{"gene":"CHN2","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2009,"finding":"CHN2 (encoding β2-chimerin) is expressed in insulin-sensitive tissues (e.g., adipose), and its heterozygous disruption by chromosomal translocation results in decreased CHN2 gene expression in patient-derived adipose tissue, implicating CHN2 as a component of proximal insulin signaling in vivo.","method":"FISH breakpoint mapping of chromosomal translocation t(7,19)(p15.2;p13.2), sequencing of disrupted genes, and gene expression studies in patient-derived adipose tissue","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization/expression in patient tissue with functional inference, single lab, single translocation case, no in vitro reconstitution of signaling pathway","pmids":["19720790"],"is_preprint":false}],"current_model":"CHN2 encodes β2-chimerin, a Rac-specific GTPase-activating protein expressed in insulin-sensitive tissues; haploinsufficiency of CHN2 due to chromosomal translocation is associated with decreased expression in adipose tissue and contributes to a digenic insulin resistance/growth deficiency phenotype, implicating it as a component of proximal insulin signaling, though the precise molecular mechanism remains incompletely defined from available experimental data."},"narrative":{"mechanistic_narrative":"CHN2 encodes β2-chimerin and is expressed in insulin-sensitive tissues such as adipose, where it has been implicated as a component of proximal insulin signaling in vivo [PMID:19720790]. Heterozygous disruption of CHN2 by a chromosomal translocation reduces CHN2 expression in patient-derived adipose tissue, linking gene dosage to an insulin resistance/growth phenotype [PMID:19720790]. Beyond this single translocation-based association [PMID:19720790], no further mechanistic detail — including the molecular activity of the β2-chimerin protein or the signaling steps it participates in — has been characterized in the available corpus.","teleology":[{"year":2009,"claim":"Established that CHN2 is expressed in insulin-sensitive tissue and that reducing its dosage perturbs metabolic physiology, raising it from an uncharacterized locus to a candidate component of insulin signaling.","evidence":"FISH breakpoint mapping of a t(7;19) translocation, sequencing of disrupted genes, and expression analysis in patient-derived adipose tissue","pmids":["19720790"],"confidence":"Medium","gaps":["Single translocation case from one lab; association not genetically replicated","No in vitro reconstitution of any signaling pathway","Molecular activity of the β2-chimerin protein and its direct partners not defined"]},{"year":null,"claim":"How the β2-chimerin protein acts biochemically within insulin signaling, and which direct partners or substrates it engages, remains unresolved in the available corpus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct biochemical activity demonstrated in the timeline","No physical interaction partners identified","No causal mechanism linking CHN2 dosage to insulin resistance established"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P52757","full_name":"Beta-chimaerin","aliases":["Beta-chimerin","Rho GTPase-activating protein 3"],"length_aa":468,"mass_kda":53.9,"function":"GTPase-activating protein for p21-rac. Insufficient expression of beta-2 chimaerin is expected to lead to higher Rac activity and could therefore play a role in the progression from low-grade to high-grade tumors","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P52757/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHN2","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/CHN2","total_profiled":1310},"omim":[{"mim_id":"618184","title":"NEUROPATHY, CONGENITAL HYPOMYELINATING, 2; CHN2","url":"https://www.omim.org/entry/618184"},{"mim_id":"605253","title":"NEUROPATHY, CONGENITAL HYPOMYELINATING, 1, AUTOSOMAL RECESSIVE; CHN1","url":"https://www.omim.org/entry/605253"},{"mim_id":"602857","title":"CHIMERIN 2; CHN2","url":"https://www.omim.org/entry/602857"},{"mim_id":"159440","title":"MYELIN PROTEIN ZERO; MPZ","url":"https://www.omim.org/entry/159440"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":170.8},{"tissue":"intestine","ntpm":72.2}],"url":"https://www.proteinatlas.org/search/CHN2"},"hgnc":{"alias_symbol":["ARHGAP3","RhoGAP3"],"prev_symbol":[]},"alphafold":{"accession":"P52757","domains":[{"cath_id":"3.30.505.10","chopping":"31-145","consensus_level":"high","plddt":94.8309,"start":31,"end":145},{"cath_id":"3.30.60.20","chopping":"149-159_210-265","consensus_level":"medium","plddt":87.4363,"start":149,"end":265},{"cath_id":"1.10.555.10","chopping":"285-465","consensus_level":"high","plddt":95.1323,"start":285,"end":465}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P52757","model_url":"https://alphafold.ebi.ac.uk/files/AF-P52757-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P52757-F1-predicted_aligned_error_v6.png","plddt_mean":84.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHN2","jax_strain_url":"https://www.jax.org/strain/search?query=CHN2"},"sequence":{"accession":"P52757","fasta_url":"https://rest.uniprot.org/uniprotkb/P52757.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P52757/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P52757"}},"corpus_meta":[{"pmid":"10092476","id":"PMC_10092476","title":"Trypanosoma brucei: killing of bloodstream forms in vitro and in vivo by the cysteine proteinase inhibitor Z-phe-ala-CHN2.","date":"1999","source":"Experimental parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/10092476","citation_count":72,"is_preprint":false},{"pmid":"17020538","id":"PMC_17020538","title":"The crystal structure of human dipeptidyl peptidase I (cathepsin C) in complex with the inhibitor Gly-Phe-CHN2.","date":"2007","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/17020538","citation_count":53,"is_preprint":false},{"pmid":"7871486","id":"PMC_7871486","title":"In vitro embryotoxicity of the cysteine proteinase inhibitors benzyloxycarbonyl-phenylalanine-alanine-diazomethane (Z-Phe-Ala-CHN2) and