{"gene":"GNAT2","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":1993,"finding":"The human GNAT2 gene encodes the cone photoreceptor-specific alpha-subunit of transducin (a G-protein) and consists of 8 exons spanning ~9967 bp. The gene has multiple transcription initiation sites and its upstream region contains a TATA box, CCAAT box, and sequences distinct from rod transducin (GNAT1) and color opsin upstream regions, indicating independently regulated cone-specific expression.","method":"Gene characterization by sequencing, Northern blot, primer extension, S1 nuclease protection assays","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct sequencing and multiple transcript mapping methods in a single focused study establishing gene structure and regulatory context","pmids":["8406495"],"is_preprint":false},{"year":1995,"finding":"The human GNAT2 gene was mapped by fluorescence in situ hybridization (FISH) to chromosome 1p13. Screening of 66 Stargardt disease patients found no disease-causing mutations in GNAT2, indicating GNAT2 is not involved in most Stargardt disease cases (negative result).","method":"Fluorescence in situ hybridization (FISH) for chromosomal mapping; PCR-SSCP and direct sequencing for mutation analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal localization by FISH confirmed, negative mutation screening result in 66 patients","pmids":["7774932"],"is_preprint":false},{"year":1997,"finding":"Expression of the GNAT2 gene is controlled by a strong silencer region between -1130 and -23, a weak cell-specific promoter between -151 and -10, and a strong downstream element between +143 and +167. DNaseI footprinting identified three major binding sites (S1, S2, S3) for putative negative trans-acting factors between -807 and -176; these factors are expressed in both retina-derived (WERI-Rb1) and non-retinal (HeLa) cell lines.","method":"Transfection of nested deletion CAT reporter constructs into WERI-Rb1 and HeLa cells; DNaseI footprinting; electrophoretic mobility shift assays (EMSA) with nuclear extracts","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, footprinting, EMSA) in a single focused study identifying cis-regulatory elements","pmids":["9008644"],"is_preprint":false},{"year":1998,"finding":"A 277 bp 5'-flanking sequence from the GNAT2 gene, coupled with a 214 bp IRBP enhancer, directs cone photoreceptor-specific expression in transgenic mice, demonstrating that this upstream region is sufficient for cone-specific transcriptional activity paralleling endogenous GNAT2 expression.","method":"Transgenic mouse reporter assay (CAT reporter gene); immunostaining for developmental expression analysis","journal":"Current eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic reporter model with immunostaining confirmation, single lab study","pmids":["9723991"],"is_preprint":false},{"year":2002,"finding":"Protein-truncation mutations in GNAT2 (encoding the cone photoreceptor-specific alpha-subunit of transducin, which couples visual pigments to the phototransduction cascade) cause autosomal recessive achromatopsia, establishing GNAT2 as the third achromatopsia gene.","method":"Genetic linkage analysis and direct mutation sequencing in five achromatopsia families","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated across five independent families with segregating protein-truncation mutations, confirmed by multiple groups","pmids":["12077706"],"is_preprint":false},{"year":2002,"finding":"A frameshift mutation in GNAT2 exon 7 (c842_843insTCAG; M280fsX291) segregates with complete autosomal recessive achromatopsia in a large consanguineous family, mapping to chromosome 1p13, identifying GNAT2 (the gene encoding cone alpha-transducin that couples cone pigments to cGMP-phosphodiesterase) as the ACHM4 locus.","method":"Autozygosity mapping with microsatellite markers; direct sequence analysis of candidate gene","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — independently confirmed locus identification in a large consanguineous family, consistent with PMID 12077706","pmids":["12205108"],"is_preprint":false},{"year":2004,"finding":"A leaky intronic GNAT2 mutation (c.461+24G→A) causes a splicing defect resulting in early translation termination, but small amounts of correctly spliced transcript are produced. This partial loss of function explains a milder (incomplete achromatopsia/oligocone trichromacy) phenotype compared to complete loss-of-function mutations, demonstrating a dosage-sensitive role for GNAT2 in cone phototransduction.","method":"Heterologous splicing experiments in COS7 cells; direct sequencing; clinical electrophysiology","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — heterologous splicing assay in COS7 cells with genotype-phenotype correlation, single lab","pmids":["15557429"],"is_preprint":false},{"year":2006,"finding":"A missense mutation in exon 6 of Gnat2 (cpfl3 allele) in mice causes cone dysfunction with progressive loss of cone alpha-transducin immunolabeling, but cones remain structurally intact (PNA-positive outer segments) at 14 weeks, demonstrating that loss of functional GNAT2 protein leads to cone phototransduction failure without immediate cone degeneration.","method":"ERG, histopathology, immunocytochemistry with cone-specific markers, linkage studies, PCR sequencing","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ERG, immunocytochemistry, genetic mapping/sequencing) in a defined mouse model, independently established functional role of GNAT2 in cone