{"gene":"SNTG2","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2000,"finding":"Gamma2-syntrophin (SNTG2) was identified as a novel member of the syntrophin family, encoded by a gene on chromosome 2p25 with at least 17 exons. Yeast two-hybrid and GST pull-down experiments demonstrated that SNTG2 directly binds the C-terminal region of dystrophin and related proteins (dystrophin-associated protein complex). Immunohistochemistry and RNA in situ hybridization showed that SNTG2 protein is expressed in rat and human central neurons, suggesting a specialized role for a modified dystrophin-associated complex in the central nervous system.","method":"Yeast two-hybrid, GST pull-down, immunohistochemistry, RNA in situ hybridization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal binding confirmed by both yeast two-hybrid and pull-down, with localization data; moderate evidence from a single lab with multiple orthogonal methods","pmids":["10747910"],"is_preprint":false},{"year":2002,"finding":"The PDZ domain of SNTG2 directly interacts with the C-terminus of SCN5A (the cardiac/intestinal Na+ channel alpha subunit). This was established by yeast two-hybrid and GST pull-down assays. Co-transfection of SNTG2 with SCN5A in HEK293 cells markedly shifted SCN5A activation kinetics and reduced Na+ current availability. In native intestinal smooth muscle cells, disruption of the SCN5A C-terminus–SNTG2 PDZ domain interaction using blocking peptides abolished mechanosensitivity of the Na+ channel, establishing SNTG2 as an essential regulator of SCN5A gating and mechanosensitivity.","method":"Yeast two-hybrid, GST pull-down, co-transfection with whole-cell patch clamp, peptide disruption in native cells, laser capture microdissection, single-cell PCR, immunohistochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (binding assay + functional electrophysiology + peptide disruption in native cells) in a single study; strong mechanistic chain","pmids":["12429735"],"is_preprint":false},{"year":2007,"finding":"SNTG2 was identified as a direct binding partner of neuroligin-3 (NL3) in a yeast two-hybrid screen, and the interaction was confirmed biochemically. SNTG2 also bound neuroligin-4X (NL4X) and NL4Y. Autism-associated missense mutations in NL3 and NL4X significantly impaired their interaction with SNTG2, implying that disruption of the NL–SNTG2 complex may contribute to autism spectrum disorder etiology.","method":"Yeast two-hybrid, co-immunoprecipitation / biochemical binding assay with autism-related mutant constructs","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, binding shown by yeast two-hybrid and biochemical assay, functional implication inferred from mutation effect on binding but no cellular phenotype rescue","pmids":["17292328"],"is_preprint":false}],"current_model":"SNTG2 (gamma2-syntrophin) is a neuronal scaffolding protein that binds the C-terminal region of dystrophin and dystrophin-related proteins via its syntrophin domain, anchors and regulates the cardiac/smooth-muscle Na+ channel SCN5A through a PDZ domain–C-terminal interaction that controls channel gating kinetics and mechanosensitivity, and interacts with autism-associated neuroligins 3 and 4X through its PDZ domain in a manner disrupted by autism-linked mutations."},"narrative":{"teleology":[{"year":2000,"claim":"Identification of SNTG2 as a new syntrophin family member that directly binds dystrophin's C-terminus established that the dystrophin-associated protein complex in central neurons includes a neuron-specific syntrophin isoform.","evidence":"Yeast two-hybrid, GST pull-down, immunohistochemistry, and RNA in situ hybridization in rat and human tissues","pmids":["10747910"],"confidence":"High","gaps":["No knockout or knockdown phenotype reported","Whether SNTG2 competes with other syntrophins for dystrophin binding sites is unresolved","Subcellular localization within neurons (e.g., synaptic vs. somatic) was not precisely defined"]},{"year":2002,"claim":"Demonstration that SNTG2's PDZ domain binds the SCN5A C-terminus and controls channel gating and mechanosensitivity revealed a direct ion-channel-regulatory function for this scaffolding protein.","evidence":"Yeast two-hybrid and GST pull-down for binding; whole-cell patch-clamp in co-transfected HEK293 cells and peptide-disruption experiments in native intestinal smooth muscle cells","pmids":["12429735"],"confidence":"High","gaps":["In vivo consequences of SNTG2 loss on SCN5A function have not been tested","Whether SNTG2 regulates other voltage-gated channels via its PDZ domain is unknown","Structural basis of the PDZ–SCN5A interaction has not been resolved"]},{"year":2007,"claim":"Discovery that SNTG2 binds neuroligins 3 and 4X—and that autism-associated mutations impair this interaction—implicated SNTG2 in the postsynaptic scaffolding of autism-relevant adhesion molecules.","evidence":"Yeast two-hybrid screen and co-immunoprecipitation with wild-type and autism-mutant neuroligin constructs","pmids":["17292328"],"confidence":"Medium","gaps":["No cellular or synaptic phenotype was reported upon disruption of the NL–SNTG2 interaction","Whether SNTG2 links neuroligins to the dystrophin complex at synapses has not been