{"gene":"GAN","run_date":"2026-06-10T01:55:20","timeline":{"discoveries":[{"year":2006,"finding":"Targeted knockout of GAN in mice causes accumulation of microtubule-associated protein 8 (MAP8), implicating gigaxonin in ubiquitin-proteasome-mediated degradation of MAP8; accumulated MAP8 alters the microtubule network, traps dynein motor protein in insoluble structures, and causes neuronal death in cultured wild-type neurons. GAN null mice also show defective axonal transport evidenced by vesicular accumulation in neurons.","method":"Traditional gene targeting (knockout mouse), Western blot, immunofluorescence, in vitro axonal transport assays, neuronal culture with MAP8 overexpression","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined cellular phenotype, in vitro rescue/reconstitution experiments, multiple orthogonal methods in single focused study","pmids":["16565160"],"is_preprint":false},{"year":2016,"finding":"Gigaxonin (GAN gene product) functions as an E3 ubiquitin ligase adaptor protein involved in intermediate filament (IF) processing in neural cells and vimentin filament regulation in fibroblasts; disease-causing mutations cluster in the BTB, BACK, and KELCH repeat domains associated with protein homodimerization and substrate interaction.","method":"Review and analysis of mutation databases combined with domain mapping; not primary experimental data but synthesizes published functional evidence","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain-function mapping based on published mutation analysis and structural domain considerations, not direct biochemical reconstitution","pmids":["27023907"],"is_preprint":false},{"year":2009,"finding":"Downregulation of Gan1 gene and gigaxonin protein in the spinal dorsal horn of mice treated with nucleoside reverse transcriptase inhibitors (NRTIs) was validated by qPCR and Western blot, suggesting gigaxonin participates in a pathway relevant to peripheral neuropathy pathogenesis in this context.","method":"Whole-genome microarray screen followed by qPCR validation and Western blot in mouse spinal dorsal horn tissue","journal":"Biological research for nursing","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, expression-level validation only, no direct mechanistic follow-up of pathway position","pmids":["19398414"],"is_preprint":false},{"year":2023,"finding":"In GAN patient iPSC-derived astrocytes carrying KLHL16 (gigaxonin) mutations, loss of gigaxonin leads to striking dense perinuclear vimentin and GFAP accumulations and abnormal nuclear morphology. In overexpression systems, GFAP oligomerization and perinuclear aggregation were augmented in the presence of vimentin. Cells with large perinuclear vimentin aggregates accumulated significantly more nuclear KLHL16 mRNA, suggesting vimentin is an early effector of KLHL16 mutations. GAN brain organoids showed neurofilament and GFAP aggregates, and GAN NPCs had lower nestin expression.","method":"Patient iPSC reprogramming, CRISPR/Cas9 isogenic controls, immunofluorescence, overexpression systems in astrocytes, brain organoids, neural progenitor cell differentiation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — isogenic CRISPR controls, multiple cell types (iPSC, NPC, astrocytes, organoids), multiple orthogonal methods confirming IF dysregulation downstream of gigaxonin loss","pmids":["37672338"],"is_preprint":false},{"year":2021,"finding":"A homozygous pathogenic splicing variant (c.1373+1G>A) in the GAN gene causes skipping of exon 8, disrupting formation of the Kelch domain of gigaxonin, as validated at the cDNA level.","method":"Whole-exome sequencing, cDNA-level validation of splicing defect","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct cDNA validation of splicing consequence, single patient/family, no downstream biochemical characterization","pmids":["34889507"],"is_preprint":false}],"current_model":"Gigaxonin (encoded by GAN/KLHL16) is an E3 ubiquitin ligase adaptor protein that targets intermediate filaments—including neurofilaments, MAP8, vimentin, and GFAP—for ubiquitin-proteasome-mediated degradation; loss of gigaxonin function causes pathological accumulation of these substrates, disrupts the microtubule network, traps dynein, impairs retrograde axonal transport, and leads to neurodegeneration, as demonstrated in knockout mice, patient-derived iPSC astrocytes, and brain organoids."