phototransduction","pmids":["17065522"],"is_preprint":false},{"year":2007,"finding":"In Gnat2(cpfl3) mutant mice lacking functional cone alpha-transducin, the secondary rod pathway (evaluated by scotopic 15-Hz flicker ERG) was completely abolished, demonstrating that GNAT2-dependent cone function is required for operation of the secondary rod signaling pathway in the retina.","method":"ERG recordings (scotopic flicker, intensity-response functions at multiple temporal frequencies) in Gnat2(cpfl3) mutant and C57BL/6J mice","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional ERG-based pathway analysis using a defined genetic model, single lab","pmids":["17408617"],"is_preprint":false},{"year":2018,"finding":"Complete knockout of Gnat2 in mice abolishes cone phototransduction (loss of cone-driven ERG a-waves) without causing cone loss, disruption of the photoreceptor mosaic, or retinal morphological changes up to 9 months, demonstrating that GNAT2 is specifically required for cone phototransduction signal initiation but not for cone cell survival.","method":"Gnat2 knockout mouse generation; ERG recordings; retinal morphology and microglia/Müller glia analysis","journal":"Experimental eye research","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with multiple orthogonal readouts (ERG, morphology, glial markers), dissociating phototransduction from survival functions","pmids":["29518352"],"is_preprint":false},{"year":2022,"finding":"In Gnat1-/-; Gnat2(cpfl3)/cpfl3 double-mutant mice (lacking both rod and cone alpha-transducin), rod and cone photoresponses are completely abolished under light-adapted conditions, yet robust visually evoked potentials persist, attributable to melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs). This establishes that GNAT2 is required for all cone-driven phototransduction input to the primary visual pathway.","method":"Visual evoked potential (VEP) recordings and ERG in Gnat1-/-; Gnat2(cpfl3)/cpfl3 mice","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional in vivo recordings in double-KO model, single lab, establishes cone-pathway specificity of GNAT2","pmids":["36605613"],"is_preprint":false},{"year":2023,"finding":"GNAT2-EGFP knock-in iPSC-derived retinal organoids show that GNAT2 expression begins as early as day 34 and exclusively labels both immature and mature cone photoreceptors, enabling live tracking of individual cone morphological maturation (inner segment mitochondria accumulation, growth at 12.2 μm³/day from day 126–153), establishing GNAT2 as a reliable marker for cone identity from early differentiation.","method":"CRISPR/Cas9 EGFP knock-in at GNAT2 locus in human iPSCs; episodic confocal live imaging of retinal organoids","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live imaging with CRISPR-tagged endogenous locus, single lab, functional labeling confirmed across multiple organoid lines","pmids":["37902188"],"is_preprint":false},{"year":2025,"finding":"In Gnat2 (cone-deficient, rod-only) mouse retinas, Sildenafil (PDE6 inhibitor) did not abolish visually evoked responses (in contrast to Gnat1 rod-deficient retinas where responses were completely removed), demonstrating that Sildenafil preferentially inhibits cone PDE6 and that GNAT2-expressing cones are the primary targets of cone phototransduction suppression by Sildenafil.","method":"Ex vivo multi-electrode array recordings from Gnat2 knockout and Gnat1 knockout mouse retinas with Sildenafil application","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — preprint, ex vivo pharmacological dissection with genetic controls, single lab, not yet peer-reviewed","pmids":["bio_10.1101_2025.10.07.680926"],"is_preprint":true}],"current_model":"GNAT2 encodes the cone photoreceptor-specific alpha-subunit of transducin, a G-protein that couples activated cone visual pigments to cGMP-phosphodiesterase to initiate the cone phototransduction cascade; loss-of-function mutations or complete knockout abolish cone-driven phototransduction and cause achromatopsia without immediate cone degeneration, while its expression is regulated by a silencer-dominated upstream region with a cone-specific promoter element sufficient to drive cone-selective transcription in vivo."},"narrative":{"mechanistic_narrative":"GNAT2 encodes the cone photoreceptor-specific alpha-subunit of transducin, the G-protein that couples activated cone visual pigments to the cGMP-phosphodiesterase effector to initiate the cone phototransduction cascade [PMID:8406495, PMID:12205108]. Genetic ablation in mice—whether by missense mutation (cpfl3) or complete knockout—abolishes cone-driven phototransduction with loss of cone-driven ERG responses, yet cones remain structurally intact with normal mosaic and morphology for months, dissociating GNAT2's signal-initiation role from any requirement for cone survival [PMID:17065522, PMID:29518352]. Loss of GNAT2 function also eliminates the secondary rod signaling pathway and removes all cone-driven input to the primary visual pathway, with residual visually evoked potentials attributable to melanopsin-expressing intrinsically photosensitive retinal ganglion cells [PMID:17408617, PMID:36605613]. In humans, protein-truncation and frameshift mutations cause autosomal recessive achromatopsia (ACHM4), and a leaky intronic splicing mutation that preserves a small amount of correctly spliced transcript produces a milder incomplete phenotype, revealing dosage-sensitive control of cone phototransduction [PMID:12077706, PMID:12205108, PMID:15557429]. GNAT2 