{"gene":"C12ORF57","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2013,"finding":"C12orf57 is expressed in multiple mouse tissues including the eye and brain, as shown by expression analysis in a disease-linked study; homozygous truncating mutations (c.1A>G; p.Met1?) and compound heterozygous missense mutations (c.152T>A; p.Leu51Gln) in C12orf57 cause a syndromic autosomal-recessive form of colobomatous microphthalmia with global developmental delay, intractable seizures, and corpus callosum abnormalities, implicating C12orf57 as required for eye and brain development.","method":"Autozygome analysis, exome sequencing, tissue expression analysis in mouse","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic loss-of-function (truncating and missense mutations) with defined developmental phenotype across two independent families; no biochemical mechanism established","pmids":["23453665"],"is_preprint":false},{"year":2013,"finding":"C12orf57 encodes a ubiquitously expressed, evolutionarily conserved 126 amino acid protein with no significant paralogs; homozygous mutations at the initiator methionine codon (loss-of-function) cause autosomal-recessive corpus callosum hypoplasia (CCH) in four independent consanguineous families, establishing that C12orf57 is required for corpus callosum development.","method":"Whole-exome sequencing in multiple consanguineous families, Sanger confirmation, expression analysis","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — replicated loss-of-function findings across four independent families, single method (genetic), no in vitro/biochemical mechanistic data","pmids":["23453666"],"is_preprint":false},{"year":2014,"finding":"Compound heterozygous loss-of-function mutations in C12orf57 (identified by exome sequencing) cause severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures, further confirming that C12orf57 is required for both brain commissure development and ocular development.","method":"Exome sequencing, Sanger validation, clinical phenotyping of two siblings from non-consanguineous parents","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — replication of loss-of-function phenotype across independent family with novel mutation, genetic method only, no biochemical mechanism","pmids":["24798461"],"is_preprint":false}],"current_model":"C12ORF57 encodes a small (~126 amino acid), ubiquitously expressed, evolutionarily conserved protein of unknown biochemical function that is required for corpus callosum development and eye morphogenesis in humans, as demonstrated by the finding that homozygous or compound heterozygous loss-of-function mutations cause an autosomal-recessive syndrome of corpus callosum hypoplasia/agenesis, chorioretinal coloboma, intellectual disability, and intractable seizures; no enzymatic activity, binding partners, or molecular pathway placement have been established."},"narrative":{"mechanistic_narrative":"C12ORF57 encodes a small (~126 amino acid), ubiquitously expressed, evolutionarily conserved protein with no significant paralogs that is required for corpus callosum development and ocular morphogenesis in humans [PMID:23453666]. Biallelic loss-of-function mutations — including truncating changes at the initiator methionine and compound heterozygous missense/loss-of-function alleles — cause an autosomal-recessive syndrome comprising corpus callosum hypoplasia or agenesis, colobomatous microphthalmia/chorioretinal coloboma, intellectual disability, and intractable seizures across multiple independent families [PMID:23453665, PMID:23453666, PMID:24798461]. Consistent with this developmental role, the gene is expressed in mouse brain and eye tissue [PMID:23453665]. No enzymatic activity, binding partners, subcellular localization, or molecular pathway placement has been established in the available corpus.","teleology":[{"year":2013,"claim":"Establishing whether C12orf57 has any role in human development, this work tied biallelic mutations to a defined syndrome, implicating the gene in eye and brain morphogenesis.","evidence":"Autozygome analysis and exome sequencing in disease families with mouse tissue expression analysis","pmids":["23453665"],"confidence":"Medium","gaps":["No biochemical function or molecular pathway identified","Causality demonstrated genetically but not by rescue or animal model","Protein localization unknown"]},{"year":2013,"claim":"Replication across four independent consanguineous families with initiator-methionine loss-of-function mutations confirmed that C12orf57 is specifically required for corpus callosum development and characterized the protein as a conserved 126-aa product with no paralogs.","evidence":"Whole-exome sequencing, Sanger confirmation, and expression analysis in multiple families","pmids":["23453666"],"confidence":"Medium","gaps":["No in vitro or biochemical mechanistic data","Single (genetic) method","No structural or functional domain assignment"]},{"year":2014,"claim":"An independent non-consanguineous family with compound heterozygous loss-of-function alleles extended the phenotypic spectrum, confirming requirement for both brain commissure and ocular development.","evidence":"Exome sequencing, Sanger validation, and clinical phenotyping of two affected