{"gene":"ANKRD33","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2009,"finding":"PANKY/ANKRD33 is a photoreceptor-specific ankyrin repeat protein that acts as a transcriptional cofactor suppressing CRX-activated photoreceptor genes; PANKY-A localizes to both nucleus and cytoplasm, its expression is directly upregulated by the CRX transcription factor, and it inhibits the DNA-binding activity of CRX as shown by electrophoretic mobility shift assay.","method":"Subcellular localization (microscopy), transactivation reporter assay, electrophoretic mobility shift assay (EMSA), expression/promoter analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (EMSA, transactivation assay, localization) in a single study from one lab","pmids":["20026326"],"is_preprint":false},{"year":2012,"finding":"Ankrd33 expression in retinal photoreceptors is downstream of NeuroD1 transcription factor; Ankrd33 mRNA is significantly down-regulated in NeuroD1 conditional knockout retinas, and the ANKRD33 protein product is selectively expressed in photoreceptor outer segments.","method":"Microarray analysis of NeuroD1 conditional knockout retinas (Cre/loxP); protein localization by selective expression pattern","journal":"Journal of neurochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-lab microarray finding with localization noted but no direct functional follow-up of ANKRD33 itself","pmids":["22784109"],"is_preprint":false}],"current_model":"ANKRD33 (PANKY) encodes a photoreceptor- and pineal gland-specific ankyrin repeat protein that localizes to the nucleus and cytoplasm, is transcriptionally activated by the CRX homeodomain factor, and functions as a transcriptional co-repressor that suppresses CRX-driven photoreceptor gene expression by inhibiting CRX DNA-binding activity; its expression is also dependent on the bHLH factor NeuroD1, and its protein product is found in photoreceptor outer segments."},"narrative":{"mechanistic_narrative":"ANKRD33 (PANKY) is a photoreceptor-specific ankyrin repeat protein that acts as a transcriptional cofactor in the retinal gene regulatory network [PMID:20026326]. Its expression is directly induced by the CRX homeodomain transcription factor, and ANKRD33 in turn suppresses CRX-activated photoreceptor genes by inhibiting CRX DNA-binding activity, as demonstrated by electrophoretic mobility shift assay, thereby forming a negative-feedback loop on CRX-driven transcription [PMID:20026326]. The PANKY-A isoform localizes to both the nucleus and the cytoplasm, consistent with a role bridging transcriptional regulation and a cytoplasmic function [PMID:20026326]. Beyond this CRX feedback role, the mechanistic detail of ANKRD33 has not been characterized in the available corpus.","teleology":[{"year":2009,"claim":"Established that ANKRD33/PANKY is not merely a photoreceptor marker but an active transcriptional regulator embedded in the CRX network, answering whether it has a function in photoreceptor gene control.","evidence":"Subcellular localization microscopy, transactivation reporter assays, and EMSA in a photoreceptor expression context","pmids":["20026326"],"confidence":"Medium","gaps":["Mechanism by which ANKRD33 inhibits CRX DNA-binding (direct interaction vs. competition) not resolved","Functional significance of dual nuclear/cytoplasmic localization not defined","No in vivo loss-of-function phenotype reported"]},{"year":2012,"claim":"Placed Ankrd33 downstream of the bHLH factor NeuroD1, linking its expression to a second photoreceptor transcriptional input and localizing the protein to outer segments.","evidence":"Microarray of NeuroD1 conditional (Cre/loxP) knockout retinas plus protein localization by expression pattern","pmids":["22784109"],"confidence":"Low","gaps":["Single-lab microarray correlation without direct functional follow-up of ANKRD33","Whether NeuroD1 regulation is direct or indirect not established","Functional role of outer-segment localization not addressed"]},{"year":null,"claim":"How ANKRD33 mechanistically suppresses CRX activity and what role it plays in photoreceptor physiology in vivo remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural basis for CRX inhibition","No knockout phenotype for ANKRD33 itself","Cytoplasmic/outer-segment function uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[],"complexes":[],"partners":["CRX"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z3H0","full_name":"Photoreceptor ankyrin repeat protein","aliases":["Ankyrin