{"gene":"EBP","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2000,"finding":"Mutations in the EBP gene (encoding emopamil-binding protein, a sterol delta8-delta7 isomerase) cause X-linked dominant chondrodysplasia punctata type 2 (CDPX2). Five novel mutations were identified (three nonsense and two frameshift), establishing that loss-of-function of EBP's isomerase activity underlies CDPX2. Gonadal and somatic mosaicism were demonstrated in affected families.","method":"PCR, conformation-sensitive gel electrophoresis, direct sequencing, restriction enzyme analysis of EBP gene in seven independent families","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct mutation analysis with molecular confirmation across multiple independent families, replicated across multiple labs (also PMID:11038443, 17949453)","pmids":["10942423"],"is_preprint":false},{"year":2000,"finding":"EBP encodes a sterol delta8-delta7 isomerase; nonsense mutations in EBP produce truncated proteins and result in abnormal sterol profiles (accumulation of dehydrocholesterol and 8(9)-cholestenol), consistent with loss of delta8-delta7 isomerase enzymatic activity. Missense mutations show variable phenotypic severity, suggesting genotype-phenotype correlation for protein-truncating versus missense variants.","method":"EBP gene sequencing in 8 Japanese CDP individuals; sterol profile analysis confirming enzymatic defect","journal":"American journal of medical genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical sterol profiling directly confirming enzymatic defect, combined with mutation analysis, replicated across independent cohorts","pmids":["11038443"],"is_preprint":false},{"year":2003,"finding":"A male patient with clinical CDPX2 features was found to be mosaic for a sterol-delta8-delta7 isomerase (EBP) gene mutation, demonstrating that single-gene somatic mosaicism for EBP mutations is sufficient to cause the CDPX2 phenotype in males.","method":"Biochemical sterol analysis and molecular mutation analysis confirming EBP mosaicism in a male patient","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single case with biochemical and molecular confirmation, single lab","pmids":["12503102"],"is_preprint":false},{"year":2003,"finding":"EBP (emopamil-binding protein) has sterol delta8-delta7 isomerase (EC 5.3.3.5) and sigma-ligand-binding activities. A paralogous protein EBPL (EBP-like) shares 31% identity/52% similarity with EBP but lacks both isomerase and sigma-ligand-binding activities when expressed in yeast. Replacement of the single divergent residue (EBP Y111W) reduced EBP catalytic activity, and transfer of this residue to EBPL (EBPL W91Y) or chimerization failed to restore activity, identifying Y111 as critical for EBP catalysis. EBP and EBPL can homodimerize.","method":"Heterologous expression of EBP and EBPL in yeast; sterol delta8-delta7 isomerase activity assays; sigma-ligand binding assays; site-directed mutagenesis (Y111W); chimeric protein construction; chemical cross-linking for homodimerization","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic activity assays with mutagenesis and chimeric protein analysis in a single rigorous study","pmids":["12760743"],"is_preprint":false},{"year":2007,"finding":"Two novel EBP mutations (3G>T and 419-422delTTCT) in CDPX2 patients were confirmed as pathogenic by demonstration of elevated serum dehydrocholesterol and 8(9)-cholestenol levels, directly linking these specific mutations to loss of EBP sterol isomerase function in vivo.","method":"EBP gene mutation analysis by sequencing; gas chromatography-mass spectroscopy of serum sterols; X-inactivation studies","journal":"The British journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — biochemical sterol profiling confirming enzymatic defect in vivo, single lab, small patient series","pmids":["17949453"],"is_preprint":false}],"current_model":"EBP (emopamil-binding protein) is an X-linked sterol delta8-delta7 isomerase (EC 5.3.3.5) that catalyzes a key step in cholesterol biosynthesis; loss-of-function mutations (nonsense, frameshift, or missense) abolish this enzymatic activity, causing accumulation of sterol intermediates (dehydrocholesterol, 8(9)-cholestenol) and resulting in X-linked dominant chondrodysplasia punctata type 2 (CDPX2), with catalytic activity dependent on residue Y111."