expression is cone-restricted and driven by a compact upstream region in which a dominant silencer constrains a weak cone-specific promoter; a 277 bp 5'-flanking fragment is sufficient to confer cone-specific transcription in vivo, and endogenous GNAT2 marks cone identity from the earliest stages of differentiation [PMID:9008644, PMID:9723991, PMID:37902188].","teleology":[{"year":1993,"claim":"Establishing that GNAT2 is a distinct cone-specific transducin alpha-subunit gene with its own regulatory architecture answered whether cone phototransduction uses a dedicated G-protein separate from rods.","evidence":"Gene characterization by sequencing, Northern blot, primer extension, and S1 nuclease protection","pmids":["8406495"],"confidence":"Medium","gaps":["Did not test the functional G-protein coupling biochemically","Trans-acting factors controlling cone-specific expression not identified"]},{"year":1995,"claim":"Chromosomal mapping to 1p13 and exclusion of GNAT2 from Stargardt disease defined where the gene sits and which disease it does not cause, narrowing candidate-gene reasoning.","evidence":"FISH chromosomal mapping and PCR-SSCP/sequencing mutation screen in 66 Stargardt patients","pmids":["7774932"],"confidence":"Medium","gaps":["Negative result; did not identify the actual disease association of GNAT2","Limited to Stargardt cohort"]},{"year":1997,"claim":"Dissecting the cis-regulatory elements clarified how cone-restricted GNAT2 transcription is controlled, identifying a silencer-dominated architecture rather than a simple activating promoter.","evidence":"Nested deletion CAT reporter assays, DNaseI footprinting, and EMSA in WERI-Rb1 and HeLa cells","pmids":["9008644"],"confidence":"Medium","gaps":["The negative trans-acting factors binding S1-S3 were not molecularly identified","Binding factors expressed in non-retinal cells, so cone specificity mechanism incomplete"]},{"year":1998,"claim":"Showing a 277 bp 5'-flanking fragment drives cone-specific expression in vivo established that the upstream region is sufficient for cone-selective transcription.","evidence":"Transgenic mouse CAT reporter assay with IRBP enhancer and developmental immunostaining","pmids":["9723991"],"confidence":"Medium","gaps":["Required an exogenous IRBP enhancer, leaving endogenous enhancer requirements unresolved","Did not map individual cone-specific elements within the fragment"]},{"year":2002,"claim":"Linking GNAT2 protein-truncation and frameshift mutations to autosomal recessive achromatopsia established the gene as an ACHM (ACHM4) cause and confirmed its non-redundant role in human cone vision.","evidence":"Linkage analysis, autozygosity mapping, and direct mutation sequencing across multiple achromatopsia families","pmids":["12077706","12205108"],"confidence":"High","gaps":["Did not establish the molecular consequence at the protein/biochemical level","Cone fate over long-term in patients not assessed"]},{"year":2004,"claim":"A leaky splicing mutation producing residual correct transcript and a milder phenotype demonstrated that GNAT2 function is dosage-sensitive, linking transcript level to disease severity.","evidence":"Heterologous splicing assay in COS7 cells with clinical electrophysiology genotype-phenotype correlation","pmids":["15557429"],"confidence":"Medium","gaps":["Quantitative threshold of protein needed for normal cone function not defined","Single-family genotype-phenotype correlation"]},{"year":2007,"claim":"Characterizing the cpfl3 mouse showed that loss of functional GNAT2 causes cone phototransduction failure while cones remain structurally intact, dissociating signaling from survival.","evidence":"ERG, histopathology, cone-marker immunocytochemistry, and genetic mapping in cpfl3 mice; scotopic flicker ERG for secondary rod pathway","pmids":["17065522","17408617"],"confidence":"High","gaps":["Long-term cone survival beyond the assessed window not determined in this study","Mechanism by which cone signaling drives the secondary rod pathway not detailed"]},{"year":2018,"claim":"A complete Gnat2 knockout confirmed that GNAT2 is specifically required for cone phototransduction initiation but dispensable for cone cell survival and retinal morphology.","evidence":"Gnat2 knockout mouse with ERG, retinal morphology, and microglia/Müller glia analysis up to 9 months","pmids":["29518352"],"confidence":"High","gaps":["Survival beyond 9 months not tested","Did not address downstream effector coupling biochemically"]},{"year":2022,"claim":"Double rod/cone transducin mutants revealed that GNAT2 supplies all cone-driven input to the primary visual pathway, with residual responses arising from ipRGCs rather than cone transducin.","evidence":"VEP and ERG recordings in Gnat1-/-; Gnat2(cpfl3)/cpfl3 mice","pmids":["36605613"],"confidence":"Medium","gaps":["Single-lab functional model","Contribution of GNAT2 to non-image-forming pathways not separated"]},{"year":2023,"claim":"Endogenous GNAT2 tagging in iPSC-derived retinal organoids established it as a reliable marker of cone identity from early differentiation, enabling live tracking of cone maturation.","evidence":"CRISPR/Cas9 EGFP knock-in at GNAT2 in human iPSCs with confocal live imaging of organoids","pmids":["37902188"],"confidence":"Medium","gaps":["Reporter marks expression, not functional G-protein activity","Does not address human disease mechanism directly"]},{"year":2025,"claim":"Pharmacological dissection using Gnat2-deficient retinas indicated that Sildenafil preferentially suppresses cone PDE6-coupled phototransduction, placing GNAT2-expressing cones as the primary target.","evidence":"Ex vivo multi-electrode array recordings from Gnat2 and Gnat1 knockout retinas with Sildenafil (preprint)","pmids":["bio_10.1101_2025.10.07.680926"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Mechanism inferred indirectly through PDE6 effector rather than measured at GNAT2"]},{"year":null,"claim":"The biochemical coupling steps by which GNAT2 transduces activated cone pigment to cGMP-phosphodiesterase, and the molecular identity of its cone-specific transcriptional regulators, remain undefined in the available corpus.