siblings","pmids":["24798461"],"confidence":"Medium","gaps":["Mechanism linking loss-of-function to phenotype unresolved","No interacting partners or substrates defined","No cellular assay of mutant protein"]},{"year":null,"claim":"The biochemical activity, subcellular localization, binding partners, and molecular pathway through which C12ORF57 controls corpus callosum and eye development remain entirely undefined.","evidence":"No mechanistic study present in the available corpus","pmids":[],"confidence":"Low","gaps":["No enzymatic or molecular activity assigned","No physical interactors identified","No pathway placement"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99622","full_name":"Protein C10","aliases":[],"length_aa":126,"mass_kda":13.2,"function":"In brain, may be required for corpus callosum development","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q99622/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C12ORF57"},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000111678","cell_line_id":"CID001866","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"membrane","grade":2}],"interactors":[{"gene":"VPS35","stoichiometry":4.0},{"gene":"AGAP3","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001866","total_profiled":1310},"omim":[{"mim_id":"615140","title":"CHROMOSOME 12 OPEN READING FRAME 57; C12ORF57","url":"https://www.omim.org/entry/615140"},{"mim_id":"218340","title":"TEMTAMY SYNDROME; TEMTYS","url":"https://www.omim.org/entry/218340"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear speckles","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/C12ORF57"},"hgnc":{"alias_symbol":["GRCC10","C10"],"prev_symbol":[]},"alphafold":{"accession":"Q99622","domains":[{"cath_id":"-","chopping":"12-104","consensus_level":"high","plddt":90.0063,"start":12,"end":104}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99622","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99622-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99622-F1-predicted_aligned_error_v6.png","plddt_mean":80.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C12ORF57","jax_strain_url":"https://www.jax.org/strain/search?query=C12ORF57"},"sequence":{"accession":"Q99622","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99622.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99622/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99622"}},"corpus_meta":[{"pmid":"12356575","id":"PMC_12356575","title":"Interaction of IL-13 and C10 in the pathogenesis of bleomycin-induced pulmonary fibrosis.","date":"2002","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12356575","citation_count":169,"is_preprint":false},{"pmid":"1353249","id":"PMC_1353249","title":"Cloning of two mouse genes encoding alpha 2-adrenergic receptor subtypes and identification of a single amino acid in the mouse alpha 2-C10 homolog responsible for an interspecies variation in antagonist binding.","date":"1992","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/1353249","citation_count":159,"is_preprint":false},{"pmid":"18768927","id":"PMC_18768927","title":"Proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma alter tight junction structure and function in the rat parotid gland Par-C10 cell line.","date":"2008","source":"American journal of physiology. 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/24798461","citation_count":11,"is_preprint":false},{"pmid":"25590860","id":"PMC_25590860","title":"Molecular details of INH-C10 binding to wt KatG and Its S315T mutant.","date":"2015","source":"Molecular pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/25590860","citation_count":11,"is_preprint":false},{"pmid":"14688","id":"PMC_14688","title":"The effect of monovalent and divalent cations on the activity of Streptococcus lactis C10 pyruvate kinase.","date":"1977","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/14688","citation_count":11,"is_preprint":false},{"pmid":"24852122","id":"PMC_24852122","title":"Biotin-c10-AppCH2ppA is an effective new chemical proteomics probe for diadenosine polyphosphate binding proteins.","date":"2014","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/24852122","citation_count":11,"is_preprint":false},{"pmid":"20416045","id":"PMC_20416045","title":"The dissemination of C10 cysteine protease genes in Bacteroides fragilis by mobile genetic elements.","date":"2010","source":"BMC microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20416045","citation_count":11,"is_preprint":false},{"pmid":"30150830","id":"PMC_30150830","title":"Antifungal activity of Lactobacillus plantarum C10 against Trichothecium roseum and its application in promotion of defense responses in muskmelon (Cucumis melo L.) fruit.","date":"2018","source":"Journal of food science and technology","url":"https://pubmed.ncbi.nlm.nih.gov/30150830","citation_count":11,"is_preprint":false},{"pmid":"16516375","id":"PMC_16516375","title":"Characterization of a clonal isolate of an oxaliplatin resistant ovarian carcinoma cell line A2780/C10.","date":"2006","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/16516375","citation_count":11,"is_preprint":false},{"pmid":"19962997","id":"PMC_19962997","title":"Pharmacological activity of C10-substituted analogs of the high-affinity kainate receptor agonist dysiherbaine.","date":"2009","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/19962997","citation_count":11,"is_preprint":false},{"pmid":"31577203","id":"PMC_31577203","title":"Characterizations and Fibrinolytic Activity of Serine Protease from Bacillus subtilis C10.","date":"2020","source":"Current pharmaceutical biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/31577203","citation_count":10,"is_preprint":false},{"pmid":"14761943","id":"PMC_14761943","title":"The binding of C10 oligomers to Escherichia coli transcription termination factor Rho.