{"gene":"GLRA1","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":1992,"finding":"The GLRA1 (STHE) gene was mapped to chromosome 5q33-q35 by linkage analysis in a large hyperekplexia pedigree, establishing its chromosomal locus and candidacy as the startle disease gene.","method":"Systematic linkage analysis with polymorphic genetic markers","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — tight linkage (lod score 7.10), replicated in subsequent studies identifying mutations in GLRA1","pmids":["1355335"],"is_preprint":false},{"year":1994,"finding":"GLRA1 encodes the alpha1 subunit of the adult glycine receptor, which assembles into a pentameric complex (3 alpha1 : 2 beta) forming a glycine-gated chloride channel; loss-of-function frameshift mutation in mouse Glra1 (oscillator) causes 90% reduction in glycine-displaceable strychnine binding, confirming alpha1 is required for functional receptor activity and that no other alpha subunit compensates.","method":"Radioligand binding ([3H]strychnine), genetic mapping, allelism testing with spasmodic mutant","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical binding assay plus genetic loss-of-function in mouse model, replicated by subsequent immunoblot study (PMID:9145798)","pmids":["7874121"],"is_preprint":false},{"year":1997,"finding":"Complete loss of GLRA1 alpha1 polypeptide in oscillator (Glra1 spd-ot) homozygous mice also causes a dramatic reduction in the postsynaptic anchoring protein gephyrin, demonstrating that alpha1 is required for normal gephyrin localization/stability at glycinergic synapses.","method":"Western blot with subunit-specific antibodies, [3H]strychnine binding, immunoanalysis","journal":"Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (binding assay + immunoblot), confirmed in null mouse model with consistent results","pmids":["9145798"],"is_preprint":false},{"year":1999,"finding":"The hyperekplexia missense mutation P250T in the cytoplasmic M1-M2 loop of GLRA1 causes strong reduction of maximum whole-cell chloride currents and altered (prolonged) desensitization recovery, with only ~5-fold increase in glycine Ki, defining the M1-M2 intracellular loop as a determinant of glycine receptor channel gating.","method":"Recombinant expression in HEK293 cells, patch-clamp electrophysiology, topological analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro electrophysiology with specific mutant, two functional readouts (current amplitude and desensitization kinetics), single lab","pmids":["9920650"],"is_preprint":false},{"year":2002,"finding":"The recessive hyperekplexia mutation S231R in transmembrane region TM1 of GLRA1 introduces a positive charge that disrupts glycine receptor biogenesis and reduces surface membrane integration without abolishing expression, identifying TM1 as a determinant of cellular receptor trafficking.","method":"Biochemical analysis, patch-clamp electrophysiology, confocal microscopy, MALDI-TOF genotyping","journal":"European journal of human genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — three orthogonal methods (biochemistry, electrophysiology, imaging) in single lab establishing trafficking mechanism","pmids":["11973623"],"is_preprint":false},{"year":2007,"finding":"The hyperekplexia dominant missense mutation S267N in GLRA1 affects agonist responses and abolishes ethanol modulation of the glycine receptor, identifying S267 in TM2 as part of the ethanol/anesthetic modulatory site.","method":"Recombinant expression, electrophysiology, pharmacological modulation assays","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional electrophysiology with specific mutant, single lab, single published study","pmids":["18043720"],"is_preprint":false},{"year":2009,"finding":"The C-terminal domain of GLRA1 (including TM3-TM4 and the intervening loop) functions as an autonomous module: coexpression of a tail construct encoding the deleted C-terminal sequence rescued glycine-gated ion channel activity in oscillator truncation mutants, demonstrating modular subunit architecture of the Cys-loop receptor.","method":"Recombinant coexpression, electrophysiology, viral infection of oscillator spinal cord neurons, immunostaining","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — functional rescue by complementation in vitro and in primary neurons, multiple orthogonal approaches, single lab","pmids":["19244519"],"is_preprint":false},{"year":2010,"finding":"Systematic functional analysis of 13 GLRA1 hyperekplexia mutations showed that recessive mutations primarily cause subcellular localization/trafficking defects (reduced surface expression), while mutations without trafficking defects alter glycine sensitivity, establishing two major pathophysiological mechanisms; additionally, mutation I244N produces a constitutive leak conductance, identifying tonic channel opening as a novel mechanism.","method":"High-content imaging of subcellular localization, patch-clamp electrophysiology in HEK293 cells expressing homomeric alpha1 or heteromeric alpha1beta GlyRs","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — systematic analysis of 13 mutations with two orthogonal methods across dominant and recessive alleles, large patient cohort","pmids":["20631190"],"is_preprint":false},{"year":2013,"finding":"The hyperekplexia missense mutation W170S in the extracellular domain of GLRA1 reduces Zn2+-mediated potentiation and enhances Zn2+ inhibition of glycine receptors without altering glycine, taurine, or β-alanine potency, identifying W170 as a critical residue for the Zn2+ potentiation site distinct from