5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBS5-F1-predicted_aligned_error_v6.png","plddt_mean":84.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GABBR1","jax_strain_url":"https://www.jax.org/strain/search?query=GABBR1"},"sequence":{"accession":"Q9UBS5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBS5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBS5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBS5"}},"corpus_meta":[{"pmid":"32881992","id":"PMC_32881992","title":"The neurotransmitter receptor Gabbr1 regulates proliferation and function of hematopoietic stem and progenitor cells.","date":"2021","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/32881992","citation_count":46,"is_preprint":false},{"pmid":"15685626","id":"PMC_15685626","title":"Evidence for the gamma-amino-butyric acid type B receptor 1 (GABBR1) gene as a susceptibility factor in obsessive-compulsive disorder.","date":"2005","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15685626","citation_count":44,"is_preprint":false},{"pmid":"19763258","id":"PMC_19763258","title":"Association and interaction analyses of GABBR1 and GABBR2 with nicotine dependence in European- and African-American populations.","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19763258","citation_count":34,"is_preprint":false},{"pmid":"27230463","id":"PMC_27230463","title":"A miRNAs panel promotes the proliferation and invasion of colorectal cancer cells by targeting GABBR1.","date":"2016","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27230463","citation_count":30,"is_preprint":false},{"pmid":"29026448","id":"PMC_29026448","title":"Newborn genome-wide DNA methylation in association with pregnancy anxiety reveals a potential role for GABBR1.","date":"2017","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/29026448","citation_count":28,"is_preprint":false},{"pmid":"36103875","id":"PMC_36103875","title":"GABBR1 monoallelic de novo variants linked to neurodevelopmental delay and epilepsy.","date":"2022","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36103875","citation_count":25,"is_preprint":false},{"pmid":"15820424","id":"PMC_15820424","title":"Possible association between the gamma-aminobutyric acid type B receptor 1 (GABBR1) gene and schizophrenia.","date":"2005","source":"European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15820424","citation_count":25,"is_preprint":false},{"pmid":"23391219","id":"PMC_23391219","title":"GABBR1 has a HERV-W LTR in its regulatory region--a possible implication for schizophrenia.","date":"2013","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/23391219","citation_count":21,"is_preprint":false},{"pmid":"21621395","id":"PMC_21621395","title":"GABBR1 gene polymorphism(G1465A)isassociated with temporal lobe epilepsy.","date":"2011","source":"Epilepsy research","url":"https://pubmed.ncbi.nlm.nih.gov/21621395","citation_count":17,"is_preprint":false},{"pmid":"18355961","id":"PMC_18355961","title":"Analysis of LGI1 promoter sequence, PDYN and GABBR1 polymorphisms in sporadic and familial lateral temporal lobe epilepsy.","date":"2008","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/18355961","citation_count":16,"is_preprint":false},{"pmid":"15799783","id":"PMC_15799783","title":"The GABBR1 locus and the G1465A variant is not associated with temporal lobe epilepsy preceded by febrile seizures.","date":"2005","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15799783","citation_count":16,"is_preprint":false},{"pmid":"26727527","id":"PMC_26727527","title":"GABBR1 and SLC6A1, Two Genes Involved in Modulation of GABA Synaptic Transmission, Influence Risk for Alcoholism: Results from Three Ethnically Diverse Populations.","date":"2016","source":"Alcoholism, clinical and experimental research","url":"https://pubmed.ncbi.nlm.nih.gov/26727527","citation_count":16,"is_preprint":false},{"pmid":"34448502","id":"PMC_34448502","title":"Adipose-derived stem cell-derived extracellular vesicles inhibit neuroblastoma growth by regulating GABBR1 activity through LINC00622-mediated transcription factor AR.","date":"2021","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/34448502","citation_count":14,"is_preprint":false},{"pmid":"26699387","id":"PMC_26699387","title":"Sympathoexcitation in Rats With Chronic Heart Failure Depends on Homeobox D10 and MicroRNA-7b Inhibiting GABBR1 Translation in Paraventricular Nucleus.","date":"2015","source":"Circulation. Heart failure","url":"https://pubmed.ncbi.nlm.nih.gov/26699387","citation_count":10,"is_preprint":false},{"pmid":"30143926","id":"PMC_30143926","title":"Variants in GABBR1 Gene Are Associated with Methamphetamine Dependence and Two Years' Relapse after Drug