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct biochemical reconstitution of cone pigment–GNAT2–PDE6 coupling in the timeline","Trans-acting factors binding the GNAT2 silencer/promoter not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,5,9]},{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[9,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P19087","full_name":"Guanine nucleotide-binding protein G(t) subunit alpha-2","aliases":["Transducin alpha-2 chain"],"length_aa":354,"mass_kda":40.2,"function":"Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. Transducin is an amplifier and one of the transducers of a visual impulse that performs the coupling between rhodopsin and cGMP-phosphodiesterase","subcellular_location":"Cell projection, cilium, photoreceptor outer segment; Photoreceptor inner segment","url":"https://www.uniprot.org/uniprotkb/P19087/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GNAT2","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GNAT2","total_profiled":1310},"omim":[{"mim_id":"613856","title":"ACHROMATOPSIA 4; ACHM4","url":"https://www.omim.org/entry/613856"},{"mim_id":"613093","title":"CONE DYSTROPHY 4; COD4","url":"https://www.omim.org/entry/613093"},{"mim_id":"607795","title":"PRE-mRNA-PROCESSING FACTOR 4; PRPF4","url":"https://www.omim.org/entry/607795"},{"mim_id":"605549","title":"CONE-ROD DYSTROPHY 8; CORD8","url":"https://www.omim.org/entry/605549"},{"mim_id":"605080","title":"CYCLIC NUCLEOTIDE-GATED CHANNEL, BETA-3; CNGB3","url":"https://www.omim.org/entry/605080"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"retina","ntpm":73.0}],"url":"https://www.proteinatlas.org/search/GNAT2"},"hgnc":{"alias_symbol":["ACHM4"],"prev_symbol":[]},"alphafold":{"accession":"P19087","domains":[{"cath_id":"1.10.400.10","chopping":"62-175","consensus_level":"high","plddt":96.3884,"start":62,"end":175},{"cath_id":"3.40.50.300","chopping":"224-337","consensus_level":"medium","plddt":96.4237,"start":224,"end":337}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P19087","model_url":"https://alphafold.ebi.ac.uk/files/AF-P19087-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P19087-F1-predicted_aligned_error_v6.png","plddt_mean":94.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GNAT2","jax_strain_url":"https://www.jax.org/strain/search?query=GNAT2"},"sequence":{"accession":"P19087","fasta_url":"https://rest.uniprot.org/uniprotkb/P19087.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P19087/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P19087"}},"corpus_meta":[{"pmid":"12077706","id":"PMC_12077706","title":"Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia.","date":"2002","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12077706","citation_count":217,"is_preprint":false},{"pmid":"17065522","id":"PMC_17065522","title":"Cone photoreceptor function loss-3, a novel mouse model of achromatopsia due to a mutation in Gnat2.","date":"2006","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/17065522","citation_count":140,"is_preprint":false},{"pmid":"12205108","id":"PMC_12205108","title":"Mapping of a novel locus for achromatopsia (ACHM4) to 1p and identification of a germline mutation in the alpha subunit of cone transducin (GNAT2).","date":"2002","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12205108","citation_count":99,"is_preprint":false},{"pmid":"15557429","id":"PMC_15557429","title":"Variant phenotypes of incomplete achromatopsia in two cousins with GNAT2 gene mutations.","date":"2004","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/15557429","citation_count":43,"is_preprint":false},{"pmid":"8406495","id":"PMC_8406495","title":"Characterization of the gene encoding human cone transducin alpha-subunit (GNAT2).","date":"1993","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8406495","citation_count":39,"is_preprint":false},{"pmid":"14609822","id":"PMC_14609822","title":"Cone dystrophy phenotype associated with a frameshift mutation (M280fsX291) in the alpha-subunit of cone specific transducin (GNAT2).","date":"2003","source":"The British journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/14609822","citation_count":39,"is_preprint":false},{"pmid":"29518352","id":"PMC_29518352","title":"Loss of cone function without degeneration in a novel Gnat2 knock-out mouse.","date":"2018","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/29518352","citation_count":37,"is_preprint":false},{"pmid":"17408617","id":"PMC_17408617","title":"Temporal response properties of the primary and secondary rod-signaling pathways in normal and Gnat2 mutant mice.","date":"2007","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/17408617","citation_count":29,"is_preprint":false},{"pmid":"27718025","id":"PMC_27718025","title":"In vivo imaging of a cone mosaic in a patient with achromatopsia associated with a GNAT2 