{"gene":"C12ORF57","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":2013,"finding":"C12orf57 encodes a highly conserved 126 amino acid protein with no significant paralogs that is ubiquitously expressed; homozygous truncating mutations at the initiator methionine codon (c.1A>G) cause autosomal recessive corpus callosum hypoplasia, establishing that C12orf57 is required for corpus callosum development in humans.","method":"Whole-exome sequencing, autozygome analysis, Sanger confirmation in four independent consanguineous families; protein conservation analysis","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — clean loss-of-function (truncating mutations) with defined developmental phenotype across four families, but no biochemical mechanism identified","pmids":["23453666"],"is_preprint":false},{"year":2013,"finding":"C12orf57 is expressed in multiple mouse tissues including the eye and brain; homozygous truncating and compound heterozygous missense mutations in C12orf57 cause a syndromic autosomal recessive condition comprising colobomatous microphthalmia, global developmental delay, intractable seizures, and corpus callosum abnormalities, implicating C12orf57 in eye and brain development.","method":"Autozygome analysis, exome sequencing, Sanger validation, mouse tissue expression analysis","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with specific developmental phenotype; expression data supports tissue-relevant role, but molecular mechanism unknown","pmids":["23453665"],"is_preprint":false},{"year":2014,"finding":"Compound heterozygous loss-of-function mutations in C12orf57 (including a novel nonsense mutation) cause severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures, confirming C12orf57 as a recessive disease gene for this syndromic neurodevelopmental disorder.","method":"Exome sequencing, Sanger confirmation, clinical phenotyping","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 — independent replication of loss-of-function phenotype in non-consanguineous siblings, but no new mechanistic insight beyond genetic requirement","pmids":["24798461"],"is_preprint":false}],"current_model":"C12orf57 encodes a highly conserved, ubiquitously expressed 126 amino acid protein of unknown biochemical function that is required for normal human brain development, particularly corpus callosum formation, and for eye development; loss-of-function mutations cause an autosomal recessive syndrome characterized by corpus callosum hypoplasia/agenesis, colobomatous microphthalmia, intellectual disability, and intractable seizures, but no direct enzymatic activity, binding partners, or molecular mechanism have been established."},"narrative":{"teleology":[{"year":2013,"claim":"Two simultaneous studies established C12orf57 as a novel disease gene: homozygous and compound heterozygous loss-of-function mutations were shown to cause autosomal recessive corpus callosum abnormalities, colobomatous microphthalmia, seizures, and intellectual disability, revealing that this previously uncharacterized, highly conserved protein is essential for brain and eye development.","evidence":"Whole-exome sequencing and autozygome analysis in multiple consanguineous and non-consanguineous families, Sanger validation, mouse tissue expression profiling","pmids":["23453666","23453665"],"confidence":"Medium","gaps":["No biochemical activity, subcellular localization, or binding partners identified","Animal models with targeted C12orf57 disruption have not been generated","Mechanism by which loss of C12orf57 leads to corpus callosum agenesis and coloboma is unknown"]},{"year":2014,"claim":"Independent replication in a non-consanguineous family confirmed C12orf57 as the causative gene for this syndromic neurodevelopmental disorder, strengthening genotype–phenotype correlation but providing no new molecular insight.","evidence":"Exome sequencing and Sanger confirmation of compound heterozygous loss-of-function mutations with detailed clinical phenotyping","pmids":["24798461"],"confidence":"Medium","gaps":["No functional assays or cellular studies performed","Protein structure and interaction network remain entirely unknown","Whether the protein acts cell-autonomously in neural or ocular progenitors is untested"]},{"year":null,"claim":"The molecular function of C12orf57 remains completely uncharacterized: no enzymatic activity, subcellular localization, signaling pathway involvement, or direct physical interactors have been experimentally determined.","evidence":"","pmids":[],"confidence":"High","gaps":["No biochemical or structural characterization of the protein","No animal knockout or knockdown model with mechanistic analysis","Downstream pathways disrupted by C12orf57 loss are unknown"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,2]}],"complexes":[],"partners":[],"other_free_text":[]},"mechanistic_narrative":"C12orf57 encodes a highly conserved 126-amino-acid protein with no known paralogs that is ubiquitously expressed, including in the brain and eye, and is required for normal corpus callosum formation and ocular development [PMID:23453666, PMID:23453665]. Homozygous or compound heterozygous loss-of-function mutations in C12orf57 cause an autosomal recessive syndrome characterized by corpus callosum hypoplasia or agenesis, colobomatous microphthalmia, intellectual disability, and intractable seizures [PMID:23453666, PMID:23453665, PMID:24798461]. No enzymatic activity, binding partners, or molecular mechanism have been identified for the encoded protein."},"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":168,"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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Theoretical and applied genetics. Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/36216960","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},{"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48180,"output_tokens":1194,"usd":0.081225},"stage2":{"model":"claude-opus-4-6","input_tokens":3991,"output_tokens":889,"usd":0.06327},"total_usd":0.144495,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the 100 abstracts, I need to identify those relevant to the human gene C12ORF57 (also called C12orf57). \n\nFrom the corpus, papers [28], [38], [82], and [97] mention C12orf57 directly. Let me analyze these:\n\n- [28] (PMID:23453665): Mutations in C12orf57 cause syndromic colobomatous microphthalmia; shows expression in mouse eye and brain tissues.\n- [38] (PMID:23453666): C12orf57 mutations at initiator methionine codon cause corpus callosum hypoplasia; describes a 126 aa protein conserved across evolution with no significant paralogs.