shown","The finding has not been independently replicated in a second laboratory"]},{"year":null,"claim":"The in vivo physiological roles of SNTG2 remain undefined: no genetic loss-of-function model or human disease association has been reported, and whether its PDZ-domain partners (SCN5A, neuroligins) are regulated simultaneously or in distinct tissue contexts is unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No animal knockout or conditional deletion phenotype exists","Full interactome of the SNTG2 PDZ domain has not been profiled","Role of SNTG2 in synaptic versus extra-synaptic compartments is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,2]}],"complexes":["dystrophin-associated protein complex"],"partners":["DMD","SCN5A","NLGN3","NLGN4X"],"other_free_text":[]},"mechanistic_narrative":"SNTG2 (gamma-2-syntrophin) is a neuronal scaffolding protein that binds the C-terminal region of dystrophin and dystrophin-related proteins via its syntrophin unique domain, linking it to a modified dystrophin-associated protein complex expressed selectively in central neurons [PMID:10747910]. Its PDZ domain directly engages the C-terminus of the voltage-gated sodium channel SCN5A, shifting channel activation kinetics and conferring mechanosensitivity in intestinal smooth muscle cells [PMID:12429735]. The same PDZ domain mediates interactions with the autism-associated synaptic adhesion molecules neuroligin-3 and neuroligin-4X, and autism-linked missense mutations in these neuroligins disrupt SNTG2 binding [PMID:17292328]."},"prefetch_data":{"uniprot":{"accession":"Q9NY99","full_name":"Gamma-2-syntrophin","aliases":["Syntrophin-5","SYN5"],"length_aa":539,"mass_kda":60.2,"function":"Adapter protein that binds to and probably organizes the subcellular localization of a variety of proteins. May link various receptors to the actin cytoskeleton and the dystrophin glycoprotein complex (By similarity)","subcellular_location":"Cell membrane, sarcolemma; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q9NY99/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNTG2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SNTG2","total_profiled":1310},"omim":[{"mim_id":"608715","title":"SYNTROPHIN, GAMMA-2; SNTG2","url":"https://www.omim.org/entry/608715"},{"mim_id":"608714","title":"SYNTROPHIN, GAMMA-1; SNTG1","url":"https://www.omim.org/entry/608714"},{"mim_id":"313430","title":"SRY-BOX 3; SOX3","url":"https://www.omim.org/entry/313430"},{"mim_id":"307700","title":"HYPOPARATHYROIDISM, X-LINKED; HYPX","url":"https://www.omim.org/entry/307700"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in some","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNTG2"},"hgnc":{"alias_symbol":["SYN5","G2SYN"],"prev_symbol":[]},"alphafold":{"accession":"Q9NY99","domains":[{"cath_id":"2.30.29.30","chopping":"27-58_218-263","consensus_level":"medium","plddt":88.5506,"start":27,"end":263},{"cath_id":"2.30.42.10","chopping":"62-160_212-217","consensus_level":"medium","plddt":86.305,"start":62,"end":217},{"cath_id":"2.30.29.30","chopping":"292-361_385-427_505-539","consensus_level":"medium","plddt":85.8663,"start":292,"end":539},{"cath_id":"2.30.29.30","chopping":"429-502","consensus_level":"medium","plddt":94.1596,"start":429,"end":502}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NY99","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NY99-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NY99-F1-predicted_aligned_error_v6.png","plddt_mean":79.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNTG2","jax_strain_url":"https://www.jax.org/strain/search?query=SNTG2"},"sequence":{"accession":"Q9NY99","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NY99.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NY99/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NY99"}},"corpus_meta":[{"pmid":"21450070","id":"PMC_21450070","title":"Long 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MCP","url":"https://pubmed.ncbi.nlm.nih.gov/23722234","citation_count":56,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"36115835","id":"PMC_36115835","title":"Quantitative fragmentomics allow affinity mapping of interactomes.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36115835","citation_count":33,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30726710","id":"PMC_30726710","title":"Rewiring of RSK-PDZ Interactome by Linear Motif Phosphorylation.","date":"2019","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/30726710","citation_count":24,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17292328","id":"PMC_17292328","title":"Neuroligins 3 and 4X interact with syntrophin-gamma2, and the interactions are affected by autism-related mutations.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17292328","citation_count":22,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22721673","id":"PMC_22721673","title":"Nef interaction with actin compromises human podocyte actin cytoskeletal integrity.","date":"2012","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22721673","citation_count":22,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25008318","id":"PMC_25008318","title":"Valosin-containing protein-interacting membrane protein (VIMP) links the endoplasmic reticulum with microtubules in concert with cytoskeleton-linking membrane protein (CLIMP)-63.