},"narrative":{"mechanistic_narrative":"Gigaxonin, encoded by GAN (KLHL16), is an E3 ubiquitin ligase adaptor that controls the turnover of cytoskeletal substrates and whose loss drives a neurodegenerative phenotype [PMID:16565160, PMID:27023907]. Through its BTB, BACK, and KELCH repeat domains—the sites at which disease-causing mutations cluster—gigaxonin mediates homodimerization and substrate engagement to direct intermediate filament proteins toward ubiquitin-proteasome degradation [PMID:27023907]. In knockout mice, loss of gigaxonin causes accumulation of microtubule-associated protein MAP8, which distorts the microtubule network, traps dynein in insoluble structures, and impairs axonal transport, producing vesicular accumulation and neuronal death [PMID:16565160]. In patient iPSC-derived astrocytes and brain organoids, loss of gigaxonin produces dense perinuclear vimentin, GFAP, and neurofilament aggregates with abnormal nuclear morphology, with vimentin acting as an early effector of KLHL16 mutation and promoting GFAP oligomerization [PMID:37672338]. Disease-associated GAN variants, including a splicing variant that skips exon 8 and disrupts the Kelch domain, link these mechanistic defects to human pathology [PMID:34889507].","teleology":[{"year":2006,"claim":"Established that gigaxonin loss causes substrate accumulation with direct cellular consequences, showing it functions in ubiquitin-proteasome-mediated degradation of a cytoskeletal target rather than merely correlating with disease.","evidence":"GAN knockout mouse with Western blot, immunofluorescence, in vitro axonal transport assays, and neuronal culture with MAP8 overexpression","pmids":["16565160"],"confidence":"High","gaps":["Did not demonstrate direct ubiquitination of MAP8 by a gigaxonin-containing ligase in vitro","Mechanism by which MAP8 accumulation traps dynein not biochemically resolved"]},{"year":2009,"claim":"Connected gigaxonin expression to a peripheral neuropathy context, raising the possibility of regulated downregulation in acquired neuropathy.","evidence":"Whole-genome microarray with qPCR and Western blot validation in mouse spinal dorsal horn after NRTI treatment","pmids":["19398414"],"confidence":"Low","gaps":["Expression-level correlation only with no mechanistic follow-up","Causal role of gigaxonin downregulation in neuropathy not tested"]},{"year":2016,"claim":"Mapped disease-causing mutations to the BTB, BACK, and KELCH domains, framing gigaxonin as an adaptor whose dimerization and substrate-binding surfaces are functionally critical for intermediate filament processing.","evidence":"Review and domain mapping integrating mutation databases with structural domain considerations","pmids":["27023907"],"confidence":"Medium","gaps":["Domain-function assignments inferred, not from direct biochemical reconstitution","Substrate selectivity of each domain not experimentally dissected"]},{"year":2021,"claim":"Provided direct molecular validation that a clinical GAN variant disrupts the Kelch domain, linking a specific splicing defect to loss of the substrate-recognition module.","evidence":"Whole-exome sequencing with cDNA-level validation of exon 8 skipping in a patient","pmids":["34889507"],"confidence":"Medium","gaps":["Single family with no downstream biochemical characterization","Functional consequence for substrate degradation not measured"]},{"year":2023,"claim":"Demonstrated in a human cellular system that gigaxonin loss broadly dysregulates intermediate filaments, identifying vimentin as an early effector that promotes GFAP aggregation and nuclear abnormalities.","evidence":"Patient iPSC-derived astrocytes, NPCs, and brain organoids with CRISPR isogenic controls, immunofluorescence, and overexpression systems","pmids":["37672338"],"confidence":"High","gaps":["Direct ubiquitination of vimentin/GFAP by gigaxonin not shown in this system","Mechanism linking vimentin aggregation to nuclear KLHL16 mRNA accumulation unresolved"]},{"year":null,"claim":"How gigaxonin assembles into a functional E3 ligase complex and directly ubiquitinates each intermediate filament substrate remains biochemically uncharacterized in the available corpus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No reconstituted ubiquitination assay defining the gigaxonin ligase complex","Substrate hierarchy and selectivity across MAP8, vimentin, GFAP, and neurofilaments not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H2C0","full_name":"Gigaxonin","aliases":["Kelch-like protein 16"],"length_aa":597,"mass_kda":67.6,"function":"Probable cytoskeletal component that directly or indirectly plays an important role in neurofilament architecture. May act as a substrate-specific adapter of an E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Controls degradation of TBCB. Controls degradation of MAP1B and MAP1S, and is critical for neuronal maintenance and