the Zn2+ inhibition site (H107).","method":"Recombinant expression of alpha1 and alpha1beta GlyRs in heterologous cells, whole-cell electrophysiology with temporal Zn2+ application, overexpression in cultured rat neurons; H107N background mutation used for site dissection","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro electrophysiology with multiple mutant combinations and temporal pharmacology dissecting two distinct Zn2+ sites, confirmed in neurons, single lab","pmids":["24198360"],"is_preprint":false},{"year":2019,"finding":"CRISPR/Cas9 knockout of glra1 in zebrafish causes strong motor dysfunction and premature death, while knockout of glra2, glra3, glra4a, or glra4b produces no obvious motor phenotype, establishing that glra1 is specifically and non-redundantly required for inhibitory neurotransmission controlling locomotion.","method":"CRISPR/Cas9-targeted mutagenesis, individual knockout of each alpha subunit, behavioral motor analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis by individual KO of all five alpha subunits in the same organism, clear phenotypic specificity for glra1","pmids":["31048868"],"is_preprint":false},{"year":2025,"finding":"GLRA1 forms a physical interaction with calmodulin in pancreatic beta cells to sustain endoplasmic reticulum calcium homeostasis; beta-cell-specific deletion of Glra1 disrupts ER calcium dynamics, amplifies ER stress, and impairs insulin gene expression and secretion, establishing a glycine-GLRA1-calmodulin-ER calcium signaling axis in beta-cell function.","method":"Co-immunoprecipitation (GLRA1-calmodulin interaction), beta-cell-specific conditional knockout, ER calcium imaging, ER stress assays, insulin secretion assays, overexpression of Shmt2","journal":"Life metabolism","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple orthogonal functional readouts (calcium imaging, ER stress, secretion) plus Co-IP for binding partner identification, single lab","pmids":["42037784"],"is_preprint":false},{"year":1996,"finding":"Homozygous deletion of exons 1-6 of GLRA1 (complete null allele) in a human patient causes non-lethal hyperekplexia with preserved proprio- and exteroceptive inhibition, demonstrating that complete loss of GLRA1 is survivable in humans (unlike in mice) and that some glycinergic functions are compensated by other mechanisms.","method":"Genomic deletion analysis, clinical phenotyping of consanguineous family","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct loss-of-function genotyping with clinical phenotypic readout, single case (consanguineous family), human genetic study","pmids":["8651283"],"is_preprint":false},{"year":2020,"finding":"Spasmodic mice carrying a Glra1 point mutation (A52S) display enhanced acoustic startle responses and significant changes in fear-related behaviors (freezing, rearing, time on back) even in a neutral context, demonstrating that partial loss of GLRA1 function affects both startle magnitude and fear-related behavioral circuits.","method":"Behavioral analysis (startle paradigm, fear conditioning context) in Glra1 spasmodic and Glrb spastic mouse mutants","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined behavioral phenotype in a genetic mouse model with specific readouts, single study","pmids":["32848605"],"is_preprint":false}],"current_model":"GLRA1 encodes the alpha1 subunit of the inhibitory glycine receptor, which assembles as a pentameric glycine-gated chloride channel (3α1:2β) at inhibitory synapses in the brainstem and spinal cord; dominant hyperekplexia mutations in TM2/M1-M2 loop alter channel gating, glycine sensitivity, desensitization, or allosteric modulation (including Zn²⁺ potentiation via W170 and ethanol modulation via S267), while recessive mutations primarily impair receptor trafficking/surface expression; loss of alpha1 also reduces postsynaptic gephyrin clustering; the modular C-terminal domain (TM3-TM4) is required for channel assembly; and in pancreatic beta cells GLRA1 interacts with calmodulin to maintain ER calcium homeostasis and sustain insulin secretion."},"narrative":{"mechanistic_narrative":"GLRA1 encodes the alpha1 subunit of the inhibitory glycine receptor, a glycine-gated chloride channel that assembles as a pentamer (3 alpha1: 2 beta) and mediates fast inhibitory neurotransmission in brainstem and spinal cord motor circuits [PMID:7874121]. Loss of alpha1 abolishes functional receptor activity, with no compensation by other alpha subunits, and also depletes the postsynaptic anchoring protein gephyrin, linking alpha1 to organization of the glycinergic postsynapse [PMID:7874121, PMID:9145798]; in zebrafish, glra1 is non-redundantly required for inhibitory control of locomotion [PMID:31048868]. The receptor is built from autonomous structural modules — the C-terminal TM3-TM4 region complements truncation mutants in trans to restore channel activity — reflecting the modular architecture of Cys-loop receptors [PMID:19244519]. Dominant hyperekplexia mutations act on channel function: residues in the cytoplasmic M1-M2 loop govern current amplitude and desensitization (P250T), TM2 residue S267 forms part of the ethanol/anesthetic modulatory site, the extracellular W170 controls Zn2+ potentiation distinct from the Zn2+ inhibition site, and I244N produces a constitutive leak conductance, whereas recessive mutations predominantly cause trafficking/surface-expression defects (e.g. TM1 residue S231R) — defining two principal pathophysiological mechanisms in startle disease [PMID:9920650, PMID:18043720, PMID:24198360, PMID:20631190, PMID:11973623]. Mutations and