Rehabilitation.","date":"2018","source":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30143926","citation_count":6,"is_preprint":false},{"pmid":"12770685","id":"PMC_12770685","title":"The gene encoding GABBR1 is not associated with childhood absence epilepsy in the Chinese Han population.","date":"2003","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/12770685","citation_count":6,"is_preprint":false},{"pmid":"11306808","id":"PMC_11306808","title":"The murine GABA(B) receptor 1: cDNA cloning, tissue distribution, structure of the Gabbr1 gene, and mapping to chromosome 17.","date":"2001","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11306808","citation_count":4,"is_preprint":false},{"pmid":"38836679","id":"PMC_38836679","title":"Glucocorticoids promote joint microenvironment alteration of GABBR1 expression associated with mitigating rheumatoid arthritis.","date":"2024","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/38836679","citation_count":2,"is_preprint":false},{"pmid":"40779845","id":"PMC_40779845","title":"Bisphenol A promotes OSCC progression via GABBR1-mediated MAPK signaling and macrophage polarization: A network toxicology based study.","date":"2025","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/40779845","citation_count":1,"is_preprint":false},{"pmid":"40612488","id":"PMC_40612488","title":"Case Report: Diagnostic assessment, developmental trajectory and treatment approaches in a case of a complex neurodevelopmental syndrome associated with non- synonymous variants in MECP2 (p. R133C) and GABBR1.","date":"2025","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/40612488","citation_count":0,"is_preprint":false},{"pmid":"41803176","id":"PMC_41803176","title":"Functional signatures of de novo GABBR1 and GABBR2 variants associated with neurodevelopmental disorders.","date":"2026","source":"NPJ genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41803176","citation_count":0,"is_preprint":false},{"pmid":"40999757","id":"PMC_40999757","title":"The GABBR1/miR-19b-3p/WNT2B axis regulates insulin resistance and liver injury in diabetes with viral infection: mechanistic and therapeutic insights.","date":"2025","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/40999757","citation_count":0,"is_preprint":false},{"pmid":"41792070","id":"PMC_41792070","title":"<em>IGHG1, HLA-DOB, </em>and <em>GABBR1</em>: Genetic Insights into Rheumatoid Arthritis Using Mendelian Randomisation and Single-Cell RNA Sequencing.","date":"2026","source":"Journal of the College of Physicians and Surgeons--Pakistan : JCPSP","url":"https://pubmed.ncbi.nlm.nih.gov/41792070","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.23.634473","title":"Development of a floxed <i>Gabbr2</i> gene allows for widespread conditional disruption of GABBR2 and recapitulates the phenotype of germline Gabbr2 knockout mice","date":"2025-01-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.23.634473","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.03.25330832","title":"Etiological basis for chronic pain genetic variation in brain and dorsal root ganglia cell types","date":"2025-07-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.03.25330832","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.22.684048","title":"Genomic signatures associated with convergent funnel-web building behavior in spiders","date":"2025-10-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.22.684048","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15211,"output_tokens":2820,"usd":0.043966},"stage2":{"model":"claude-opus-4-6","input_tokens":6125,"output_tokens":1954,"usd":0.119212},"total_usd":0.163178,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"GABBR1 encodes a subunit of the obligatory GABAB heterodimeric receptor; de novo missense variants in GABBR1 (p.Glu368Asp, p.Ala397Val, p.Ala535Thr, p.Gly673Asp) reduce GABA potency and/or efficacy, with p.Gly673Asp in transmembrane domain 3 abolishing receptor activity by preventing the receptor from reaching the cell surface, and p.Glu368Asp located near the orthosteric binding site reducing GABA potency and efficacy.\",\n      \"method\": \"In vitro functional characterization in transfected HEK293 cells; active-site and transmembrane domain mutagenesis; cell-surface expression assay\",\n      \"journal\": \"American Journal of Human Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro functional assay with multiple variant characterizations, active-site mutagenesis, and cell-surface trafficking assessment in a single rigorous study\",\n      \"pmids\": [\"36103875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"De novo missense variants in GABBR1 produce a spectrum of gain- and loss-of-function alterations including: (i) increased constitutive activity with decreased GABA efficacy, (ii) significant reduction in GABA potency, and (iii) reduced surface expression resulting in decreased GABA efficacy, demonstrating that functional characterization is necessary beyond computational predictions.