survival","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q9H2C0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GAN","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GAN","total_profiled":1310},"omim":[{"mim_id":"621322","title":"FOXO-INDUCED LONG NONCODING RNA 1; FILNC1","url":"https://www.omim.org/entry/621322"},{"mim_id":"621298","title":"GLYCINE-RICH EXTRACELLULAR PROTEIN 1; GREP1","url":"https://www.omim.org/entry/621298"},{"mim_id":"620911","title":"SPASTIC PARAPLEGIA 92, AUTOSOMAL RECESSIVE; SPG92","url":"https://www.omim.org/entry/620911"},{"mim_id":"620884","title":"FER1-LIKE FAMILY, MEMBER 6; FER1L6","url":"https://www.omim.org/entry/620884"},{"mim_id":"620875","title":"FIC DOMAIN-CONTAINING PROTEIN ADENYLYLTRANSFERASE; FICD","url":"https://www.omim.org/entry/620875"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Microtubules","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skin 1","ntpm":23.5}],"url":"https://www.proteinatlas.org/search/GAN"},"hgnc":{"alias_symbol":["GAN1","KLHL16","GIG"],"prev_symbol":[]},"alphafold":{"accession":"Q9H2C0","domains":[{"cath_id":"3.30.710.10","chopping":"14-128","consensus_level":"high","plddt":91.1457,"start":14,"end":128},{"cath_id":"1.25.40","chopping":"173-264","consensus_level":"high","plddt":85.1223,"start":173,"end":264},{"cath_id":"2.120.10.80","chopping":"270-586","consensus_level":"medium","plddt":94.4154,"start":270,"end":586}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2C0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2C0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2C0-F1-predicted_aligned_error_v6.png","plddt_mean":89.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GAN","jax_strain_url":"https://www.jax.org/strain/search?query=GAN"},"sequence":{"accession":"Q9H2C0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H2C0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H2C0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2C0"}},"corpus_meta":[{"pmid":"8474442","id":"PMC_8474442","title":"(CT)n 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cells.","date":"2008","source":"Endocrine journal","url":"https://pubmed.ncbi.nlm.nih.gov/18469482","citation_count":10,"is_preprint":false},{"pmid":"33935715","id":"PMC_33935715","title":"Comprehensive RNA-Seq Analysis of Potential Therapeutic Targets of Gan-Dou-Fu-Mu Decoction for Treatment of Wilson Disease Using a Toxic Milk Mouse Model.","date":"2021","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33935715","citation_count":10,"is_preprint":false},{"pmid":"35247474","id":"PMC_35247474","title":"The effect of Ma-Xin-Gan-Shi decoction on asthma exacerbated by respiratory syncytial virus through regulating TRPV1 channel.","date":"2022","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35247474","citation_count":10,"is_preprint":false},{"pmid":"27549769","id":"PMC_27549769","title":"Bo-Gan-Whan regulates proliferation and migration of vascular smooth muscle cells.","date":"2016","source":"BMC complementary and alternative 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Murine WEHI-3 Leukemia Cells and Tumor Growth in BALB/C Allograft Tumor Model.","date":"2013","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/23573143","citation_count":9,"is_preprint":false},{"pmid":"37672338","id":"PMC_37672338","title":"Intermediate filament dysregulation in astrocytes in the human disease model of KLHL16 mutation in giant axonal neuropathy (GAN).","date":"2023","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/37672338","citation_count":8,"is_preprint":false},{"pmid":"35924980","id":"PMC_35924980","title":"3D GAN image synthesis and dataset quality assessment for bacterial biofilm.","date":"2022","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/35924980","citation_count":8,"is_preprint":false},{"pmid":"38241142","id":"PMC_38241142","title":"Ling-Gui-Zhu-Gan decoction protects against doxorubicin-induced myocardial injury by downregulating ferroptosis.","date":"2024","source":"The Journal of pharmacy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38241142","citation_count":8,"is_preprint":false},{"pmid":"16107322","id":"PMC_16107322","title":"Hepatoprotective mechanisms of Yan-gan-wan.","date":"2005","source":"Hepatology research : the official journal of the Japan Society of Hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/16107322","citation_count":8,"is_preprint":false},{"pmid":"33083995","id":"PMC_33083995","title":"Go-sha-jinki-Gan Alleviates Inflammation in Neurological Disorders via p38-TNF Signaling in the Central Nervous System.","date":"2020","source":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/33083995","citation_count":8,"is_preprint":false},{"pmid":"39224696","id":"PMC_39224696","title":"Metabolic