deletions of GLRA1 cause hyperekplexia (startle disease), with complete loss surviving in humans [PMID:1355335, PMID:8651283]. Beyond its synaptic role, GLRA1 physically interacts with calmodulin in pancreatic beta cells to maintain ER calcium homeostasis and sustain insulin gene expression and secretion [PMID:42037784].","teleology":[{"year":1992,"claim":"Establishing the chromosomal locus of the startle disease gene was needed to identify the molecular cause of hyperekplexia; linkage to 5q33-q35 nominated GLRA1 as the candidate.","evidence":"Linkage analysis with polymorphic markers in a large hyperekplexia pedigree","pmids":["1355335"],"confidence":"High","gaps":["Linkage alone did not identify causal mutations or the gene product's function","Did not establish receptor subunit composition"]},{"year":1994,"claim":"It was unknown whether alpha1 was strictly required for receptor function; loss-of-function in the oscillator mouse showed alpha1 is non-redundant for forming the glycine-gated chloride channel.","evidence":"Radioligand [3H]strychnine binding and genetic mapping in mouse oscillator/spasmodic mutants","pmids":["7874121"],"confidence":"High","gaps":["Did not resolve which structural regions control gating versus trafficking","Stoichiometry inferred biochemically, not structurally"]},{"year":1997,"claim":"Whether alpha1 organizes the postsynaptic scaffold was unclear; complete loss of alpha1 was shown to deplete gephyrin, linking the receptor to synaptic anchoring.","evidence":"Western blot and [3H]strychnine binding in oscillator null mice","pmids":["9145798"],"confidence":"High","gaps":["Did not define whether the alpha1-gephyrin relationship is direct or activity-dependent","Mechanism of gephyrin destabilization unresolved"]},{"year":1996,"claim":"It was unknown whether complete GLRA1 loss is survivable in humans; a homozygous exon 1-6 deletion produced non-lethal hyperekplexia with preserved inhibition, indicating partial compensation.","evidence":"Genomic deletion analysis and clinical phenotyping in a consanguineous family","pmids":["8651283"],"confidence":"Medium","gaps":["Single consanguineous family","Compensatory mechanism not identified"]},{"year":1999,"claim":"The functional role of the cytoplasmic loop was undefined; P250T showed the M1-M2 loop determines channel gating via current amplitude and desensitization recovery.","evidence":"Recombinant expression and patch-clamp electrophysiology in HEK293 cells","pmids":["9920650"],"confidence":"High","gaps":["Single mutation in a heterologous system","Synaptic consequences not measured"]},{"year":2002,"claim":"How recessive mutations cause disease was unclear; S231R in TM1 was shown to impair biogenesis and surface integration, defining a trafficking mechanism.","evidence":"Biochemistry, patch-clamp, confocal microscopy on recombinant receptors","pmids":["11973623"],"confidence":"High","gaps":["Trafficking machinery responsible not identified","Single mutation analyzed"]},{"year":2007,"claim":"The molecular site of ethanol/anesthetic modulation was undefined; S267N abolished ethanol modulation, placing S267 in TM2 at the modulatory site.","evidence":"Recombinant expression with pharmacological modulation electrophysiology","pmids":["18043720"],"confidence":"Medium","gaps":["Single lab, single study","Physiological relevance of ethanol site to hyperekplexia unclear"]},{"year":2010,"claim":"Whether hyperekplexia mutations fall into mechanistic classes was unresolved; systematic analysis of 13 mutations established that recessive alleles cause trafficking defects and non-trafficking alleles alter glycine sensitivity, with I244N revealing a constitutive leak mechanism.","evidence":"High-content imaging and patch-clamp of homomeric and heteromeric GlyRs in HEK293 cells","pmids":["20631190"],"confidence":"High","gaps":["In vitro classification not validated in vivo","Leak conductance mechanism structurally undefined"]},{"year":2009,"claim":"Subunit architecture was poorly defined; coexpression of an isolated C-terminal TM3-TM4 module rescued channel activity in truncation mutants, demonstrating modular assembly.","evidence":"Recombinant coexpression complementation, electrophysiology, viral rescue in oscillator neurons","pmids":["19244519"],"confidence":"High","gaps":["Structural basis of inter-module assembly not resolved","Efficiency relative to native receptor unclear"]},{"year":2013,"claim":"The residues controlling Zn2+ allosteric potentiation were unknown; W170S reduced Zn2+ potentiation and enhanced Zn2+ inhibition, mapping the potentiation site distinct from H107 inhibition.","evidence":"Recombinant expression with temporal Zn2+ electrophysiology and H107N background dissection, confirmed in neurons","pmids":["24198360"],"confidence":"High","gaps":["Single lab","Endogenous Zn2+ regulation in vivo not addressed"]},{"year":2019,"claim":"Whether alpha1 is uniquely required among alpha subunits was untested; individual CRISPR knockouts showed only glra1 loss causes motor dysfunction, establishing non-redundancy.","evidence":"CRISPR/Cas9 knockout of each alpha subunit with behavioral analysis in zebrafish","pmids":["31048868"],"confidence":"High","gaps":["Does not address subunit roles in other circuits or species","Molecular basis of non-redundancy not detailed"]},{"year":2020,"claim":"Whether partial GLRA1 dysfunction affects circuits beyond startle was unclear; spasmodic A52S mice showed altered fear-related behaviors alongside enhanced startle.","evidence":"Behavioral startle and fear-context analysis in Glra1 spasmodic