\",\n      \"method\": \"In vitro functional characterization of receptor variants; surface expression assays; pharmacological receptor assays\",\n      \"journal\": \"NPJ Genomic Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple orthogonal functional readouts for several variants\",\n      \"pmids\": [\"41803176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GABBR1 is required for hematopoietic stem and progenitor cell (HSPC) proliferation and self-renewal; Gabbr1-knockout mice show significantly reduced HSPC numbers in bone marrow, diminished competitive reconstitution capacity, a slow/non-cycling state of HSPCs, and defects in B-cell lineage differentiation. Ex vivo GABBR1 agonist treatment of human cord blood HSPCs significantly increased long-term engraftment in immunodeficient mice.\",\n      \"method\": \"Constitutive Gabbr1 knockout mouse model; competitive transplantation assay; colony-forming unit assay; in vitro coculture differentiation; imaging mass spectrometry of GABA in bone marrow niche; ex vivo agonist/antagonist treatment prior to xenograft transplantation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype plus multiple orthogonal functional readouts and pharmacological validation\",\n      \"pmids\": [\"32881992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In the paraventricular nucleus (PVN), angiotensin II acting via AT1R induces HoxD10, which upregulates miR-7b; miR-7b binds the 3'UTR of GABBR1 mRNA to inhibit its translation, thereby reducing GABBR1 protein levels and contributing to sympathoexcitation in chronic heart failure. This ANG II/AT1R/HoxD10/miR-7b/GABBR1 pathway was validated in vivo and in vitro.\",\n      \"method\": \"Luciferase reporter assay with GABBR1 3'UTR; targeted mutagenesis of miR-7b binding site; miR-7b antisense infusion in PVN; HoxD10 silencing/overexpression; AT1R knockdown in vivo; coronary artery ligation CHF rat model\",\n      \"journal\": \"Circulation: Heart Failure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — luciferase reporter with mutagenesis, multiple in vivo interventions, and consistent mechanistic pathway validated by multiple orthogonal approaches\",\n      \"pmids\": [\"26699387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-106a/b, miR-20a/b, and miR-17 (miR-17-92 cluster members) promote colorectal cancer cell proliferation and invasion by directly binding the 3'UTR of GABBR1, reducing its expression; GABBR1 functions as a tumor suppressor in colorectal cancer, as its inhibition mimics miRNA overexpression and its overexpression blocks miRNA-promoted proliferation and invasion.\",\n      \"method\": \"Luciferase reporter assay with GABBR1 3'UTR; RT-PCR; western blotting; MTT/BrdU proliferation assays; Transwell invasion assay; forced expression and knockdown experiments in HCT116 and HT-29 cells\",\n      \"journal\": \"Cancer Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase reporter confirming direct miRNA-3'UTR binding plus functional rescue experiments, single lab\",\n      \"pmids\": [\"27230463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Two alternatively spliced cDNA variants of murine GABBR1 were identified, both predominantly expressed in the CNS. The deduced protein structures are highly homologous to rat and human receptors. Alternative splicing occurs at the same position as in the human gene, though the mouse gene has an additional 5' exon. The Gabbr1 gene was mapped to mouse chromosome 17 in a region homologous to human 6p21.3.\",\n      \"method\": \"cDNA cloning; tissue distribution analysis; genomic structure comparison; radiation hybrid mapping\",\n      \"journal\": \"Cytogenetics and Cell Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct molecular cloning and mapping with structural characterization, single study\",\n      \"pmids\": [\"11306808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADSC-derived extracellular vesicles carry LINC00622 into neuroblastoma cells, where LINC00622 inhibits transcription factor AR (androgen receptor), leading to increased GABBR1 expression and suppression of neuroblastoma cell proliferation, invasion, and migration.