},"narrative":{"mechanistic_narrative":"EBP (emopamil-binding protein) is an X-linked sterol delta8-delta7 isomerase (EC 5.3.3.5) that catalyzes a step in cholesterol biosynthesis, and its loss of function causes X-linked dominant chondrodysplasia punctata type 2 (CDPX2) [PMID:10942423, PMID:11038443]. Heterologous expression confirms that EBP possesses both sterol delta8-delta7 isomerase and sigma-ligand-binding activities, with residue Y111 being critical for catalysis: the Y111W substitution reduces activity, while transfer of this residue to the inactive paralog EBPL fails to confer isomerase function [PMID:12760743]. EBP can homodimerize [PMID:12760743]. Pathogenic nonsense, frameshift, and missense mutations abolish isomerase activity, producing characteristic accumulation of sterol intermediates—dehydrocholesterol and 8(9)-cholestenol—detectable in patient serum [PMID:11038443, PMID:17949453]; somatic and gonadal mosaicism for EBP mutations is sufficient to produce the CDPX2 phenotype, including in males [PMID:10942423, PMID:12503102]. Beyond the catalytic role of Y111 and the disease-associated sterol defect, no further structural or regulatory mechanism has been characterized in the available corpus.","teleology":[{"year":2000,"claim":"Established that EBP encodes a sterol delta8-delta7 isomerase whose loss of function is the genetic cause of CDPX2, defining the disease gene and its enzymatic basis.","evidence":"Mutation analysis (nonsense and frameshift variants) of the EBP gene across seven independent families, with demonstration of gonadal and somatic mosaicism","pmids":["10942423"],"confidence":"High","gaps":["Did not directly assay the enzymatic consequence of individual mutations in vitro","Genotype-phenotype mechanism for variable severity unresolved"]},{"year":2000,"claim":"Linked EBP truncating mutations to a biochemical sterol defect, confirming that the disease arises specifically from loss of delta8-delta7 isomerase activity.","evidence":"EBP sequencing in CDP patients combined with sterol profile analysis showing accumulation of dehydrocholesterol and 8(9)-cholestenol","pmids":["11038443"],"confidence":"High","gaps":["Did not establish structural basis of catalysis","Missense severity correlation not mechanistically explained"]},{"year":2003,"claim":"Showed that single-gene somatic mosaicism for an EBP mutation is sufficient to produce the CDPX2 phenotype even in males, clarifying how the X-linked dominant condition can manifest in hemizygous individuals.","evidence":"Biochemical sterol analysis and molecular mutation analysis in a single male patient","pmids":["12503102"],"confidence":"Medium","gaps":["Single case without independent replication","Extent of tissue mosaicism not quantified"]},{"year":2003,"claim":"Resolved the catalytic determinant of EBP by identifying residue Y111 as critical for isomerase activity and distinguishing EBP from its inactive paralog EBPL.","evidence":"Heterologous expression in yeast with isomerase and sigma-ligand binding assays, site-directed mutagenesis (Y111W), chimeric constructs, and cross-linking for homodimerization","pmids":["12760743"],"confidence":"High","gaps":["No high-resolution structure of the active site","Mechanism of sigma-ligand binding relative to catalysis unclear","Functional significance of homodimerization not defined"]},{"year":2007,"claim":"Validated additional patient mutations as pathogenic by demonstrating the in vivo sterol biochemical signature, reinforcing the enzymatic loss-of-function model.","evidence":"EBP sequencing, gas chromatography-mass spectroscopy of serum sterols, and X-inactivation studies in CDPX2 patients","pmids":["17949453"],"confidence":"Medium","gaps":["Small patient series from a single lab","No in vitro enzymatic assay of the new variants"]},{"year":null,"claim":"The structural basis of EBP catalysis and the physiological role of its sigma-ligand binding and homodimerization remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No atomic structure of EBP","Functional purpose of sigma-ligand binding within cholesterol biosynthesis unknown","Role of homodimerization in activity undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[1,3]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,3]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15125","full_name":"3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase","aliases":["Cholestenol Delta-isomerase","Cholesterol-5,6-epoxide hydrolase subunit EBP","Delta(8)-Delta(7) sterol isomerase","D8-D7 sterol isomerase","Emopamil-binding protein"],"length_aa":230,"mass_kda":26.4,"function":"Isomerase that catalyzes the conversion of Delta(8)-sterols to their corresponding