mice","pmids":["32848605"],"confidence":"Medium","gaps":["Behavioral correlation does not establish circuit mechanism","Single study"]},{"year":2025,"claim":"A non-neuronal role for GLRA1 was unknown; it was shown to bind calmodulin in pancreatic beta cells to maintain ER calcium homeostasis and support insulin secretion, defining a glycine-GLRA1-calmodulin-ER calcium axis.","evidence":"Co-IP, beta-cell-specific conditional knockout, ER calcium imaging, ER stress and insulin secretion assays","pmids":["42037784"],"confidence":"High","gaps":["Single lab","Whether interaction depends on channel activity not resolved","Mechanistic link between calmodulin binding and ER calcium undefined"]},{"year":null,"claim":"How alpha1 mechanistically stabilizes gephyrin and how its calmodulin-dependent ER calcium role in beta cells relates to its channel function remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of the receptor-gephyrin interface from the corpus","Channel-dependence of beta-cell calmodulin axis unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[1,3,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,7]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10]}],"complexes":["Glycine receptor (alpha1/beta pentamer)"],"partners":["GLRB","GPHN","CALM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P23415","full_name":"Glycine receptor subunit alpha-1","aliases":["Glycine receptor 48 kDa subunit","Glycine receptor strychnine-binding subunit"],"length_aa":457,"mass_kda":52.6,"function":"Subunit of heteromeric glycine-gated chloride channels (PubMed:14551753, PubMed:23994010, PubMed:25730860, PubMed:37821459). Plays an important role in the down-regulation of neuronal excitability (PubMed:8298642, PubMed:9009272). Contributes to the generation of inhibitory postsynaptic currents (PubMed:25445488). Channel activity is potentiated by ethanol (PubMed:25973519). Potentiation of channel activity by intoxicating levels of ethanol contribute to the sedative effects of ethanol (By similarity)","subcellular_location":"Postsynaptic cell membrane; Synapse; Perikaryon; Cell projection, dendrite; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P23415/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GLRA1","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/GLRA1","total_profiled":1310},"omim":[{"mim_id":"617362","title":"DEAH-BOX HELICASE 37; DHX37","url":"https://www.omim.org/entry/617362"},{"mim_id":"604159","title":"SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, GLYCINE), MEMBER 5; SLC6A5","url":"https://www.omim.org/entry/604159"},{"mim_id":"305990","title":"GLYCINE RECEPTOR, ALPHA-2 SUBUNIT; GLRA2","url":"https://www.omim.org/entry/305990"},{"mim_id":"184850","title":"STIFF-PERSON SYNDROME; SPS","url":"https://www.omim.org/entry/184850"},{"mim_id":"153550","title":"CHROMOSOME 5q DELETION SYNDROME","url":"https://www.omim.org/entry/153550"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"retina","ntpm":2.3}],"url":"https://www.proteinatlas.org/search/GLRA1"},"hgnc":{"alias_symbol":[],"prev_symbol":["STHE"]},"alphafold":{"accession":"P23415","domains":[{"cath_id":"2.70.170.10","chopping":"43-246","consensus_level":"high","plddt":93.8497,"start":43,"end":246},{"cath_id":"1.20.58.390","chopping":"249-346_421-455","consensus_level":"high","plddt":92.1314,"start":249,"end":455}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23415","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23415-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23415-F1-predicted_aligned_error_v6.png","plddt_mean":84.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GLRA1","jax_strain_url":"https://www.jax.org/strain/search?query=GLRA1"},"sequence":{"accession":"P23415","fasta_url":"https://rest.uniprot.org/uniprotkb/P23415.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23415/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23415"}},"corpus_meta":[{"pmid":"3161206","id":"PMC_3161206","title":"Determination 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gene.","date":"2012","source":"Journal of child neurology","url":"https://pubmed.ncbi.nlm.nih.gov/23143726","citation_count":8,"is_preprint":false},{"pmid":"28758885","id":"PMC_28758885","title":"Dimensional Traits of Schizotypy Associated With Glycine Receptor GLRA1 Polymorphism: An Exploratory Candidate-Gene Association Study.","date":"2017","source":"Journal of personality disorders","url":"https://pubmed.ncbi.nlm.nih.gov/28758885","citation_count":7,"is_preprint":false},{"pmid":"37222814","id":"PMC_37222814","title":"A loss-of-function variant in canine GLRA1 associates with a neurological disorder resembling human hyperekplexia.","date":"2023","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37222814","citation_count":6,"is_preprint":false},{"pmid":"29602144","id":"PMC_29602144","title":"Weird Laughing in Hyperekplexia: A new phenotype associated with a novel mutation in the GLRA1 gene?","date":"2018","source":"Seizure","url":"https://pubmed.ncbi.nlm.nih.gov/29602144","citation_count":6,"is_preprint":false},{"pmid":"28985719","id":"PMC_28985719","title":"A novel compound mutation in GLRA1 cause hyperekplexia in a Chinese boy- a case report and review of the literature.","date":"2017","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28985719","citation_count":5,"is_preprint":false},{"pmid":"30182260","id":"PMC_30182260","title":"A novel nonsense autosomal dominant mutation in the GLRA1 gene causing hyperekplexia.","date":"2018","source":"Journal of neural transmission (Vienna, Austria : 