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14761943","citation_count":10,"is_preprint":false},{"pmid":"16086586","id":"PMC_16086586","title":"Aromatase reaction of 3-deoxyandrogens: steric mode of the C-19 oxygenation and cleavage of the C10-C19 bond by human placental aromatase.","date":"2005","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16086586","citation_count":10,"is_preprint":false},{"pmid":"7915279","id":"PMC_7915279","title":"Site-specific enzymatic hydrolysis of taxanes at C-10 and C-13.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7915279","citation_count":10,"is_preprint":false},{"pmid":"9145228","id":"PMC_9145228","title":"The enhancing mechanism of capric acid (C10) from a suppository on rectal drug absorption through a paracellular pathway.","date":"1997","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/9145228","citation_count":10,"is_preprint":false},{"pmid":"3000521","id":"PMC_3000521","title":"Irreversible autonomic actions by lophotoxin suggest utility as a probe for both C6 and C10 nicotinic receptors.","date":"1985","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/3000521","citation_count":10,"is_preprint":false},{"pmid":"21413759","id":"PMC_21413759","title":"Stereoselective total synthesis of (+)-oploxyne A, (-)-oploxyne B, and their C-10 epimers and structure revision of natural oploxyne B.","date":"2011","source":"The Journal of organic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21413759","citation_count":10,"is_preprint":false},{"pmid":"36216960","id":"PMC_36216960","title":"Fine-mapping and candidate gene analysis of qFL-c10-1 controlling fiber length in upland cotton (Gossypium hirsutum L.).","date":"2022","source":"TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/36216960","citation_count":9,"is_preprint":false},{"pmid":"22559742","id":"PMC_22559742","title":"Ectopic ERK expression induces phenotypic conversion of C10 cells and alters DNA methyltransferase expression.","date":"2012","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/22559742","citation_count":9,"is_preprint":false},{"pmid":"34175717","id":"PMC_34175717","title":"Structure-activity relationship study of dihydroartemisinin C-10 hemiacetal derivatives as Toll-like receptor 4 antagonists.","date":"2021","source":"Bioorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34175717","citation_count":9,"is_preprint":false},{"pmid":"2296022","id":"PMC_2296022","title":"Alkylation of DNA by C-10 of 2,7-diaminomitosene.","date":"1990","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2296022","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48945,"output_tokens":1184,"usd":0.082297,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7341,"output_tokens":1197,"usd":0.033315,"stage2_stop_reason":"end_turn"},"total_usd":0.115612,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the 100 papers, I need to identify which ones are about C12ORF57 (also known as GRCC10 or C10 in the context of this human gene).\n\nAfter careful review:\n- Papers [1], [4], [9], [15], [17], [31], [33], [37], [45], [46], [49], [63], [78] are about the murine CC chemokine C10 (CCL6) — a different protein/gene, not C12ORF57.\n- Papers [2], [6], [7], [25], [40], [71], [81] are about the alpha2-C10 adrenergic receptor — a different gene.\n- Papers [28], [38], [82] are directly about C12ORF57 (the human gene).\n- Paper [84] is about Streptococcus lactis C10 pyruvate kinase — unrelated.\n- All other papers describe chemical compounds, other organisms' genes, or unrelated proteins with \"C10\" in their names.\n\nOnly papers [28], [38], and [82] describe the canonical C12ORF57 gene. These are the genetic disease papers identifying mutations but with limited mechanistic content. Let me extract what mechanistic findings exist.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"C12orf57 is expressed in multiple mouse tissues including the eye and brain, as shown by expression analysis in a disease-linked study; homozygous truncating mutations (c.1A>G; p.Met1?) and compound heterozygous missense mutations (c.152T>A; p.Leu51Gln) in C12orf57 cause a syndromic autosomal-recessive form of colobomatous microphthalmia with global developmental delay, intractable seizures, and corpus callosum abnormalities, implicating C12orf57 as required for eye and brain development.