repeat domain-containing protein 33"],"length_aa":452,"mass_kda":49.4,"function":"Acts as a transcriptional repressor for CRX-activated photoreceptor gene regulation","subcellular_location":"Cytoplasm, cytosol; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q7Z3H0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANKRD33","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ANKRD33","total_profiled":1310},"omim":[{"mim_id":"620857","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 33; ANKRD33","url":"https://www.omim.org/entry/620857"},{"mim_id":"620055","title":"PWP1 HOMOLOG, ENDONUCLEIN; PWP1","url":"https://www.omim.org/entry/620055"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"retina","ntpm":17.0}],"url":"https://www.proteinatlas.org/search/ANKRD33"},"hgnc":{"alias_symbol":["DKFZp686O1689","PANKY"],"prev_symbol":["C12orf7"]},"alphafold":{"accession":"Q7Z3H0","domains":[{"cath_id":"1.25.40.20","chopping":"97-196","consensus_level":"medium","plddt":84.8075,"start":97,"end":196},{"cath_id":"-","chopping":"203-251","consensus_level":"medium","plddt":74.7059,"start":203,"end":251},{"cath_id":"-","chopping":"254-265_303-326","consensus_level":"medium","plddt":81.6894,"start":254,"end":326}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z3H0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z3H0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z3H0-F1-predicted_aligned_error_v6.png","plddt_mean":60.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANKRD33","jax_strain_url":"https://www.jax.org/strain/search?query=ANKRD33"},"sequence":{"accession":"Q7Z3H0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z3H0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z3H0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z3H0"}},"corpus_meta":[{"pmid":"22784109","id":"PMC_22784109","title":"NeuroD1 is required for survival of photoreceptors but not pinealocytes: results from targeted gene deletion studies.","date":"2012","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22784109","citation_count":30,"is_preprint":false},{"pmid":"33859359","id":"PMC_33859359","title":"Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.","date":"2021","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/33859359","citation_count":21,"is_preprint":false},{"pmid":"30071075","id":"PMC_30071075","title":"A genome-wide association study of energy intake and expenditure.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30071075","citation_count":19,"is_preprint":false},{"pmid":"20026326","id":"PMC_20026326","title":"Panky, a novel photoreceptor-specific ankyrin repeat protein, is a transcriptional cofactor that suppresses CRX-regulated photoreceptor genes.","date":"2009","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/20026326","citation_count":16,"is_preprint":false},{"pmid":"31934309","id":"PMC_31934309","title":"Novel eye genes systematically discovered through an integrated analysis of mouse transcriptomes and phenome.","date":"2019","source":"Computational and structural biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/31934309","citation_count":14,"is_preprint":false},{"pmid":"38372747","id":"PMC_38372747","title":"Genome-wide DNA methylation analysis related to ALS patient progression and survival.","date":"2024","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/38372747","citation_count":12,"is_preprint":false},{"pmid":"18312453","id":"PMC_18312453","title":"Characterization of five novel large deletions causing hereditary haemorrhagic telangiectasia.","date":"2008","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18312453","citation_count":8,"is_preprint":false},{"pmid":"37606455","id":"PMC_37606455","title":"Excessive Gestational Weight Gain Alters DNA Methylation and Influences Foetal and Neonatal Body Composition.","date":"2023","source":"Epigenomes","url":"https://pubmed.ncbi.nlm.nih.gov/37606455","citation_count":4,"is_preprint":false},{"pmid":"37205010","id":"PMC_37205010","title":"The Underlying Mechanism Involved in Gefitinib Resistance and Corresponding Experiment Validation in Lung Cancer.","date":"2023","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/37205010","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6544,"output_tokens":612,"usd":0.014406,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6965,"output_tokens":1196,"usd":0.032363,"stage2_stop_reason":"end_turn"},"total_usd":0.046769,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"PANKY/ANKRD33 is a photoreceptor-specific ankyrin repeat protein that acts as a transcriptional cofactor suppressing CRX-activated photoreceptor genes; PANKY-A localizes to both nucleus and cytoplasm, its expression is directly upregulated by the CRX transcription factor, and it inhibits the DNA-binding activity of CRX as shown by electrophoretic mobility shift assay.