1996)","url":"https://pubmed.ncbi.nlm.nih.gov/30182260","citation_count":4,"is_preprint":false},{"pmid":"2054477","id":"PMC_2054477","title":"[Increasing the sensitivity of in vitro transformed hamster embryo cells (STHE strain) to cytolysis by resident and activated macrophages].","date":"1991","source":"Biulleten' eksperimental'noi biologii i meditsiny","url":"https://pubmed.ncbi.nlm.nih.gov/2054477","citation_count":3,"is_preprint":false},{"pmid":"36434917","id":"PMC_36434917","title":"Four Turkish families with hyperekplexia: A missense mutation and the exon 1-7 deletion in the GLRA1 gene.","date":"2022","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/36434917","citation_count":2,"is_preprint":false},{"pmid":"32332682","id":"PMC_32332682","title":"C.292G>A, a novel glycine receptor alpha 1 subunit gene (GLRA1) mutation found in a Chinese patient with hyperekplexia: A case report.","date":"2020","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32332682","citation_count":2,"is_preprint":false},{"pmid":"25036534","id":"PMC_25036534","title":"Neonatal hyperekplexia with homozygous p.R392H mutation in GLRA1.","date":"2014","source":"Epileptic disorders : international epilepsy journal with videotape","url":"https://pubmed.ncbi.nlm.nih.gov/25036534","citation_count":2,"is_preprint":false},{"pmid":"14673895","id":"PMC_14673895","title":"Magnetic resonance spectroscopy of cerebral cortex is normal in hereditary hyperekplexia due to mutations in the GLRA1 gene.","date":"2003","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/14673895","citation_count":2,"is_preprint":false},{"pmid":"1786389","id":"PMC_1786389","title":"[In vitro selection of cell variants resistant to macrophage and hydrogen peroxide cytotoxic activity in spontaneous transformed cells of the STHE strain].","date":"1991","source":"Biulleten' eksperimental'noi biologii i meditsiny","url":"https://pubmed.ncbi.nlm.nih.gov/1786389","citation_count":1,"is_preprint":false},{"pmid":"1810496","id":"PMC_1810496","title":"[The tumorigenicity and metastasis of low-malignancy STHE-strain cells undergoing in vitro selection with peritoneal exudate cells].","date":"1991","source":"Biulleten' eksperimental'noi biologii i meditsiny","url":"https://pubmed.ncbi.nlm.nih.gov/1810496","citation_count":1,"is_preprint":false},{"pmid":"41194486","id":"PMC_41194486","title":"A Novel Variant in GLRA1 Associated With Emotional Stimulus-Sensitive Hemichoreic Movements.","date":"2025","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/41194486","citation_count":1,"is_preprint":false},{"pmid":"42037784","id":"PMC_42037784","title":"Glycine-GLRA1-calmodulin signaling regulates endoplasmic reticulum calcium to sustain insulin secretion and β-cell function.","date":"2025","source":"Life metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/42037784","citation_count":0,"is_preprint":false},{"pmid":"41578547","id":"PMC_41578547","title":"A case of childhood hyperekplexia due to a novel nonsense variant in the GLRA1 gene.","date":"2026","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41578547","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19751,"output_tokens":3173,"usd":0.053424,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10700,"output_tokens":3795,"usd":0.074188,"stage2_stop_reason":"end_turn"},"total_usd":0.127612,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"The GLRA1 (STHE) gene was mapped to chromosome 5q33-q35 by linkage analysis in a large hyperekplexia pedigree, establishing its chromosomal locus and candidacy as the startle disease gene.\",\n      \"method\": \"Systematic linkage analysis with polymorphic genetic markers\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tight linkage (lod score 7.10), replicated in subsequent studies identifying mutations in GLRA1\",\n      \"pmids\": [\"1355335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"GLRA1 encodes the alpha1 subunit of the adult glycine receptor, which assembles into a pentameric complex (3 alpha1 : 2 beta) forming a glycine-gated chloride channel; loss-of-function frameshift mutation in mouse Glra1 (oscillator) causes 90% reduction in glycine-displaceable strychnine binding, confirming alpha1 is required for functional receptor activity and that no other alpha subunit compensates.\",\n      \"method\": \"Radioligand binding ([3H]strychnine), genetic mapping, allelism testing with spasmodic mutant\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical binding assay plus genetic loss-of-function in mouse model, replicated by subsequent immunoblot study (PMID:9145798)\",\n      \"pmids\": [\"7874121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Complete loss of GLRA1 alpha1 polypeptide in oscillator (Glra1 spd-ot) homozygous mice also causes a dramatic reduction in the postsynaptic anchoring protein gephyrin, demonstrating that alpha1 is required for normal gephyrin localization/stability at glycinergic synapses.\",\n      \"method\": \"Western blot with subunit-specific antibodies, [3H]strychnine binding, immunoanalysis\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (binding assay + immunoblot), confirmed in null mouse model with consistent results\",\n      \"pmids\": [\"9145798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The hyperekplexia missense mutation P250T in the cytoplasmic M1-M2 loop of GLRA1 causes strong reduction of maximum whole-cell chloride currents and altered (prolonged) desensitization recovery, with only ~5-fold increase in glycine Ki, defining the M1-M2 intracellular loop as a determinant of glycine receptor channel gating.