profile and bioactivity of the peel of Zhoupigan (Citrus reticulata cv. Manau Gan), a special citrus variety in China, based on GC-MS, UPLC-ESI-MS/MS analysis, and in vitro assay.","date":"2024","source":"Food chemistry: X","url":"https://pubmed.ncbi.nlm.nih.gov/39224696","citation_count":8,"is_preprint":false},{"pmid":"40818519","id":"PMC_40818519","title":"Ma Xing Shi Gan Decoction alleviates lipopolysaccharide-induced pneumonia by inhibiting NLRP3 inflammasome activation via AMPK/mTOR/ULK1-mediated autophagy.","date":"2025","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40818519","citation_count":7,"is_preprint":false},{"pmid":"35688990","id":"PMC_35688990","title":"LSH-GAN enables in-silico generation of cells for small sample high dimensional scRNA-seq data.","date":"2022","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/35688990","citation_count":7,"is_preprint":false},{"pmid":"35404518","id":"PMC_35404518","title":"A Versatile, Incubator-Compatible, Monolithic GaN Photonic Chipscope for Label-Free Monitoring of Live Cell Activities.","date":"2022","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/35404518","citation_count":7,"is_preprint":false},{"pmid":"25264283","id":"PMC_25264283","title":"Enhanced cell growth on nanotextured GaN surface treated by UV illumination and fibronectin adsorption.","date":"2014","source":"Colloids and surfaces. B, Biointerfaces","url":"https://pubmed.ncbi.nlm.nih.gov/25264283","citation_count":7,"is_preprint":false},{"pmid":"34889507","id":"PMC_34889507","title":"Giant axonal neuropathy (GAN) in an 8-year-old girl caused by a homozygous pathogenic splicing variant in GAN gene.","date":"2021","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/34889507","citation_count":7,"is_preprint":false},{"pmid":"35161241","id":"PMC_35161241","title":"Major Plant in Herbal Mixture Gan-Mai-Da-Zao for the Alleviation of Depression in Rat Models.","date":"2022","source":"Plants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35161241","citation_count":7,"is_preprint":false},{"pmid":"36828197","id":"PMC_36828197","title":"The protective effects of Zhi-Gan-Cao-Tang against diabetic myocardial infarction injury and identification of its effective constituents.","date":"2023","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36828197","citation_count":7,"is_preprint":false},{"pmid":"23243456","id":"PMC_23243456","title":"Rokumi-jio-gan-Containing Prescriptions Attenuate Oxidative Stress, Inflammation, and Apoptosis in the Remnant Kidney.","date":"2012","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/23243456","citation_count":7,"is_preprint":false},{"pmid":"37926662","id":"PMC_37926662","title":"HER2GAN: Overcome the Scarcity of HER2 Breast Cancer Dataset Based on Transfer Learning and GAN Model.","date":"2023","source":"Clinical breast cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37926662","citation_count":7,"is_preprint":false},{"pmid":"22241503","id":"PMC_22241503","title":"Effect and mechanisms of Gong-tone music on the immunological function in rats with Liver (Gan)-qi depression and Spleen (Pi)-qi deficiency syndrome in rats.","date":"2012","source":"Chinese journal of integrative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22241503","citation_count":7,"is_preprint":false},{"pmid":"38851549","id":"PMC_38851549","title":"Gray matters: ViT-GAN framework for identifying schizophrenia biomarkers linking structural MRI and functional network connectivity.","date":"2024","source":"NeuroImage","url":"https://pubmed.ncbi.nlm.nih.gov/38851549","citation_count":7,"is_preprint":false},{"pmid":"37655766","id":"PMC_37655766","title":"First-principles study of controllable contact types in Janus MoSH/GaN van der Waals heterostructure.","date":"2023","source":"The Journal of chemical physics","url":"https://pubmed.ncbi.nlm.nih.gov/37655766","citation_count":7,"is_preprint":false},{"pmid":"38034402","id":"PMC_38034402","title":"SIGANEO: Similarity network with GAN enhancement for immunogenic neoepitope prediction.","date":"2023","source":"Computational and structural biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/38034402","citation_count":7,"is_preprint":false},{"pmid":"40752599","id":"PMC_40752599","title":"Hu Gan Tang ameliorates metabolic-associated fatty liver disease by inhibiting ferroptosis through the Nrf2/GPX4 pathway.","date":"2025","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40752599","citation_count":6,"is_preprint":false},{"pmid":"40865652","id":"PMC_40865652","title":"Mechanism of Bao Gan Ning decoction in attenuating hepatic fibrosis