Delta(7)-isomers a catalytic step in the postlanosterol biosynthesis of cholesterol Component of the microsomal antiestrogen binding site (AEBS), a multiproteic complex at the ER membrane that consists of an association between EBP and 7-dehydrocholesterol reductase/DHCR7 (PubMed:15175332, PubMed:20615952). This complex is responsible for cholesterol-5,6-epoxide hydrolase (ChEH) activity, which consists in the hydration of cholesterol-5,6-epoxides (5,6-EC) into cholestane-3beta,5alpha,6beta-triol (CT) (PubMed:20615952). The precise role of each component of this complex has not been described yet (PubMed:20615952)","subcellular_location":"Endoplasmic reticulum membrane; Nucleus envelope; Cytoplasmic vesicle","url":"https://www.uniprot.org/uniprotkb/Q15125/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EBP","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000147155","cell_line_id":"CID000289","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"er","grade":2}],"interactors":[{"gene":"DHCR24","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000289","total_profiled":1310},"omim":[{"mim_id":"621163","title":"ADIPOGENESIS REGULATORY FACTOR; ADIRF","url":"https://www.omim.org/entry/621163"},{"mim_id":"620787","title":"T-CELL ACTIVATION INHIBITOR, MITOCHONDRIAL; TCAIM","url":"https://www.omim.org/entry/620787"},{"mim_id":"620560","title":"CEBPA DIVERGENT TRANSCRIPT; CEBPA-DT","url":"https://www.omim.org/entry/620560"},{"mim_id":"619640","title":"LYSINE DEMETHYLASE 7A; KDM7A","url":"https://www.omim.org/entry/619640"},{"mim_id":"619246","title":"SPEXIN HORMONE; SPX","url":"https://www.omim.org/entry/619246"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear membrane","reliability":"Supported"},{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":307.1}],"url":"https://www.proteinatlas.org/search/EBP"},"hgnc":{"alias_symbol":["D8D7I","CPX","CPXD","CHO2"],"prev_symbol":["CDPX2"]},"alphafold":{"accession":"Q15125","domains":[{"cath_id":"-","chopping":"27-219","consensus_level":"high","plddt":97.9755,"start":27,"end":219}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15125","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15125-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15125-F1-predicted_aligned_error_v6.png","plddt_mean":95.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EBP","jax_strain_url":"https://www.jax.org/strain/search?query=EBP"},"sequence":{"accession":"Q15125","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15125.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15125/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15125"}},"corpus_meta":[{"pmid":"2850264","id":"PMC_2850264","title":"Isolation 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responses.","date":"2011","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/21810656","citation_count":49,"is_preprint":false},{"pmid":"26118414","id":"PMC_26118414","title":"Endogenous prostaglandin E2 potentiates anti-inflammatory phenotype of macrophage through the CREB-C/EBP-β cascade.","date":"2015","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26118414","citation_count":48,"is_preprint":false},{"pmid":"9796920","id":"PMC_9796920","title":"STAT6, NF-kappaB and C/EBP in CD23 expression and IgE production.","date":"1998","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9796920","citation_count":47,"is_preprint":false},{"pmid":"8680485","id":"PMC_8680485","title":"Control of adipocyte differentiation by CCAAT/enhancer binding protein alpha (C/EBP alpha).","date":"1996","source":"International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity","url":"https://pubmed.ncbi.nlm.nih.gov/8680485","citation_count":47,"is_preprint":false},{"pmid":"22815824","id":"PMC_22815824","title":"C/EBP homologous protein (CHOP) deficiency aggravates hippocampal cell apoptosis and impairs memory performance.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22815824","citation_count":45,"is_preprint":false},{"pmid":"12177065","id":"PMC_12177065","title":"C/EBP gamma has a stimulatory role on the IL-6 and IL-8 promoters.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12177065","citation_count":42,"is_preprint":false},{"pmid":"22776069","id":"PMC_22776069","title":"Inhibition of CD200R1 expression by C/EBP β in reactive microglial cells.","date":"2012","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/22776069","citation_count":42,"is_preprint":false},{"pmid":"25766403","id":"PMC_25766403","title":"The role of C/EBP-β LIP in multidrug resistance.","date":"2015","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/25766403","citation_count":42,"is_preprint":false},{"pmid":"31487963","id":"PMC_31487963","title":"Function and Transcriptional Regulation of Bovine TORC2 Gene in Adipocytes: Roles of C/EBP, XBP1, INSM1 and ZNF263.