\",\n      \"method\": \"PKH26-labeled EV coculture; gene knockdown/overexpression; CCK-8/invasion/migration assays; xenograft tumor experiment in nude mice; western blotting; RT-PCR\",\n      \"journal\": \"Journal of Leukocyte Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple functional assays with in vivo validation, but pathway placement of LINC00622/AR→GABBR1 is single-lab with indirect evidence for AR regulation of GABBR1\",\n      \"pmids\": [\"34448502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GABBR1 modulates p38 MAPK signaling in the context of rheumatoid arthritis; glucocorticoid treatment reduces GABBR1 expression in joint tissue and synovial fluid mononuclear cells, with concurrent reduction in p38 MAPK expression and joint inflammation.\",\n      \"method\": \"Collagen-induced arthritis mouse model; immunohistochemistry; western blotting; ex vivo and in vitro dexamethasone treatment of peripheral blood and synovial fluid mononuclear cells\",\n      \"journal\": \"Cellular and Molecular Biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — correlative western blot evidence for GABBR1/p38 MAPK linkage, no direct mechanistic demonstration of GABBR1 acting on MAPK\",\n      \"pmids\": [\"38836679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GABBR1 regulates insulin resistance and liver injury through a GABBR1/miR-19b-3p/WNT2B axis; GABBR1 overexpression reduces miR-19b-3p levels, which in turn increases WNT2B expression, alleviating palmitic acid- and poly I:C-induced hepatocyte damage, inflammation, and insulin resistance in vitro and in a diabetic mouse model.\",\n      \"method\": \"miR-19b-3p and GABBR1 overexpression/knockdown in AML12 cells; CCK-8 assay; ELISA; immunofluorescence; western blot; diabetic mouse model with liver injury assessment\",\n      \"journal\": \"Cell Cycle\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, indirect axis (GABBR1 regulation of miRNA and downstream target), no direct binding or reconstitution evidence\",\n      \"pmids\": [\"40999757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GABBR1 and GABBR2 heterodimerize to form a functional GABAB receptor; global knockout of either GABBR1 or GABBR2 in mice results in the same phenotype (spontaneous epileptiform activity, hyperlocomotor activity, hyperalgesia, impaired memory, premature death), consistent with obligatory heterodimerization for functional receptor formation.\",\n      \"method\": \"Germline knockout mouse models; CRISPR-generated conditional floxed Gabbr2 mice bred with Actin-Cre; phenotypic comparison of global knockouts\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via dual knockout with identical phenotypes supports obligatory heterodimerization; foundational finding replicated in preprint context\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"GABBR1 encodes the subunit 1 of the obligatory heterodimeric GABAB G protein-coupled receptor, where it contributes the orthosteric GABA-binding site; pathogenic variants reduce GABA potency/efficacy or impair surface trafficking, and GABBR1 activity is regulated post-transcriptionally by miRNAs (miR-7b, miR-17/20/106 family) binding its 3'UTR, while receptor signaling controls neuronal excitability, sympathetic tone via a PVN ANG II/AT1R/HoxD10/miR-7b pathway, and hematopoietic stem cell proliferation in the bone marrow niche.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GABBR1 encodes the ligand-binding subunit of the obligatory GABAB heterodimeric G protein-coupled receptor, which requires heterodimerization with GABBR2 for surface expression and function. The GABBR1 subunit harbors the orthosteric GABA-binding site in its Venus flytrap domain, and de novo missense variants at or near this site reduce GABA potency and efficacy, while transmembrane-domain variants can abolish receptor activity by preventing cell-surface trafficking; additional variants produce gain-of-function constitutive activity, demonstrating a bidirectional spectrum of pathogenic mechanisms [PMID:36103875, PMID:41803176]. Beyond its canonical role in neuronal inhibition and control of sympathetic tone—where its expression is regulated post-transcriptionally by miR-7b downstream of an angiotensin II/AT1R/HoxD10 pathway in the paraventricular nucleus [PMID:26699387]—GABBR1 is required for hematopoietic stem and progenitor cell proliferation, self-renewal, and B-cell differentiation, as demonstrated by reduced bone-marrow HSPC numbers and competitive reconstitution failure in Gabbr1-knockout mice [PMID:32881992]. GABBR1 expression is also regulated by miR-17/20/106 family members via direct 3′-UTR binding, and its downregulation promotes colorectal cancer cell proliferation and invasion, consistent with a tumor-suppressive role in that context [PMID:27230463].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Cloning of murine Gabbr1 established the gene's conserved structure, CNS-predominant expression, and alternative splicing pattern shared with the human orthologue, providing the molecular framework for subsequent functional studies.