variant.","date":"2016","source":"Japanese journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/27718025","citation_count":25,"is_preprint":false},{"pmid":"31058429","id":"PMC_31058429","title":"Mutation spectrum and clinical investigation of achromatopsia patients with mutations in the GNAT2 gene.","date":"2019","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/31058429","citation_count":20,"is_preprint":false},{"pmid":"9008644","id":"PMC_9008644","title":"Localization of upstream silencer elements involved in the expression of cone transducin alpha-subunit (GNAT2).","date":"1997","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/9008644","citation_count":16,"is_preprint":false},{"pmid":"9723991","id":"PMC_9723991","title":"A CAT reporter construct containing 277bp GNAT2 promoter and 214bp IRBP enhancer is specifically expressed by cone photoreceptor cells in transgenic mice.","date":"1998","source":"Current eye research","url":"https://pubmed.ncbi.nlm.nih.gov/9723991","citation_count":15,"is_preprint":false},{"pmid":"21107338","id":"PMC_21107338","title":"Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene.","date":"2010","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21107338","citation_count":14,"is_preprint":false},{"pmid":"8662225","id":"PMC_8662225","title":"GNAI3, GNAT2, AMPD2, GSTM are clustered in 120 kb of Chinese hamster chromosome 1q.","date":"1996","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/8662225","citation_count":11,"is_preprint":false},{"pmid":"15459792","id":"PMC_15459792","title":"[Molecular genetic findings in patients with congenital cone dysfunction. Mutations in the CNGA3, CNGB3, or GNAT2 genes].","date":"2004","source":"Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft","url":"https://pubmed.ncbi.nlm.nih.gov/15459792","citation_count":11,"is_preprint":false},{"pmid":"7774932","id":"PMC_7774932","title":"Mapping of the human cone transducin alpha-subunit (GNAT2) gene to 1p13 and negative mutation analysis in patients with Stargardt disease.","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/7774932","citation_count":9,"is_preprint":false},{"pmid":"37902188","id":"PMC_37902188","title":"Episodic live imaging of cone photoreceptor maturation in GNAT2-EGFP retinal organoids.","date":"2023","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/37902188","citation_count":6,"is_preprint":false},{"pmid":"39349166","id":"PMC_39349166","title":"The Plastidial Protein Acetyltransferase GNAT1 Forms a Complex With GNAT2, yet Their Interaction Is Dispensable for State Transitions.","date":"2024","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/39349166","citation_count":6,"is_preprint":false},{"pmid":"36605613","id":"PMC_36605613","title":"Robust visual cortex evoked potentials (VEP) in Gnat1 and Gnat2 knockout mice.","date":"2022","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36605613","citation_count":4,"is_preprint":false},{"pmid":"36909527","id":"PMC_36909527","title":"Episodic live imaging of cone photoreceptor maturation in GNAT2-EGFP retinal organoids.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36909527","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.07.680926","title":"Sildenafil-driven cone PDE6 inhibition alters receptive-field properties of retinal ganglion cells ex vivo","date":"2025-10-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.07.680926","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11968,"output_tokens":3239,"usd":0.042244,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10790,"output_tokens":3482,"usd":0.0705,"stage2_stop_reason":"end_turn"},"total_usd":0.112744,"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\": 1993,\n      \"finding\": \"The human GNAT2 gene encodes the cone photoreceptor-specific alpha-subunit of transducin (a G-protein) and consists of 8 exons spanning ~9967 bp. The gene has multiple transcription initiation sites and its upstream region contains a TATA box, CCAAT box, and sequences distinct from rod transducin (GNAT1) and color opsin upstream regions, indicating independently regulated cone-specific expression.\",\n      \"method\": \"Gene characterization by sequencing, Northern blot, primer extension, S1 nuclease protection assays\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct sequencing and multiple transcript mapping methods in a single focused study establishing gene structure and regulatory context\",\n      \"pmids\": [\"8406495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The human GNAT2 gene was mapped by fluorescence in situ hybridization (FISH) to chromosome 1p13. Screening of 66 Stargardt disease patients found no disease-causing mutations in GNAT2, indicating GNAT2 is not involved in most Stargardt disease cases (negative result).\",\n      \"method\": \"Fluorescence in situ hybridization (FISH) for chromosomal mapping; PCR-SSCP and direct sequencing for mutation analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal localization by FISH confirmed, negative mutation screening result in 66 patients\",\n      \"pmids\": [\"7774932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Expression of the GNAT2 gene is controlled by a strong silencer region between -1130 and -23, a weak cell-specific promoter between -151 and -10, and a strong downstream element between +143 and +167. DNaseI footprinting identified three major binding sites (S1, S2, S3) for putative negative trans-acting factors between -807 and -176; these factors are expressed in both retina-derived (WERI-Rb1) and non-retinal (HeLa) cell lines.