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31487963","citation_count":42,"is_preprint":false},{"pmid":"11596110","id":"PMC_11596110","title":"Retinoblastoma protein complexes with C/EBP proteins and activates C/EBP-mediated transcription.","date":"2001","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11596110","citation_count":41,"is_preprint":false},{"pmid":"28111277","id":"PMC_28111277","title":"C/EBP-Induced Transdifferentiation Reveals Granulocyte-Macrophage Precursor-like Plasticity of B Cells.","date":"2017","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28111277","citation_count":41,"is_preprint":false},{"pmid":"8440378","id":"PMC_8440378","title":"Differential adrenergic regulation of C/EBP alpha and C/EBP beta in brown adipose tissue.","date":"1993","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8440378","citation_count":41,"is_preprint":false},{"pmid":"24398327","id":"PMC_24398327","title":"miRNA-130a regulates C/EBP-ε expression during granulopoiesis.","date":"2014","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/24398327","citation_count":40,"is_preprint":false},{"pmid":"12855590","id":"PMC_12855590","title":"RUNX/AML and C/EBP factors regulate CD11a integrin expression in myeloid cells through overlapping regulatory elements.","date":"2003","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12855590","citation_count":40,"is_preprint":false},{"pmid":"12503102","id":"PMC_12503102","title":"X-linked dominant chondrodysplasia punctata (CDPX2) caused by single gene mosaicism in a male.","date":"2003","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/12503102","citation_count":39,"is_preprint":false},{"pmid":"12202226","id":"PMC_12202226","title":"Interaction between TGFbeta signaling proteins and C/EBP controls basal and Tat-mediated transcription of HIV-1 LTR in astrocytes.","date":"2002","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/12202226","citation_count":38,"is_preprint":false},{"pmid":"24797079","id":"PMC_24797079","title":"C/EBP transcription factors regulate NADPH oxidase in human aortic smooth muscle cells.","date":"2014","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24797079","citation_count":38,"is_preprint":false},{"pmid":"12970736","id":"PMC_12970736","title":"Regulation of Bcl-2 expression by C/EBP in t(14;18) lymphoma cells.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12970736","citation_count":37,"is_preprint":false},{"pmid":"11861297","id":"PMC_11861297","title":"Macrophage functional maturation and cytokine production are impaired in C/EBP epsilon-deficient mice.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11861297","citation_count":37,"is_preprint":false},{"pmid":"23881867","id":"PMC_23881867","title":"Reciprocal modulation of C/EBP-α and C/EBP-β by IL-13 in activated microglia prevents neuronal death.","date":"2013","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23881867","citation_count":36,"is_preprint":false},{"pmid":"19297554","id":"PMC_19297554","title":"C/EBP-beta modulates transcription of tubulointerstitial nephritis antigen in obstructive uropathy.","date":"2009","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/19297554","citation_count":36,"is_preprint":false},{"pmid":"31909714","id":"PMC_31909714","title":"Roles of C/EBP class bZip proteins in the growth and cell competition of Rp ('Minute') mutants in Drosophila.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31909714","citation_count":36,"is_preprint":false},{"pmid":"21543584","id":"PMC_21543584","title":"AP-1 protein induction during monopoiesis favors C/EBP: AP-1 heterodimers over C/EBP homodimerization and stimulates FosB transcription.","date":"2011","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/21543584","citation_count":36,"is_preprint":false},{"pmid":"15064728","id":"PMC_15064728","title":"Identification of murine and human XCP1 genes as C/EBP-epsilon-dependent members of FIZZ/Resistin gene family.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15064728","citation_count":35,"is_preprint":false},{"pmid":"23646198","id":"PMC_23646198","title":"Ablation of C/EBP homologous protein does not protect T17M RHO mice from retinal degeneration.