\",\n      \"method\": \"Subcellular localization (microscopy), transactivation reporter assay, electrophoretic mobility shift assay (EMSA), expression/promoter analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (EMSA, transactivation assay, localization) in a single study from one lab\",\n      \"pmids\": [\"20026326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Ankrd33 expression in retinal photoreceptors is downstream of NeuroD1 transcription factor; Ankrd33 mRNA is significantly down-regulated in NeuroD1 conditional knockout retinas, and the ANKRD33 protein product is selectively expressed in photoreceptor outer segments.\",\n      \"method\": \"Microarray analysis of NeuroD1 conditional knockout retinas (Cre/loxP); protein localization by selective expression pattern\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-lab microarray finding with localization noted but no direct functional follow-up of ANKRD33 itself\",\n      \"pmids\": [\"22784109\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANKRD33 (PANKY) encodes a photoreceptor- and pineal gland-specific ankyrin repeat protein that localizes to the nucleus and cytoplasm, is transcriptionally activated by the CRX homeodomain factor, and functions as a transcriptional co-repressor that suppresses CRX-driven photoreceptor gene expression by inhibiting CRX DNA-binding activity; its expression is also dependent on the bHLH factor NeuroD1, and its protein product is found in photoreceptor outer segments.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANKRD33 (PANKY) is a photoreceptor-specific ankyrin repeat protein that acts as a transcriptional cofactor in the retinal gene regulatory network [#0]. Its expression is directly induced by the CRX homeodomain transcription factor, and ANKRD33 in turn suppresses CRX-activated photoreceptor genes by inhibiting CRX DNA-binding activity, as demonstrated by electrophoretic mobility shift assay, thereby forming a negative-feedback loop on CRX-driven transcription [#0]. The PANKY-A isoform localizes to both the nucleus and the cytoplasm, consistent with a role bridging transcriptional regulation and a cytoplasmic function [#0]. Beyond this CRX feedback role, the mechanistic detail of ANKRD33 has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that ANKRD33/PANKY is not merely a photoreceptor marker but an active transcriptional regulator embedded in the CRX network, answering whether it has a function in photoreceptor gene control.\",\n      \"evidence\": \"Subcellular localization microscopy, transactivation reporter assays, and EMSA in a photoreceptor expression context\",\n      \"pmids\": [\"20026326\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which ANKRD33 inhibits CRX DNA-binding (direct interaction vs. competition) not resolved\",\n        \"Functional significance of dual nuclear/cytoplasmic localization not defined\",\n        \"No in vivo loss-of-function phenotype reported\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed Ankrd33 downstream of the bHLH factor NeuroD1, linking its expression to a second photoreceptor transcriptional input and localizing the protein to outer segments.\",\n      \"evidence\": \"Microarray of NeuroD1 conditional (Cre/loxP) knockout retinas plus protein localization by expression pattern\",\n      \"pmids\": [\"22784109\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single-lab microarray correlation without direct functional follow-up of ANKRD33\",\n        \"Whether NeuroD1 regulation is direct or indirect not established\",\n        \"Functional role of outer-segment localization not addressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ANKRD33 mechanistically suppresses CRX activity and what role it plays in photoreceptor physiology in vivo remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural basis for CRX inhibition\",\n        \"No knockout phenotype for ANKRD33 itself\",\n        \"Cytoplasmic/outer-segment function uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"CRX\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}