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25008318","citation_count":17,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"40437099","id":"PMC_40437099","title":"EndoMAP.v1 charts the structural landscape of human early endosome complexes.","date":"2025","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/40437099","citation_count":6,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21880,"output_tokens":253,"usd":0.034717},"stage2":{"model":"","input_tokens":0,"output_tokens":0,"usd":0.0},"total_usd":0.171823,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":30179,"output_tokens":1468,"usd":0.056279},"round2_rules_fired":"R1","round2_stage2":{"model":"claude-opus-4-6","input_tokens":4487,"output_tokens":1258,"usd":0.080827}},"stage1_raw":"```json\n{\n  \"discoveries\": [],\n  \"current_model\": \"No mechanistic findings in the available literature.\"\n}\n```\n\n**Rationale:** After reviewing all 40 papers, none contain direct experimental mechanistic findings about the human/mammalian SNTG2 (gamma-2-syntrophin) protein itself. The papers mentioning SNTG2 describe it only in the context of chromosomal deletions associated with intellectual disability/obesity phenotypes (genomic/clinical studies), expression correlation studies, or epigenetic association studies — all of which fall under the EXCLUDE criteria (expression correlation, IHC, transcriptomics, GWAS/CNV associations, pure phenotype descriptions without molecular mechanism). \n\nThe large number of papers about \"Syn5\" refer to the marine cyanophage Syn5 (a bacteriophage), which is a symbol collision and entirely unrelated to the human gene SNTG2. No papers in this corpus establish the molecular mechanism, binding partners, enzymatic activity, structure, or direct cellular function of the SNTG2 protein through direct experiment.\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\nMost papers in the retrieved corpus are about cyanophage Syn5 (EXCLUDE - symbol collision with a bacteriophage), syntaxin 5 / Syn5 SNARE (EXCLUDE - different gene), maize varieties named SYN5 (EXCLUDE - plant symbol collision), or are expression/epigenetic association studies with no mechanism (EXCLUDE - no mechanistic content).\n\n**KEEP papers (about canonical human SNTG2 / gamma2-syntrophin protein):**\n- PMID:10747910 — Original characterization of gamma1- and gamma2-syntrophins as dystrophin-binding proteins\n- PMID:12429735 — Syntrophin gamma2 regulates SCN5A gating via PDZ domain interaction\n- PMID:17292328 — SNTG2 binds neuroligins 3/4X; autism mutations affect this interaction\n- PMID:28514442, 25416956, 32296183, 33961781 — Large interactome studies (BioPlex, HuRI) that capture SNTG2 interactions (KEEP if mechanistic content about SNTG2 binding partners)\n- PMID:26053890, 23722234, 36115835, 30726710 — PDZ domain interaction studies (KEEP if they report SNTG2 PDZ binding affinities)\n\n**EXCLUDE papers:** All cyanophage Syn5 papers, syntaxin-5 papers, maize papers, pure expression/GWAS/epigenetic studies, chromosomal deletion case reports with no mechanism, and papers with no mechanistic data on SNTG2 protein.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Gamma2-syntrophin (SNTG2) was identified as a novel member of the syntrophin family, encoded by a gene on chromosome 2p25 with at least 17 exons. Yeast two-hybrid and GST pull-down experiments demonstrated that SNTG2 directly binds the C-terminal region of dystrophin and related proteins (dystrophin-associated protein complex). Immunohistochemistry and RNA in situ hybridization showed that SNTG2 protein is expressed in rat and human central neurons, suggesting a specialized role for a modified dystrophin-associated complex in the central nervous system.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, immunohistochemistry, RNA in situ hybridization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal binding confirmed by both yeast two-hybrid and pull-down, with localization data; moderate evidence from a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"10747910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The PDZ domain of SNTG2 directly interacts with the C-terminus of SCN5A (the cardiac/intestinal Na+ channel alpha subunit). This was established by yeast two-hybrid and GST pull-down assays. Co-transfection of SNTG2 with SCN5A in HEK293 cells markedly shifted SCN5A activation kinetics and reduced Na+ current availability. In native intestinal smooth muscle cells, disruption of the SCN5A C-terminus–SNTG2 PDZ domain interaction using blocking peptides abolished mechanosensitivity of the Na+ channel, establishing SNTG2 as an essential regulator of SCN5A gating and mechanosensitivity.