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23646198","citation_count":35,"is_preprint":false},{"pmid":"15519652","id":"PMC_15519652","title":"Suppression of C/EBP alpha expression in biliary cell differentiation from hepatoblasts during mouse liver development.","date":"2004","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/15519652","citation_count":34,"is_preprint":false},{"pmid":"18166146","id":"PMC_18166146","title":"C/EBP homologous protein is crucial for the acceleration of experimental pancreatitis.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18166146","citation_count":33,"is_preprint":false},{"pmid":"16220546","id":"PMC_16220546","title":"C/EBP homologous protein is necessary for normal osteoblastic function.","date":"2006","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16220546","citation_count":33,"is_preprint":false},{"pmid":"1525039","id":"PMC_1525039","title":"Characterization and developmental expression of Xenopus C/EBP gene.","date":"1992","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/1525039","citation_count":32,"is_preprint":false},{"pmid":"8314590","id":"PMC_8314590","title":"The human C/EBP delta (CRP3/CELF) gene: structure and chromosomal localization.","date":"1993","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8314590","citation_count":32,"is_preprint":false},{"pmid":"12890646","id":"PMC_12890646","title":"Regulation of elastin gene transcription by interleukin-1 beta-induced C/EBP beta isoforms.","date":"2003","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12890646","citation_count":32,"is_preprint":false},{"pmid":"20829351","id":"PMC_20829351","title":"C/EBP{delta} and STAT-1 are required for TLR8 transcriptional activity.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20829351","citation_count":31,"is_preprint":false},{"pmid":"21238538","id":"PMC_21238538","title":"Progesterone induces expression of the prolactin receptor gene through cooperative action of Sp1 and C/EBP.","date":"2011","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/21238538","citation_count":31,"is_preprint":false},{"pmid":"29425932","id":"PMC_29425932","title":"Ablation of C/EBP homologous protein attenuates renal fibrosis after ureteral obstruction by reducing autophagy and microtubule disruption.","date":"2018","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/29425932","citation_count":31,"is_preprint":false},{"pmid":"22396222","id":"PMC_22396222","title":"Artemisinic acid is a regulator of adipocyte differentiation and C/EBP δ expression.","date":"2012","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22396222","citation_count":29,"is_preprint":false},{"pmid":"19465518","id":"PMC_19465518","title":"C/EBP{alpha} is required for pulmonary cytoprotection during hyperoxia.","date":"2009","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19465518","citation_count":29,"is_preprint":false},{"pmid":"8810039","id":"PMC_8810039","title":"Functional characterization of the repeated UASINO element in the promoters of the INO1 and CHO2 genes of yeast.","date":"1996","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/8810039","citation_count":28,"is_preprint":false},{"pmid":"9546609","id":"PMC_9546609","title":"Expression of C/EBP alpha, beta and delta in fetal and postnatal subcutaneous adipose tissue.","date":"1998","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9546609","citation_count":28,"is_preprint":false},{"pmid":"21308746","id":"PMC_21308746","title":"Role of C/EBP-β, p38 MAPK, and MKK6 in IL-1β-mediated C3 gene regulation in astrocytes.","date":"2011","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21308746","citation_count":27,"is_preprint":false},{"pmid":"29884649","id":"PMC_29884649","title":"Impaired DNA demethylation of C/EBP sites causes premature aging.","date":"2018","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/29884649","citation_count":26,"is_preprint":false},{"pmid":"18650268","id":"PMC_18650268","title":"Corticosteroids induce COX-2 expression in cardiomyocytes: role of glucocorticoid receptor and C/EBP-beta.","date":"2008","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18650268","citation_count":26,"is_preprint":false},{"pmid":"21600648","id":"PMC_21600648","title":"C/EBP-α and C/EBP-β-mediated adipogenesis of human mesenchymal stem cells (hMSCs) using PLGA nanoparticles complexed with poly(ethyleneimmine).","date":"2011","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/21600648","citation_count":26,"is_preprint":false},{"pmid":"24850428","id":"PMC_24850428","title":"C/EBP