\",\n      \"evidence\": \"cDNA cloning, tissue distribution analysis, and radiation hybrid mapping in mouse\",\n      \"pmids\": [\"11306808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional assay performed—expression pattern only\",\n        \"Protein-level validation of splice variants not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of a complete ANG II/AT1R/HoxD10/miR-7b pathway that post-transcriptionally silences GABBR1 in the hypothalamic PVN revealed how GABBR1 levels are dynamically regulated to modulate sympathetic outflow in heart failure.\",\n      \"evidence\": \"Luciferase reporter with 3′-UTR mutagenesis, miR-7b antisense PVN infusion, AT1R knockdown, and coronary-artery-ligation CHF rat model\",\n      \"pmids\": [\"26699387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether this pathway operates in PVN neurons of species other than rat is untested\",\n        \"Direct electrophysiological consequences of miR-7b-mediated GABBR1 reduction in PVN neurons not measured\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstration that miR-17/20/106 family members directly target the GABBR1 3′-UTR to suppress its expression broadened the post-transcriptional regulatory landscape of GABBR1 and implicated its loss in colorectal cancer proliferation and invasion.\",\n      \"evidence\": \"Luciferase reporter assay, forced expression/knockdown rescue in HCT116 and HT-29 cells, proliferation and invasion assays\",\n      \"pmids\": [\"27230463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Tumor-suppressive role of GABBR1 demonstrated only in cell lines, not validated in patient-derived models or in vivo\",\n        \"Downstream signaling pathway by which GABBR1 suppresses proliferation/invasion not identified\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Gabbr1 knockout mice revealed a non-neuronal role for GABBR1 in hematopoietic stem cell self-renewal, proliferation, and B-cell differentiation, establishing the bone marrow niche as a GABA-responsive compartment.\",\n      \"evidence\": \"Constitutive Gabbr1 KO mice, competitive transplantation, colony-forming assays, imaging mass spectrometry of GABA in bone marrow, ex vivo agonist treatment of human cord blood HSPCs followed by xenograft\",\n      \"pmids\": [\"32881992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cell-intrinsic versus niche-mediated contributions not fully dissected\",\n        \"Downstream G-protein signaling cascade mediating HSPC self-renewal not characterized\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Functional characterization of de novo GABBR1 missense variants established that the orthosteric binding site and transmembrane domains are critical determinants of receptor activity and surface trafficking, linking GABBR1 variants to a neurodevelopmental disorder.\",\n      \"evidence\": \"In vitro GABA dose-response curves, cell-surface expression assays, and active-site mutagenesis in transfected HEK293 cells\",\n      \"pmids\": [\"36103875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for how each variant disrupts function not resolved at atomic level\",\n        \"Patient phenotype–genotype correlation limited by small cohort size\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Expanded variant characterization demonstrated that GABBR1 pathogenic variants produce both gain- and loss-of-function effects—including increased constitutive activity—establishing a bidirectional disease mechanism that cannot be predicted computationally.\",\n      \"evidence\": \"In vitro pharmacological receptor assays and surface expression measurements for multiple novel variants\",\n      \"pmids\": [\"41803176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether gain-of-function variants respond differently to baclofen or other GABAB modulators is untested\",\n        \"In vivo neurophysiological consequences of constitutively active variants not modeled\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of GABBR1-GABBR2 heterodimer assembly, the full downstream signaling cascade in non-neuronal tissues (bone marrow, liver), and variant-specific therapeutic strategies remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of disease-associated GABBR1 variant heterodimers\",\n        \"Signaling intermediates between GABBR1 activation and HSPC self-renewal unknown\",\n        \"Pharmacological rescue strategies for trafficking-deficient variants not explored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"complexes\": [\n      \"GABAB receptor heterodimer (GABBR1-GABBR2)\"\n    ],\n    \"partners\": [\n      \"GABBR2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}