\",\n      \"method\": \"Transfection of nested deletion CAT reporter constructs into WERI-Rb1 and HeLa cells; DNaseI footprinting; electrophoretic mobility shift assays (EMSA) with nuclear extracts\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, footprinting, EMSA) in a single focused study identifying cis-regulatory elements\",\n      \"pmids\": [\"9008644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"A 277 bp 5'-flanking sequence from the GNAT2 gene, coupled with a 214 bp IRBP enhancer, directs cone photoreceptor-specific expression in transgenic mice, demonstrating that this upstream region is sufficient for cone-specific transcriptional activity paralleling endogenous GNAT2 expression.\",\n      \"method\": \"Transgenic mouse reporter assay (CAT reporter gene); immunostaining for developmental expression analysis\",\n      \"journal\": \"Current eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic reporter model with immunostaining confirmation, single lab study\",\n      \"pmids\": [\"9723991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Protein-truncation mutations in GNAT2 (encoding the cone photoreceptor-specific alpha-subunit of transducin, which couples visual pigments to the phototransduction cascade) cause autosomal recessive achromatopsia, establishing GNAT2 as the third achromatopsia gene.\",\n      \"method\": \"Genetic linkage analysis and direct mutation sequencing in five achromatopsia families\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across five independent families with segregating protein-truncation mutations, confirmed by multiple groups\",\n      \"pmids\": [\"12077706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A frameshift mutation in GNAT2 exon 7 (c842_843insTCAG; M280fsX291) segregates with complete autosomal recessive achromatopsia in a large consanguineous family, mapping to chromosome 1p13, identifying GNAT2 (the gene encoding cone alpha-transducin that couples cone pigments to cGMP-phosphodiesterase) as the ACHM4 locus.\",\n      \"method\": \"Autozygosity mapping with microsatellite markers; direct sequence analysis of candidate gene\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independently confirmed locus identification in a large consanguineous family, consistent with PMID 12077706\",\n      \"pmids\": [\"12205108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A leaky intronic GNAT2 mutation (c.461+24G→A) causes a splicing defect resulting in early translation termination, but small amounts of correctly spliced transcript are produced. This partial loss of function explains a milder (incomplete achromatopsia/oligocone trichromacy) phenotype compared to complete loss-of-function mutations, demonstrating a dosage-sensitive role for GNAT2 in cone phototransduction.\",\n      \"method\": \"Heterologous splicing experiments in COS7 cells; direct sequencing; clinical electrophysiology\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — heterologous splicing assay in COS7 cells with genotype-phenotype correlation, single lab\",\n      \"pmids\": [\"15557429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A missense mutation in exon 6 of Gnat2 (cpfl3 allele) in mice causes cone dysfunction with progressive loss of cone alpha-transducin immunolabeling, but cones remain structurally intact (PNA-positive outer segments) at 14 weeks, demonstrating that loss of functional GNAT2 protein leads to cone phototransduction failure without immediate cone degeneration.\",\n      \"method\": \"ERG, histopathology, immunocytochemistry with cone-specific markers, linkage studies, PCR sequencing\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ERG, immunocytochemistry, genetic mapping/sequencing) in a defined mouse model, independently established functional role of GNAT2 in cone phototransduction\",\n      \"pmids\": [\"17065522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Gnat2(cpfl3) mutant mice lacking functional cone alpha-transducin, the secondary rod pathway (evaluated by scotopic 15-Hz flicker ERG) was completely abolished, demonstrating that GNAT2-dependent cone function is required for operation of the secondary rod signaling pathway in the retina.\",\n      \"method\": \"ERG recordings (scotopic flicker, intensity-response functions at multiple temporal frequencies) in Gnat2(cpfl3) mutant and C57BL/6J mice\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional ERG-based pathway analysis using a defined genetic model, single lab\",\n      \"pmids\": [\"17408617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Complete knockout of Gnat2 in mice abolishes cone phototransduction (loss of cone-driven ERG a-waves) without causing cone loss, disruption of the photoreceptor mosaic, or retinal morphological changes up to 9 months, demonstrating that GNAT2 is specifically required for cone phototransduction signal initiation but not for cone cell survival.\",\n      \"method\": \"Gnat2 knockout mouse generation; ERG recordings; retinal morphology and microglia/Müller glia analysis\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with multiple orthogonal readouts (ERG, morphology, glial markers), dissociating phototransduction from survival functions\",\n      \"pmids\": [\"29518352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Gnat1-/-; Gnat2(cpfl3)/cpfl3 double-mutant mice (lacking both rod and cone alpha-transducin), rod and cone photoresponses are completely abolished under light-adapted conditions, yet robust visually evoked potentials persist, attributable to melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs). This establishes that GNAT2 is required for all cone-driven phototransduction input to the primary visual pathway.