homologous protein inhibits tissue repair in response to gut injury and is inversely regulated with chronic inflammation.","date":"2014","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24850428","citation_count":26,"is_preprint":false},{"pmid":"12760743","id":"PMC_12760743","title":"Cloning of an emopamil-binding protein (EBP)-like protein that lacks sterol delta8-delta7 isomerase activity.","date":"2003","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12760743","citation_count":25,"is_preprint":false},{"pmid":"19222842","id":"PMC_19222842","title":"Cyclic regulation of transcription factor C/EBP beta in human endometrium.","date":"2009","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/19222842","citation_count":25,"is_preprint":false},{"pmid":"18406180","id":"PMC_18406180","title":"Sumoylation and the function of CCAAT enhancer binding protein alpha (C/EBP alpha).","date":"2008","source":"Blood cells, molecules & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/18406180","citation_count":24,"is_preprint":false},{"pmid":"11012671","id":"PMC_11012671","title":"Regulation of Gadd45gamma expression by C/EBP.","date":"2000","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11012671","citation_count":23,"is_preprint":false},{"pmid":"17949453","id":"PMC_17949453","title":"Novel EBP gene mutations in Conradi-Hünermann-Happle syndrome.","date":"2007","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/17949453","citation_count":23,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50069,"output_tokens":1771,"usd":0.088386,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8127,"output_tokens":1861,"usd":0.04358,"stage2_stop_reason":"end_turn"},"total_usd":0.131966,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify which papers are about the canonical EBP gene (also known as D8D7I, CPXD, CHO2, CDPX2) — which encodes emopamil-binding protein, a sterol delta8-delta7 isomerase involved in cholesterol biosynthesis and whose mutations cause X-linked dominant chondrodysplasia punctata type 2 (CDPX2).\n\nThe vast majority of papers (1-18, 20-34, 36-48, 50-59, 61-75, 77-95, 97-99) are about C/EBP transcription factors (CCAAT/enhancer-binding proteins), which are completely different proteins — not the EBP gene queried here. These are symbol collisions.\n\nPapers 35, 49, 67, 96, 100 are about the actual EBP gene (emopamil-binding protein / sterol delta8-delta7 isomerase / CDPX2 gene).\n\nPaper 19 is about yeast CHO2 — but this is a yeast phospholipid methyltransferase gene, not an ortholog of human EBP (which is a sterol isomerase). This is a symbol collision (different gene function entirely).\n\nPaper 89 is about yeast CHO2 promoter regulation — same issue, symbol collision.\n\nLet me extract discoveries only from papers 35, 49, 67, 96, 100.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Mutations in the EBP gene (encoding emopamil-binding protein, a sterol delta8-delta7 isomerase) cause X-linked dominant chondrodysplasia punctata type 2 (CDPX2). Five novel mutations were identified (three nonsense and two frameshift), establishing that loss-of-function of EBP's isomerase activity underlies CDPX2. Gonadal and somatic mosaicism were demonstrated in affected families.\",\n      \"method\": \"PCR, conformation-sensitive gel electrophoresis, direct sequencing, restriction enzyme analysis of EBP gene in seven independent families\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct mutation analysis with molecular confirmation across multiple independent families, replicated across multiple labs (also PMID:11038443, 17949453)\",\n      \"pmids\": [\"10942423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"EBP encodes a sterol delta8-delta7 isomerase; nonsense mutations in EBP produce truncated proteins and result in abnormal sterol profiles (accumulation of dehydrocholesterol and 8(9)-cholestenol), consistent with loss of delta8-delta7 isomerase enzymatic activity. Missense mutations show variable phenotypic severity, suggesting genotype-phenotype correlation for protein-truncating versus missense variants.\",\n      \"method\": \"EBP gene sequencing in 8 Japanese CDP individuals; sterol profile analysis confirming enzymatic defect\",\n      \"journal\": \"American journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical sterol profiling directly confirming enzymatic defect, combined with mutation analysis, replicated across independent cohorts\",\n      \"pmids\": [\"11038443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A male patient with clinical CDPX2 features was found to be mosaic for a sterol-delta8-delta7 isomerase (EBP) gene mutation, demonstrating that single-gene somatic mosaicism for EBP mutations is sufficient to cause the CDPX2 phenotype in males.