\",\n      \"method\": \"Autozygome analysis, exome sequencing, tissue expression analysis in mouse\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic loss-of-function (truncating and missense mutations) with defined developmental phenotype across two independent families; no biochemical mechanism established\",\n      \"pmids\": [\"23453665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"C12orf57 encodes a ubiquitously expressed, evolutionarily conserved 126 amino acid protein with no significant paralogs; homozygous mutations at the initiator methionine codon (loss-of-function) cause autosomal-recessive corpus callosum hypoplasia (CCH) in four independent consanguineous families, establishing that C12orf57 is required for corpus callosum development.\",\n      \"method\": \"Whole-exome sequencing in multiple consanguineous families, Sanger confirmation, expression analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — replicated loss-of-function findings across four independent families, single method (genetic), no in vitro/biochemical mechanistic data\",\n      \"pmids\": [\"23453666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Compound heterozygous loss-of-function mutations in C12orf57 (identified by exome sequencing) cause severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures, further confirming that C12orf57 is required for both brain commissure development and ocular development.\",\n      \"method\": \"Exome sequencing, Sanger validation, clinical phenotyping of two siblings from non-consanguineous parents\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — replication of loss-of-function phenotype across independent family with novel mutation, genetic method only, no biochemical mechanism\",\n      \"pmids\": [\"24798461\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C12ORF57 encodes a small (~126 amino acid), ubiquitously expressed, evolutionarily conserved protein of unknown biochemical function that is required for corpus callosum development and eye morphogenesis in humans, as demonstrated by the finding that homozygous or compound heterozygous loss-of-function mutations cause an autosomal-recessive syndrome of corpus callosum hypoplasia/agenesis, chorioretinal coloboma, intellectual disability, and intractable seizures; no enzymatic activity, binding partners, or molecular pathway placement have been established.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"C12ORF57 encodes a small (~126 amino acid), ubiquitously expressed, evolutionarily conserved protein with no significant paralogs that is required for corpus callosum development and ocular morphogenesis in humans [#1]. Biallelic loss-of-function mutations — including truncating changes at the initiator methionine and compound heterozygous missense/loss-of-function alleles — cause an autosomal-recessive syndrome comprising corpus callosum hypoplasia or agenesis, colobomatous microphthalmia/chorioretinal coloboma, intellectual disability, and intractable seizures across multiple independent families [#0, #1, #2]. Consistent with this developmental role, the gene is expressed in mouse brain and eye tissue [#0]. No enzymatic activity, binding partners, subcellular localization, or molecular pathway placement has been established in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing whether C12orf57 has any role in human development, this work tied biallelic mutations to a defined syndrome, implicating the gene in eye and brain morphogenesis.\",\n      \"evidence\": \"Autozygome analysis and exome sequencing in disease families with mouse tissue expression analysis\",\n      \"pmids\": [\"23453665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical function or molecular pathway identified\", \"Causality demonstrated genetically but not by rescue or animal model\", \"Protein localization unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Replication across four independent consanguineous families with initiator-methionine loss-of-function mutations confirmed that C12orf57 is specifically required for corpus callosum development and characterized the protein as a conserved 126-aa product with no paralogs.\",\n      \"evidence\": \"Whole-exome sequencing, Sanger confirmation, and expression analysis in multiple families\",\n      \"pmids\": [\"23453666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro or biochemical mechanistic data\", \"Single (genetic) method\", \"No structural or functional domain assignment\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"An independent non-consanguineous family with compound heterozygous loss-of-function alleles extended the phenotypic spectrum, confirming requirement for both brain commissure and ocular development.\",\n      \"evidence\": \"Exome sequencing, Sanger validation, and clinical phenotyping of two affected siblings\",\n      \"pmids\": [\"24798461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking loss-of-function to phenotype unresolved\", \"No interacting partners or substrates defined\", \"No cellular assay of mutant protein\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical activity, subcellular localization, binding partners, and molecular pathway through which C12ORF57 controls corpus callosum and eye development remain entirely undefined.\",\n      \"evidence\": \"No mechanistic study present in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No enzymatic or molecular activity assigned\", \"No physical interactors identified\", \"No pathway placement\"]\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":{"faith_supported":3,"faith_total":3,"faith_pct":100.0}}