\",\n      \"method\": \"Recombinant expression in HEK293 cells, patch-clamp electrophysiology, topological analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro electrophysiology with specific mutant, two functional readouts (current amplitude and desensitization kinetics), single lab\",\n      \"pmids\": [\"9920650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The recessive hyperekplexia mutation S231R in transmembrane region TM1 of GLRA1 introduces a positive charge that disrupts glycine receptor biogenesis and reduces surface membrane integration without abolishing expression, identifying TM1 as a determinant of cellular receptor trafficking.\",\n      \"method\": \"Biochemical analysis, patch-clamp electrophysiology, confocal microscopy, MALDI-TOF genotyping\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — three orthogonal methods (biochemistry, electrophysiology, imaging) in single lab establishing trafficking mechanism\",\n      \"pmids\": [\"11973623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The hyperekplexia dominant missense mutation S267N in GLRA1 affects agonist responses and abolishes ethanol modulation of the glycine receptor, identifying S267 in TM2 as part of the ethanol/anesthetic modulatory site.\",\n      \"method\": \"Recombinant expression, electrophysiology, pharmacological modulation assays\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional electrophysiology with specific mutant, single lab, single published study\",\n      \"pmids\": [\"18043720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The C-terminal domain of GLRA1 (including TM3-TM4 and the intervening loop) functions as an autonomous module: coexpression of a tail construct encoding the deleted C-terminal sequence rescued glycine-gated ion channel activity in oscillator truncation mutants, demonstrating modular subunit architecture of the Cys-loop receptor.\",\n      \"method\": \"Recombinant coexpression, electrophysiology, viral infection of oscillator spinal cord neurons, immunostaining\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional rescue by complementation in vitro and in primary neurons, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"19244519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Systematic functional analysis of 13 GLRA1 hyperekplexia mutations showed that recessive mutations primarily cause subcellular localization/trafficking defects (reduced surface expression), while mutations without trafficking defects alter glycine sensitivity, establishing two major pathophysiological mechanisms; additionally, mutation I244N produces a constitutive leak conductance, identifying tonic channel opening as a novel mechanism.\",\n      \"method\": \"High-content imaging of subcellular localization, patch-clamp electrophysiology in HEK293 cells expressing homomeric alpha1 or heteromeric alpha1beta GlyRs\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — systematic analysis of 13 mutations with two orthogonal methods across dominant and recessive alleles, large patient cohort\",\n      \"pmids\": [\"20631190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The hyperekplexia missense mutation W170S in the extracellular domain of GLRA1 reduces Zn2+-mediated potentiation and enhances Zn2+ inhibition of glycine receptors without altering glycine, taurine, or β-alanine potency, identifying W170 as a critical residue for the Zn2+ potentiation site distinct from the Zn2+ inhibition site (H107).\",\n      \"method\": \"Recombinant expression of alpha1 and alpha1beta GlyRs in heterologous cells, whole-cell electrophysiology with temporal Zn2+ application, overexpression in cultured rat neurons; H107N background mutation used for site dissection\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro electrophysiology with multiple mutant combinations and temporal pharmacology dissecting two distinct Zn2+ sites, confirmed in neurons, single lab\",\n      \"pmids\": [\"24198360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CRISPR/Cas9 knockout of glra1 in zebrafish causes strong motor dysfunction and premature death, while knockout of glra2, glra3, glra4a, or glra4b produces no obvious motor phenotype, establishing that glra1 is specifically and non-redundantly required for inhibitory neurotransmission controlling locomotion.\",\n      \"method\": \"CRISPR/Cas9-targeted mutagenesis, individual knockout of each alpha subunit, behavioral motor analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis by individual KO of all five alpha subunits in the same organism, clear phenotypic specificity for glra1\",\n      \"pmids\": [\"31048868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GLRA1 forms a physical interaction with calmodulin in pancreatic beta cells to sustain endoplasmic reticulum calcium homeostasis; beta-cell-specific deletion of Glra1 disrupts ER calcium dynamics, amplifies ER stress, and impairs insulin gene expression and secretion, establishing a glycine-GLRA1-calmodulin-ER calcium signaling axis in beta-cell function.\",\n      \"method\": \"Co-immunoprecipitation (GLRA1-calmodulin interaction), beta-cell-specific conditional knockout, ER calcium imaging, ER stress assays, insulin secretion assays, overexpression of Shmt2\",\n      \"journal\": \"Life metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple orthogonal functional readouts (calcium imaging, ER stress, secretion) plus Co-IP for binding partner identification, single lab\",\n      \"pmids\": [\"42037784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Homozygous deletion of exons 1-6 of GLRA1 (complete null allele) in a human patient causes non-lethal hyperekplexia with preserved proprio- and exteroceptive inhibition, demonstrating that complete loss of GLRA1 is survivable in humans (unlike in mice) and that some glycinergic functions are compensated by other mechanisms.