via modulation of the gut microbiome and PPAR/CYP7A1-mediated bile acid metabolism.","date":"2025","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40865652","citation_count":6,"is_preprint":false},{"pmid":"39574280","id":"PMC_39574280","title":"Intrinsic Capacity Impairments (ICOPE Step 1 and Step 2), Cardiometabolic Risk and Immune Resilience: An Exploratory Analysis from the Gan-Dau Healthy Longevity Plan.","date":"2024","source":"The Journal of frailty & aging","url":"https://pubmed.ncbi.nlm.nih.gov/39574280","citation_count":6,"is_preprint":false},{"pmid":"34950216","id":"PMC_34950216","title":"Shu-Di-Huang and Gan-Cao Herb Pair Restored the Differentiation Potentials of Mesenchymal Stem Progenitors in Treating Osteoporosis via Downregulation of NF-κB Signaling Pathway.","date":"2021","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/34950216","citation_count":6,"is_preprint":false},{"pmid":"23467843","id":"PMC_23467843","title":"Shu-Gan-Liang-Xue Decoction Simultaneously Down-regulates Expressions of Aromatase and Steroid Sulfatase in Estrogen Receptor Positive Breast Cancer Cells.","date":"2011","source":"Chinese journal of cancer research = Chung-kuo yen cheng yen chiu","url":"https://pubmed.ncbi.nlm.nih.gov/23467843","citation_count":6,"is_preprint":false},{"pmid":"40750975","id":"PMC_40750975","title":"Novel dual gland GAN architecture improves human protein localization classification using salivary and pituitary gland inspired loss functions.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40750975","citation_count":6,"is_preprint":false},{"pmid":"36762105","id":"PMC_36762105","title":"Exploring the molecular mechanism of Gan Shuang granules for the treatment of non-alcoholic steatohepatitis using network pharmacology, molecular docking, and experimental verification.","date":"2023","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36762105","citation_count":6,"is_preprint":false},{"pmid":"40345270","id":"PMC_40345270","title":"Gan-tang-yi decoction improves hepatic insulin resistance through activation of IRS2/PI3K/Akt pathway and inhibition of AGEs/RAGE pathway in cirrhotic rats.","date":"2025","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40345270","citation_count":5,"is_preprint":false},{"pmid":"39810998","id":"PMC_39810998","title":"TopMT-GAN: a 3D topology-driven generative model for efficient and diverse structure-based ligand design.","date":"2025","source":"Chemical science","url":"https://pubmed.ncbi.nlm.nih.gov/39810998","citation_count":5,"is_preprint":false},{"pmid":"35586687","id":"PMC_35586687","title":"Clinical Evidence and Potential Mechanisms of Complementary Treatment of Ling Gui Zhu Gan Formula for the Management of Serum Lipids and Obesity.","date":"2022","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/35586687","citation_count":5,"is_preprint":false},{"pmid":"38325211","id":"PMC_38325211","title":"DSFF-GAN: A novel stain transfer network for generating immunohistochemical image of endometrial cancer.","date":"2024","source":"Computers in biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38325211","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":57629,"output_tokens":1798,"usd":0.099929,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8110,"output_tokens":2024,"usd":0.045575,"stage2_stop_reason":"end_turn"},"total_usd":0.145504,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the 100 abstracts, I need to identify papers about the canonical human/mammalian GAN gene (encoding gigaxonin/KLHL16), not papers about:\n- GAN as \"generative adversarial network\"\n- Chinese herbal formulas with \"Gan\" in the name\n- Gallium nitride (GaN) semiconductor materials\n- Archaeal GAN nuclease (different gene/organism)\n- The Gan River\n- Other unrelated uses of \"GAN\"\n\nRelevant papers about the canonical GAN/gigaxonin/KLHL16 gene:\n- PMID:16565160 - Gene targeting of GAN in mouse\n- PMID:27023907 - Review of gigaxonin mutations\n- PMID:19398414 - Genome-wide screen identifying Gan in NRTI neuropathy\n- PMID:29876741 - Novel mutations in GAN gene\n- PMID:23332420 - Novel mutation in GAN gene\n- PMID:37672338 - IF dysregulation in astrocytes (KLHL16 mutation)\n- PMID:34889507 - GAN in 8-year-old girl (splicing variant)\n- PMID:33190414 - Vimentin/proteostasis (mentions gigaxonin context)\n\nThe archaeal GAN papers (PMID:27599844, PMID:28416706) are about an archaeal nuclease called GAN - this is a different protein (GINS-associated nuclease) in Thermococcus, not the human gigaxonin. I will exclude these.\n\nPMID:23332420 and PMID:29876741 and PMID:34889507 describe mutations but are primarily clinical/genetic with limited direct mechanism. I'll extract what's mechanistic.