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-transfection with whole-cell patch clamp, peptide disruption in native cells, laser capture microdissection, single-cell PCR, immunohistochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (binding assay + functional electrophysiology + peptide disruption in native cells) in a single study; strong mechanistic chain\",\n      \"pmids\": [\"12429735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SNTG2 was identified as a direct binding partner of neuroligin-3 (NL3) in a yeast two-hybrid screen, and the interaction was confirmed biochemically. SNTG2 also bound neuroligin-4X (NL4X) and NL4Y. Autism-associated missense mutations in NL3 and NL4X significantly impaired their interaction with SNTG2, implying that disruption of the NL–SNTG2 complex may contribute to autism spectrum disorder etiology.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation / biochemical binding assay with autism-related mutant constructs\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, binding shown by yeast two-hybrid and biochemical assay, functional implication inferred from mutation effect on binding but no cellular phenotype rescue\",\n      \"pmids\": [\"17292328\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNTG2 (gamma2-syntrophin) is a neuronal scaffolding protein that binds the C-terminal region of dystrophin and dystrophin-related proteins via its syntrophin domain, anchors and regulates the cardiac/smooth-muscle Na+ channel SCN5A through a PDZ domain–C-terminal interaction that controls channel gating kinetics and mechanosensitivity, and interacts with autism-associated neuroligins 3 and 4X through its PDZ domain in a manner disrupted by autism-linked mutations.\"\n}\n```","stage2_raw":"\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"SNTG2 (gamma-2-syntrophin) is a neuronal scaffolding protein that binds the C-terminal region of dystrophin and dystrophin-related proteins via its syntrophin unique domain, linking it to a modified dystrophin-associated protein complex expressed selectively in central neurons [PMID:10747910]. Its PDZ domain directly engages the C-terminus of the voltage-gated sodium channel SCN5A, shifting channel activation kinetics and conferring mechanosensitivity in intestinal smooth muscle cells [PMID:12429735]. The same PDZ domain mediates interactions with the autism-associated synaptic adhesion molecules neuroligin-3 and neuroligin-4X, and autism-linked missense mutations in these neuroligins disrupt SNTG2 binding [PMID:17292328].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of SNTG2 as a new syntrophin family member that directly binds dystrophin's C-terminus established that the dystrophin-associated protein complex in central neurons includes a neuron-specific syntrophin isoform.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, immunohistochemistry, and RNA in situ hybridization in rat and human tissues\",\n      \"pmids\": [\"10747910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No knockout or knockdown phenotype reported\",\n        \"Whether SNTG2 competes with other syntrophins for dystrophin binding sites is unresolved\",\n        \"Subcellular localization within neurons (e.g., synaptic vs. somatic) was not precisely defined\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstration that SNTG2's PDZ domain binds the SCN5A C-terminus and controls channel gating and mechanosensitivity revealed a direct ion-channel-regulatory function for this scaffolding protein.\",\n      \"evidence\": \"Yeast two-hybrid and GST pull-down for binding; whole-cell patch-clamp in co-transfected HEK293 cells and peptide-disruption experiments in native intestinal smooth muscle cells\",\n      \"pmids\": [\"12429735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo consequences of SNTG2 loss on SCN5A function have not been tested\",\n        \"Whether SNTG2 regulates other voltage-gated channels via its PDZ domain is unknown\",\n        \"Structural basis of the PDZ–SCN5A interaction has not been resolved\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that SNTG2 binds neuroligins 3 and 4X—and that autism-associated mutations impair this interaction—implicated SNTG2 in the postsynaptic scaffolding of autism-relevant adhesion molecules.\",\n      \"evidence\": \"Yeast two-hybrid screen and co-immunoprecipitation with wild-type and autism-mutant neuroligin constructs\",\n      \"pmids\": [\"17292328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No cellular or synaptic phenotype was reported upon disruption of the NL–SNTG2 interaction\",\n        \"Whether SNTG2 links neuroligins to the dystrophin complex at synapses has not been shown\",\n        \"The finding has not been independently replicated in a second laboratory\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The in vivo physiological roles of SNTG2 remain undefined: no genetic loss-of-function model or human disease association has been reported, and whether its PDZ-domain partners (SCN5A, neuroligins) are regulated simultaneously or in distinct tissue contexts is unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No animal knockout or conditional deletion phenotype exists\",\n        \"Full interactome of the SNTG2 PDZ domain has not been profiled\",\n        \"Role of SNTG2 in synaptic versus extra-synaptic compartments is undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\n      \"dystrophin-associated protein complex\"\n    ],\n    \"partners\": [\n      \"DMD\",\n      \"SCN5A\",\n      \"NLGN3\",\n      \"NLGN4X\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}