\",\n      \"method\": \"Genomic deletion analysis, clinical phenotyping of consanguineous family\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct loss-of-function genotyping with clinical phenotypic readout, single case (consanguineous family), human genetic study\",\n      \"pmids\": [\"8651283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Spasmodic mice carrying a Glra1 point mutation (A52S) display enhanced acoustic startle responses and significant changes in fear-related behaviors (freezing, rearing, time on back) even in a neutral context, demonstrating that partial loss of GLRA1 function affects both startle magnitude and fear-related behavioral circuits.\",\n      \"method\": \"Behavioral analysis (startle paradigm, fear conditioning context) in Glra1 spasmodic and Glrb spastic mouse mutants\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined behavioral phenotype in a genetic mouse model with specific readouts, single study\",\n      \"pmids\": [\"32848605\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GLRA1 encodes the alpha1 subunit of the inhibitory glycine receptor, which assembles as a pentameric glycine-gated chloride channel (3α1:2β) at inhibitory synapses in the brainstem and spinal cord; dominant hyperekplexia mutations in TM2/M1-M2 loop alter channel gating, glycine sensitivity, desensitization, or allosteric modulation (including Zn²⁺ potentiation via W170 and ethanol modulation via S267), while recessive mutations primarily impair receptor trafficking/surface expression; loss of alpha1 also reduces postsynaptic gephyrin clustering; the modular C-terminal domain (TM3-TM4) is required for channel assembly; and in pancreatic beta cells GLRA1 interacts with calmodulin to maintain ER calcium homeostasis and sustain insulin secretion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GLRA1 encodes the alpha1 subunit of the inhibitory glycine receptor, a glycine-gated chloride channel that assembles as a pentamer (3 alpha1 : 2 beta) and mediates fast inhibitory neurotransmission in brainstem and spinal cord motor circuits [#1]. Loss of alpha1 abolishes functional receptor activity, with no compensation by other alpha subunits, and also depletes the postsynaptic anchoring protein gephyrin, linking alpha1 to organization of the glycinergic postsynapse [#1, #2]; in zebrafish, glra1 is non-redundantly required for inhibitory control of locomotion [#9]. The receptor is built from autonomous structural modules — the C-terminal TM3-TM4 region complements truncation mutants in trans to restore channel activity — reflecting the modular architecture of Cys-loop receptors [#6]. Dominant hyperekplexia mutations act on channel function: residues in the cytoplasmic M1-M2 loop govern current amplitude and desensitization (P250T), TM2 residue S267 forms part of the ethanol/anesthetic modulatory site, the extracellular W170 controls Zn2+ potentiation distinct from the Zn2+ inhibition site, and I244N produces a constitutive leak conductance, whereas recessive mutations predominantly cause trafficking/surface-expression defects (e.g. TM1 residue S231R) — defining two principal pathophysiological mechanisms in startle disease [#3, #5, #8, #7, #4]. Mutations and deletions of GLRA1 cause hyperekplexia (startle disease), with complete loss surviving in humans [#0, #11]. Beyond its synaptic role, GLRA1 physically interacts with calmodulin in pancreatic beta cells to maintain ER calcium homeostasis and sustain insulin gene expression and secretion [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing the chromosomal locus of the startle disease gene was needed to identify the molecular cause of hyperekplexia; linkage to 5q33-q35 nominated GLRA1 as the candidate.\",\n      \"evidence\": \"Linkage analysis with polymorphic markers in a large hyperekplexia pedigree\",\n      \"pmids\": [\"1355335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Linkage alone did not identify causal mutations or the gene product's function\", \"Did not establish receptor subunit composition\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"It was unknown whether alpha1 was strictly required for receptor function; loss-of-function in the oscillator mouse showed alpha1 is non-redundant for forming the glycine-gated chloride channel.\",\n      \"evidence\": \"Radioligand [3H]strychnine binding and genetic mapping in mouse oscillator/spasmodic mutants\",\n      \"pmids\": [\"7874121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which structural regions control gating versus trafficking\", \"Stoichiometry inferred biochemically, not structurally\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Whether alpha1 organizes the postsynaptic scaffold was unclear; complete loss of alpha1 was shown to deplete gephyrin, linking the receptor to synaptic anchoring.\",\n      \"evidence\": \"Western blot and [3H]strychnine binding in oscillator null mice\",\n      \"pmids\": [\"9145798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define whether the alpha1-gephyrin relationship is direct or activity-dependent\", \"Mechanism of gephyrin destabilization unresolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"It was unknown whether complete GLRA1 loss is survivable in humans; a homozygous exon 1-6 deletion produced non-lethal hyperekplexia with preserved inhibition, indicating partial compensation.