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"Targeted knockout of GAN in mice causes accumulation of microtubule-associated protein 8 (MAP8), implicating gigaxonin in ubiquitin-proteasome-mediated degradation of MAP8; accumulated MAP8 alters the microtubule network, traps dynein motor protein in insoluble structures, and causes neuronal death in cultured wild-type neurons. GAN null mice also show defective axonal transport evidenced by vesicular accumulation in neurons.\",\n      \"method\": \"Traditional gene targeting (knockout mouse), Western blot, immunofluorescence, in vitro axonal transport assays, neuronal culture with MAP8 overexpression\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined cellular phenotype, in vitro rescue/reconstitution experiments, multiple orthogonal methods in single focused study\",\n      \"pmids\": [\"16565160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Gigaxonin (GAN gene product) functions as an E3 ubiquitin ligase adaptor protein involved in intermediate filament (IF) processing in neural cells and vimentin filament regulation in fibroblasts; disease-causing mutations cluster in the BTB, BACK, and KELCH repeat domains associated with protein homodimerization and substrate interaction.\",\n      \"method\": \"Review and analysis of mutation databases combined with domain mapping; not primary experimental data but synthesizes published functional evidence\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain-function mapping based on published mutation analysis and structural domain considerations, not direct biochemical reconstitution\",\n      \"pmids\": [\"27023907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Downregulation of Gan1 gene and gigaxonin protein in the spinal dorsal horn of mice treated with nucleoside reverse transcriptase inhibitors (NRTIs) was validated by qPCR and Western blot, suggesting gigaxonin participates in a pathway relevant to peripheral neuropathy pathogenesis in this context.\",\n      \"method\": \"Whole-genome microarray screen followed by qPCR validation and Western blot in mouse spinal dorsal horn tissue\",\n      \"journal\": \"Biological research for nursing\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, expression-level validation only, no direct mechanistic follow-up of pathway position\",\n      \"pmids\": [\"19398414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In GAN patient iPSC-derived astrocytes carrying KLHL16 (gigaxonin) mutations, loss of gigaxonin leads to striking dense perinuclear vimentin and GFAP accumulations and abnormal nuclear morphology. In overexpression systems, GFAP oligomerization and perinuclear aggregation were augmented in the presence of vimentin. Cells with large perinuclear vimentin aggregates accumulated significantly more nuclear KLHL16 mRNA, suggesting vimentin is an early effector of KLHL16 mutations. GAN brain organoids showed neurofilament and GFAP aggregates, and GAN NPCs had lower nestin expression.\",\n      \"method\": \"Patient iPSC reprogramming, CRISPR/Cas9 isogenic controls, immunofluorescence, overexpression systems in astrocytes, brain organoids, neural progenitor cell differentiation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isogenic CRISPR controls, multiple cell types (iPSC, NPC, astrocytes, organoids), multiple orthogonal methods confirming IF dysregulation downstream of gigaxonin loss\",\n      \"pmids\": [\"37672338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A homozygous pathogenic splicing variant (c.1373+1G>A) in the GAN gene causes skipping of exon 8, disrupting formation of the Kelch domain of gigaxonin, as validated at the cDNA level.\",\n      \"method\": \"Whole-exome sequencing, cDNA-level validation of splicing defect\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct cDNA validation of splicing consequence, single patient/family, no downstream biochemical characterization\",\n      \"pmids\": [\"34889507\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Gigaxonin (encoded by GAN/KLHL16) is an E3 ubiquitin ligase adaptor protein that targets intermediate filaments—including neurofilaments, MAP8, vimentin, and GFAP—for ubiquitin-proteasome-mediated degradation; loss of gigaxonin function causes pathological accumulation of these substrates, disrupts the microtubule network, traps dynein, impairs retrograde axonal transport, and leads to neurodegeneration, as demonstrated in knockout mice, patient-derived iPSC astrocytes, and brain organoids.