\",\n      \"method\": \"Visual evoked potential (VEP) recordings and ERG in Gnat1-/-; Gnat2(cpfl3)/cpfl3 mice\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vivo recordings in double-KO model, single lab, establishes cone-pathway specificity of GNAT2\",\n      \"pmids\": [\"36605613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GNAT2-EGFP knock-in iPSC-derived retinal organoids show that GNAT2 expression begins as early as day 34 and exclusively labels both immature and mature cone photoreceptors, enabling live tracking of individual cone morphological maturation (inner segment mitochondria accumulation, growth at 12.2 μm³/day from day 126–153), establishing GNAT2 as a reliable marker for cone identity from early differentiation.\",\n      \"method\": \"CRISPR/Cas9 EGFP knock-in at GNAT2 locus in human iPSCs; episodic confocal live imaging of retinal organoids\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live imaging with CRISPR-tagged endogenous locus, single lab, functional labeling confirmed across multiple organoid lines\",\n      \"pmids\": [\"37902188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Gnat2 (cone-deficient, rod-only) mouse retinas, Sildenafil (PDE6 inhibitor) did not abolish visually evoked responses (in contrast to Gnat1 rod-deficient retinas where responses were completely removed), demonstrating that Sildenafil preferentially inhibits cone PDE6 and that GNAT2-expressing cones are the primary targets of cone phototransduction suppression by Sildenafil.\",\n      \"method\": \"Ex vivo multi-electrode array recordings from Gnat2 knockout and Gnat1 knockout mouse retinas with Sildenafil application\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, ex vivo pharmacological dissection with genetic controls, single lab, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.10.07.680926\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"GNAT2 encodes the cone photoreceptor-specific alpha-subunit of transducin, a G-protein that couples activated cone visual pigments to cGMP-phosphodiesterase to initiate the cone phototransduction cascade; loss-of-function mutations or complete knockout abolish cone-driven phototransduction and cause achromatopsia without immediate cone degeneration, while its expression is regulated by a silencer-dominated upstream region with a cone-specific promoter element sufficient to drive cone-selective transcription in vivo.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GNAT2 encodes the cone photoreceptor-specific alpha-subunit of transducin, the G-protein that couples activated cone visual pigments to the cGMP-phosphodiesterase effector to initiate the cone phototransduction cascade [#0, #5]. Genetic ablation in mice—whether by missense mutation (cpfl3) or complete knockout—abolishes cone-driven phototransduction with loss of cone-driven ERG responses, yet cones remain structurally intact with normal mosaic and morphology for months, dissociating GNAT2's signal-initiation role from any requirement for cone survival [#7, #9]. Loss of GNAT2 function also eliminates the secondary rod signaling pathway and removes all cone-driven input to the primary visual pathway, with residual visually evoked potentials attributable to melanopsin-expressing intrinsically photosensitive retinal ganglion cells [#8, #10]. In humans, protein-truncation and frameshift mutations cause autosomal recessive achromatopsia (ACHM4), and a leaky intronic splicing mutation that preserves a small amount of correctly spliced transcript produces a milder incomplete phenotype, revealing dosage-sensitive control of cone phototransduction [#4, #5, #6]. GNAT2 expression is cone-restricted and driven by a compact upstream region in which a dominant silencer constrains a weak cone-specific promoter; a 277 bp 5'-flanking fragment is sufficient to confer cone-specific transcription in vivo, and endogenous GNAT2 marks cone identity from the earliest stages of differentiation [#2, #3, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that GNAT2 is a distinct cone-specific transducin alpha-subunit gene with its own regulatory architecture answered whether cone phototransduction uses a dedicated G-protein separate from rods.\",\n      \"evidence\": \"Gene characterization by sequencing, Northern blot, primer extension, and S1 nuclease protection\",\n      \"pmids\": [\"8406495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not test the functional G-protein coupling biochemically\", \"Trans-acting factors controlling cone-specific expression not identified\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Chromosomal mapping to 1p13 and exclusion of GNAT2 from Stargardt disease defined where the gene sits and which disease it does not cause, narrowing candidate-gene reasoning.\",\n      \"evidence\": \"FISH chromosomal mapping and PCR-SSCP/sequencing mutation screen in 66 Stargardt patients\",\n      \"pmids\": [\"7774932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result; did not identify the actual disease association of GNAT2\", \"Limited to Stargardt cohort\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Dissecting the cis-regulatory elements clarified how cone-restricted GNAT2 transcription is controlled, identifying a silencer-dominated architecture rather than a simple activating promoter.