\",\n      \"evidence\": \"Genomic deletion analysis and clinical phenotyping in a consanguineous family\",\n      \"pmids\": [\"8651283\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single consanguineous family\", \"Compensatory mechanism not identified\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"The functional role of the cytoplasmic loop was undefined; P250T showed the M1-M2 loop determines channel gating via current amplitude and desensitization recovery.\",\n      \"evidence\": \"Recombinant expression and patch-clamp electrophysiology in HEK293 cells\",\n      \"pmids\": [\"9920650\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single mutation in a heterologous system\", \"Synaptic consequences not measured\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"How recessive mutations cause disease was unclear; S231R in TM1 was shown to impair biogenesis and surface integration, defining a trafficking mechanism.\",\n      \"evidence\": \"Biochemistry, patch-clamp, confocal microscopy on recombinant receptors\",\n      \"pmids\": [\"11973623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking machinery responsible not identified\", \"Single mutation analyzed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The molecular site of ethanol/anesthetic modulation was undefined; S267N abolished ethanol modulation, placing S267 in TM2 at the modulatory site.\",\n      \"evidence\": \"Recombinant expression with pharmacological modulation electrophysiology\",\n      \"pmids\": [\"18043720\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, single study\", \"Physiological relevance of ethanol site to hyperekplexia unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Whether hyperekplexia mutations fall into mechanistic classes was unresolved; systematic analysis of 13 mutations established that recessive alleles cause trafficking defects and non-trafficking alleles alter glycine sensitivity, with I244N revealing a constitutive leak mechanism.\",\n      \"evidence\": \"High-content imaging and patch-clamp of homomeric and heteromeric GlyRs in HEK293 cells\",\n      \"pmids\": [\"20631190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro classification not validated in vivo\", \"Leak conductance mechanism structurally undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Subunit architecture was poorly defined; coexpression of an isolated C-terminal TM3-TM4 module rescued channel activity in truncation mutants, demonstrating modular assembly.\",\n      \"evidence\": \"Recombinant coexpression complementation, electrophysiology, viral rescue in oscillator neurons\",\n      \"pmids\": [\"19244519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of inter-module assembly not resolved\", \"Efficiency relative to native receptor unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The residues controlling Zn2+ allosteric potentiation were unknown; W170S reduced Zn2+ potentiation and enhanced Zn2+ inhibition, mapping the potentiation site distinct from H107 inhibition.\",\n      \"evidence\": \"Recombinant expression with temporal Zn2+ electrophysiology and H107N background dissection, confirmed in neurons\",\n      \"pmids\": [\"24198360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"Endogenous Zn2+ regulation in vivo not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Whether alpha1 is uniquely required among alpha subunits was untested; individual CRISPR knockouts showed only glra1 loss causes motor dysfunction, establishing non-redundancy.\",\n      \"evidence\": \"CRISPR/Cas9 knockout of each alpha subunit with behavioral analysis in zebrafish\",\n      \"pmids\": [\"31048868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address subunit roles in other circuits or species\", \"Molecular basis of non-redundancy not detailed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether partial GLRA1 dysfunction affects circuits beyond startle was unclear; spasmodic A52S mice showed altered fear-related behaviors alongside enhanced startle.\",\n      \"evidence\": \"Behavioral startle and fear-context analysis in Glra1 spasmodic mice\",\n      \"pmids\": [\"32848605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Behavioral correlation does not establish circuit mechanism\", \"Single study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A non-neuronal role for GLRA1 was unknown; it was shown to bind calmodulin in pancreatic beta cells to maintain ER calcium homeostasis and support insulin secretion, defining a glycine-GLRA1-calmodulin-ER calcium axis.\",\n      \"evidence\": \"Co-IP, beta-cell-specific conditional knockout, ER calcium imaging, ER stress and insulin secretion assays\",\n      \"pmids\": [\"42037784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single lab\", \"Whether interaction depends on channel activity not resolved\", \"Mechanistic link between calmodulin binding and ER calcium undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How alpha1 mechanistically stabilizes gephyrin and how its calmodulin-dependent ER calcium role in beta cells relates to its channel function remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the receptor-gephyrin interface from the corpus\", \"Channel-dependence of beta-cell calmodulin axis unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [1, 3, 7]},\n      {\"term_id\": \"GO:0005216\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\"Glycine receptor (alpha1/beta pentamer)\"],\n    \"partners\": [\"GLRB\", \"GPHN\", \"CALM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}