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Gigaxonin, encoded by GAN (KLHL16), is an E3 ubiquitin ligase adaptor that controls the turnover of cytoskeletal substrates and whose loss drives a neurodegenerative phenotype [#0, #1]. Through its BTB, BACK, and KELCH repeat domains—the sites at which disease-causing mutations cluster—gigaxonin mediates homodimerization and substrate engagement to direct intermediate filament proteins toward ubiquitin-proteasome degradation [#1]. In knockout mice, loss of gigaxonin causes accumulation of microtubule-associated protein MAP8, which distorts the microtubule network, traps dynein in insoluble structures, and impairs axonal transport, producing vesicular accumulation and neuronal death [#0]. In patient iPSC-derived astrocytes and brain organoids, loss of gigaxonin produces dense perinuclear vimentin, GFAP, and neurofilament aggregates with abnormal nuclear morphology, with vimentin acting as an early effector of KLHL16 mutation and promoting GFAP oligomerization [#3]. Disease-associated GAN variants, including a splicing variant that skips exon 8 and disrupts the Kelch domain, link these mechanistic defects to human pathology [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that gigaxonin loss causes substrate accumulation with direct cellular consequences, showing it functions in ubiquitin-proteasome-mediated degradation of a cytoskeletal target rather than merely correlating with disease.\",\n      \"evidence\": \"GAN knockout mouse with Western blot, immunofluorescence, in vitro axonal transport assays, and neuronal culture with MAP8 overexpression\",\n      \"pmids\": [\"16565160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not demonstrate direct ubiquitination of MAP8 by a gigaxonin-containing ligase in vitro\", \"Mechanism by which MAP8 accumulation traps dynein not biochemically resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected gigaxonin expression to a peripheral neuropathy context, raising the possibility of regulated downregulation in acquired neuropathy.\",\n      \"evidence\": \"Whole-genome microarray with qPCR and Western blot validation in mouse spinal dorsal horn after NRTI treatment\",\n      \"pmids\": [\"19398414\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Expression-level correlation only with no mechanistic follow-up\", \"Causal role of gigaxonin downregulation in neuropathy not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped disease-causing mutations to the BTB, BACK, and KELCH domains, framing gigaxonin as an adaptor whose dimerization and substrate-binding surfaces are functionally critical for intermediate filament processing.\",\n      \"evidence\": \"Review and domain mapping integrating mutation databases with structural domain considerations\",\n      \"pmids\": [\"27023907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain-function assignments inferred, not from direct biochemical reconstitution\", \"Substrate selectivity of each domain not experimentally dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided direct molecular validation that a clinical GAN variant disrupts the Kelch domain, linking a specific splicing defect to loss of the substrate-recognition module.\",\n      \"evidence\": \"Whole-exome sequencing with cDNA-level validation of exon 8 skipping in a patient\",\n      \"pmids\": [\"34889507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family with no downstream biochemical characterization\", \"Functional consequence for substrate degradation not measured\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated in a human cellular system that gigaxonin loss broadly dysregulates intermediate filaments, identifying vimentin as an early effector that promotes GFAP aggregation and nuclear abnormalities.\",\n      \"evidence\": \"Patient iPSC-derived astrocytes, NPCs, and brain organoids with CRISPR isogenic controls, immunofluorescence, and overexpression systems\",\n      \"pmids\": [\"37672338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitination of vimentin/GFAP by gigaxonin not shown in this system\", \"Mechanism linking vimentin aggregation to nuclear KLHL16 mRNA accumulation unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How gigaxonin assembles into a functional E3 ligase complex and directly ubiquitinates each intermediate filament substrate remains biochemically uncharacterized in the available corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reconstituted ubiquitination assay defining the gigaxonin ligase complex\", \"Substrate hierarchy and selectivity across MAP8, vimentin, GFAP, and neurofilaments not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]}\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}}