\",\n      \"evidence\": \"Nested deletion CAT reporter assays, DNaseI footprinting, and EMSA in WERI-Rb1 and HeLa cells\",\n      \"pmids\": [\"9008644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The negative trans-acting factors binding S1-S3 were not molecularly identified\", \"Binding factors expressed in non-retinal cells, so cone specificity mechanism incomplete\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showing a 277 bp 5'-flanking fragment drives cone-specific expression in vivo established that the upstream region is sufficient for cone-selective transcription.\",\n      \"evidence\": \"Transgenic mouse CAT reporter assay with IRBP enhancer and developmental immunostaining\",\n      \"pmids\": [\"9723991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Required an exogenous IRBP enhancer, leaving endogenous enhancer requirements unresolved\", \"Did not map individual cone-specific elements within the fragment\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linking GNAT2 protein-truncation and frameshift mutations to autosomal recessive achromatopsia established the gene as an ACHM (ACHM4) cause and confirmed its non-redundant role in human cone vision.\",\n      \"evidence\": \"Linkage analysis, autozygosity mapping, and direct mutation sequencing across multiple achromatopsia families\",\n      \"pmids\": [\"12077706\", \"12205108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the molecular consequence at the protein/biochemical level\", \"Cone fate over long-term in patients not assessed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"A leaky splicing mutation producing residual correct transcript and a milder phenotype demonstrated that GNAT2 function is dosage-sensitive, linking transcript level to disease severity.\",\n      \"evidence\": \"Heterologous splicing assay in COS7 cells with clinical electrophysiology genotype-phenotype correlation\",\n      \"pmids\": [\"15557429\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative threshold of protein needed for normal cone function not defined\", \"Single-family genotype-phenotype correlation\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Characterizing the cpfl3 mouse showed that loss of functional GNAT2 causes cone phototransduction failure while cones remain structurally intact, dissociating signaling from survival.\",\n      \"evidence\": \"ERG, histopathology, cone-marker immunocytochemistry, and genetic mapping in cpfl3 mice; scotopic flicker ERG for secondary rod pathway\",\n      \"pmids\": [\"17065522\", \"17408617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term cone survival beyond the assessed window not determined in this study\", \"Mechanism by which cone signaling drives the secondary rod pathway not detailed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A complete Gnat2 knockout confirmed that GNAT2 is specifically required for cone phototransduction initiation but dispensable for cone cell survival and retinal morphology.\",\n      \"evidence\": \"Gnat2 knockout mouse with ERG, retinal morphology, and microglia/Müller glia analysis up to 9 months\",\n      \"pmids\": [\"29518352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Survival beyond 9 months not tested\", \"Did not address downstream effector coupling biochemically\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Double rod/cone transducin mutants revealed that GNAT2 supplies all cone-driven input to the primary visual pathway, with residual responses arising from ipRGCs rather than cone transducin.\",\n      \"evidence\": \"VEP and ERG recordings in Gnat1-/-; Gnat2(cpfl3)/cpfl3 mice\",\n      \"pmids\": [\"36605613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional model\", \"Contribution of GNAT2 to non-image-forming pathways not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Endogenous GNAT2 tagging in iPSC-derived retinal organoids established it as a reliable marker of cone identity from early differentiation, enabling live tracking of cone maturation.\",\n      \"evidence\": \"CRISPR/Cas9 EGFP knock-in at GNAT2 in human iPSCs with confocal live imaging of organoids\",\n      \"pmids\": [\"37902188\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reporter marks expression, not functional G-protein activity\", \"Does not address human disease mechanism directly\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Pharmacological dissection using Gnat2-deficient retinas indicated that Sildenafil preferentially suppresses cone PDE6-coupled phototransduction, placing GNAT2-expressing cones as the primary target.\",\n      \"evidence\": \"Ex vivo multi-electrode array recordings from Gnat2 and Gnat1 knockout retinas with Sildenafil (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.07.680926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Mechanism inferred indirectly through PDE6 effector rather than measured at GNAT2\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical coupling steps by which GNAT2 transduces activated cone pigment to cGMP-phosphodiesterase, and the molecular identity of its cone-specific transcriptional regulators, remain undefined in the available corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical reconstitution of cone pigment–GNAT2–PDE6 coupling in the timeline\", \"Trans-acting factors binding the GNAT2 silencer/promoter not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5, 9]},\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}