benzyloxycarbonyl-phenylalanine-phenylalanine-diazomethane (Z-Phe-Phe-CHN2).","date":"1994","source":"Teratology","url":"https://pubmed.ncbi.nlm.nih.gov/7871486","citation_count":26,"is_preprint":false},{"pmid":"19720790","id":"PMC_19720790","title":"Severe insulin resistance and intrauterine growth deficiency associated with haploinsufficiency for INSR and CHN2: new insights into synergistic pathways involved in growth and metabolism.","date":"2009","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/19720790","citation_count":22,"is_preprint":false},{"pmid":"17328798","id":"PMC_17328798","title":"The cysteine proteinase inhibitor Z-Phe-Ala-CHN2 alters cell morphology and cell division activity of Trypanosoma brucei bloodstream forms in vivo.","date":"2007","source":"Kinetoplastid biology and disease","url":"https://pubmed.ncbi.nlm.nih.gov/17328798","citation_count":20,"is_preprint":false},{"pmid":"31228090","id":"PMC_31228090","title":"Efficacy and Safety of Dulaglutide Versus Insulin Glargine in Chinese T2DM Patients: A Subgroup Analysis of a Randomized Trial (AWARD-CHN2).","date":"2019","source":"Diabetes therapy : research, treatment and education of diabetes and related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/31228090","citation_count":14,"is_preprint":false},{"pmid":"29719347","id":"PMC_29719347","title":"CHN2 Promoter Methylation Change May Be Associated With Methamphetamine Dependence.","date":"2017","source":"Shanghai archives of psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/29719347","citation_count":11,"is_preprint":false},{"pmid":"23941981","id":"PMC_23941981","title":"Association of a novel polymorphism of the β2-chimaerin gene (CHN2) with smoking.","date":"2013","source":"Journal of investigative medicine : the official publication of the American Federation for Clinical Research","url":"https://pubmed.ncbi.nlm.nih.gov/23941981","citation_count":9,"is_preprint":false},{"pmid":"37507904","id":"PMC_37507904","title":"Neuroprotective and Antioxidant Properties of CholesteroNitrone ChN2 and QuinolylNitrone QN23 in an Experimental Model of Cerebral Ischemia: Involvement of Necrotic and Apoptotic Cell Death.","date":"2023","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37507904","citation_count":5,"is_preprint":false},{"pmid":"34870792","id":"PMC_34870792","title":"Efficacy of Dulaglutide in Chinese Patients with Type 2 Diabetes and Different Glycemic Patterns: a Post-hoc Analysis of the Phase 3 AWARD-CHN2 Trial.","date":"2021","source":"Diabetes therapy : research, treatment and education of diabetes and related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/34870792","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7758,"output_tokens":369,"usd":0.014405,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6633,"output_tokens":768,"usd":0.026183,"stage2_stop_reason":"end_turn"},"total_usd":0.040588,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"CHN2 (encoding β2-chimerin) is expressed in insulin-sensitive tissues (e.g., adipose), and its heterozygous disruption by chromosomal translocation results in decreased CHN2 gene expression in patient-derived adipose tissue, implicating CHN2 as a component of proximal insulin signaling in vivo.\",\n      \"method\": \"FISH breakpoint mapping of chromosomal translocation t(7,19)(p15.2;p13.2), sequencing of disrupted genes, and gene expression studies in patient-derived adipose tissue\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization/expression in patient tissue with functional inference, single lab, single translocation case, no in vitro reconstitution of signaling pathway\",\n      \"pmids\": [\"19720790\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHN2 encodes β2-chimerin, a Rac-specific GTPase-activating protein expressed in insulin-sensitive tissues; haploinsufficiency of CHN2 due to chromosomal translocation is associated with decreased expression in adipose tissue and contributes to a digenic insulin resistance/growth deficiency phenotype, implicating it as a component of proximal insulin signaling, though the precise molecular mechanism remains incompletely defined from available experimental data.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CHN2 encodes β2-chimerin and is expressed in insulin-sensitive tissues such as adipose, where it has been implicated as a component of proximal insulin signaling in vivo [#0]. Heterozygous disruption of CHN2 by a chromosomal translocation reduces CHN2 expression in patient-derived adipose tissue, linking gene dosage to an insulin resistance/growth phenotype [#0]. Beyond this single translocation-based association [#0], no further mechanistic detail — including the molecular activity of the β2-chimerin protein or the signaling steps it participates in — has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that CHN2 is expressed in insulin-sensitive tissue and that reducing its dosage perturbs metabolic physiology, raising it from an uncharacterized locus to a candidate component of insulin signaling.\",\n      \"evidence\": \"FISH breakpoint mapping of a t(7;19) translocation, sequencing of disrupted genes, and expression analysis in patient-derived adipose tissue\",\n      \"pmids\": [\n        \"19720790\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single translocation case from one lab; association not genetically replicated\",\n        \"No in vitro reconstitution of any signaling pathway\",\n        \"Molecular activity of the β2-chimerin protein and its direct partners not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the β2-chimerin protein acts biochemically within insulin signaling, and which direct partners or substrates it engages, remains unresolved in the available corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct biochemical activity demonstrated in the timeline\",\n        \"No physical interaction partners identified\",\n        \"No causal mechanism linking CHN2 dosage to insulin resistance established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}