\n- [82] (PMID:24798461): Compound heterozygous loss-of-function mutations in C12orf57 cause intellectual disability, corpus callosum hypoplasia, chorioretinal coloboma, and seizures.\n- [97] discusses cotton fiber gene qFL-c10-1/GhFL10 — this is a plant gene collision, skip.\n\nThe other papers are clearly about different genes/molecules (C10 chemokines, alpha2-C10 adrenergic receptor, artemisinin C10 chemistry, etc.) — all symbol collisions or irrelevant.\n\nThe mechanistic findings from [28], [38], and [82] are largely genetic/clinical with limited direct mechanistic experiments. Paper [38] notes the protein is 126 aa, conserved, no paralogs, ubiquitously expressed — established by sequencing/expression analysis. Paper [28] shows expression in mouse tissues by expression studies.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"C12orf57 encodes a highly conserved 126 amino acid protein with no significant paralogs that is ubiquitously expressed; homozygous truncating mutations at the initiator methionine codon (c.1A>G) cause autosomal recessive corpus callosum hypoplasia, establishing that C12orf57 is required for corpus callosum development in humans.\",\n      \"method\": \"Whole-exome sequencing, autozygome analysis, Sanger confirmation in four independent consanguineous families; protein conservation analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function (truncating mutations) with defined developmental phenotype across four families, but no biochemical mechanism identified\",\n      \"pmids\": [\"23453666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"C12orf57 is expressed in multiple mouse tissues including the eye and brain; homozygous truncating and compound heterozygous missense mutations in C12orf57 cause a syndromic autosomal recessive condition comprising colobomatous microphthalmia, global developmental delay, intractable seizures, and corpus callosum abnormalities, implicating C12orf57 in eye and brain development.\",\n      \"method\": \"Autozygome analysis, exome sequencing, Sanger validation, mouse tissue expression analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific developmental phenotype; expression data supports tissue-relevant role, but molecular mechanism unknown\",\n      \"pmids\": [\"23453665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Compound heterozygous loss-of-function mutations in C12orf57 (including a novel nonsense mutation) cause severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures, confirming C12orf57 as a recessive disease gene for this syndromic neurodevelopmental disorder.\",\n      \"method\": \"Exome sequencing, Sanger confirmation, clinical phenotyping\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — independent replication of loss-of-function phenotype in non-consanguineous siblings, but no new mechanistic insight beyond genetic requirement\",\n      \"pmids\": [\"24798461\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C12orf57 encodes a highly conserved, ubiquitously expressed 126 amino acid protein of unknown biochemical function that is required for normal human brain development, particularly corpus callosum formation, and for eye development; loss-of-function mutations cause an autosomal recessive syndrome characterized by corpus callosum hypoplasia/agenesis, colobomatous microphthalmia, intellectual disability, and intractable seizures, but no direct enzymatic activity, binding partners, or molecular mechanism have been established.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"C12orf57 encodes a highly conserved 126-amino-acid protein with no known paralogs that is ubiquitously expressed, including in the brain and eye, and is required for normal corpus callosum formation and ocular development [PMID:23453666, PMID:23453665]. Homozygous or compound heterozygous loss-of-function mutations in C12orf57 cause an autosomal recessive syndrome characterized by corpus callosum hypoplasia or agenesis, colobomatous microphthalmia, intellectual disability, and intractable seizures [PMID:23453666, PMID:23453665, PMID:24798461]. No enzymatic activity, binding partners, or molecular mechanism have been identified for the encoded protein.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Two simultaneous studies established C12orf57 as a novel disease gene: homozygous and compound heterozygous loss-of-function mutations were shown to cause autosomal recessive corpus callosum abnormalities, colobomatous microphthalmia, seizures, and intellectual disability, revealing that this previously uncharacterized, highly conserved protein is essential for brain and eye development.\",\n      \"evidence\": \"Whole-exome sequencing and autozygome analysis in multiple consanguineous and non-consanguineous families, Sanger validation, mouse tissue expression profiling\",\n      \"pmids\": [\"23453666\", \"23453665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No biochemical activity, subcellular localization, or binding partners identified\",\n        \"Animal models with targeted C12orf57 disruption have not been generated\",\n        \"Mechanism by which loss of C12orf57 leads to corpus callosum agenesis and coloboma is unknown\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Independent replication in a non-consanguineous family confirmed C12orf57 as the causative gene for this syndromic neurodevelopmental disorder, strengthening genotype–phenotype correlation but providing no new molecular insight.\",\n      \"evidence\": \"Exome sequencing and Sanger confirmation of compound heterozygous loss-of-function mutations with detailed clinical phenotyping\",\n      \"pmids\": [\"24798461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional assays or cellular studies performed\",\n        \"Protein structure and interaction network remain entirely unknown\",\n        \"Whether the protein acts cell-autonomously in neural or ocular progenitors is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular function of C12orf57 remains completely uncharacterized: no enzymatic activity, subcellular localization, signaling pathway involvement, or direct physical interactors have been experimentally determined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No biochemical or structural characterization of the protein\",\n        \"No animal knockout or knockdown model with mechanistic analysis\",\n        \"Downstream pathways disrupted by C12orf57 loss are unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1266738\",\n        \"supporting_discovery_ids\": [0, 1, 2]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```"}