\",\n      \"method\": \"Biochemical sterol analysis and molecular mutation analysis confirming EBP mosaicism in a male patient\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single case with biochemical and molecular confirmation, single lab\",\n      \"pmids\": [\"12503102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EBP (emopamil-binding protein) has sterol delta8-delta7 isomerase (EC 5.3.3.5) and sigma-ligand-binding activities. A paralogous protein EBPL (EBP-like) shares 31% identity/52% similarity with EBP but lacks both isomerase and sigma-ligand-binding activities when expressed in yeast. Replacement of the single divergent residue (EBP Y111W) reduced EBP catalytic activity, and transfer of this residue to EBPL (EBPL W91Y) or chimerization failed to restore activity, identifying Y111 as critical for EBP catalysis. EBP and EBPL can homodimerize.\",\n      \"method\": \"Heterologous expression of EBP and EBPL in yeast; sterol delta8-delta7 isomerase activity assays; sigma-ligand binding assays; site-directed mutagenesis (Y111W); chimeric protein construction; chemical cross-linking for homodimerization\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic activity assays with mutagenesis and chimeric protein analysis in a single rigorous study\",\n      \"pmids\": [\"12760743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Two novel EBP mutations (3G>T and 419-422delTTCT) in CDPX2 patients were confirmed as pathogenic by demonstration of elevated serum dehydrocholesterol and 8(9)-cholestenol levels, directly linking these specific mutations to loss of EBP sterol isomerase function in vivo.\",\n      \"method\": \"EBP gene mutation analysis by sequencing; gas chromatography-mass spectroscopy of serum sterols; X-inactivation studies\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — biochemical sterol profiling confirming enzymatic defect in vivo, single lab, small patient series\",\n      \"pmids\": [\"17949453\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EBP (emopamil-binding protein) is an X-linked sterol delta8-delta7 isomerase (EC 5.3.3.5) that catalyzes a key step in cholesterol biosynthesis; loss-of-function mutations (nonsense, frameshift, or missense) abolish this enzymatic activity, causing accumulation of sterol intermediates (dehydrocholesterol, 8(9)-cholestenol) and resulting in X-linked dominant chondrodysplasia punctata type 2 (CDPX2), with catalytic activity dependent on residue Y111.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EBP (emopamil-binding protein) is an X-linked sterol delta8-delta7 isomerase (EC 5.3.3.5) that catalyzes a step in cholesterol biosynthesis, and its loss of function causes X-linked dominant chondrodysplasia punctata type 2 (CDPX2) [#0, #1]. Heterologous expression confirms that EBP possesses both sterol delta8-delta7 isomerase and sigma-ligand-binding activities, with residue Y111 being critical for catalysis: the Y111W substitution reduces activity, while transfer of this residue to the inactive paralog EBPL fails to confer isomerase function [#3]. EBP can homodimerize [#3]. Pathogenic nonsense, frameshift, and missense mutations abolish isomerase activity, producing characteristic accumulation of sterol intermediates—dehydrocholesterol and 8(9)-cholestenol—detectable in patient serum [#1, #4]; somatic and gonadal mosaicism for EBP mutations is sufficient to produce the CDPX2 phenotype, including in males [#0, #2]. Beyond the catalytic role of Y111 and the disease-associated sterol defect, no further structural or regulatory mechanism has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that EBP encodes a sterol delta8-delta7 isomerase whose loss of function is the genetic cause of CDPX2, defining the disease gene and its enzymatic basis.\",\n      \"evidence\": \"Mutation analysis (nonsense and frameshift variants) of the EBP gene across seven independent families, with demonstration of gonadal and somatic mosaicism\",\n      \"pmids\": [\"10942423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not directly assay the enzymatic consequence of individual mutations in vitro\", \"Genotype-phenotype mechanism for variable severity unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Linked EBP truncating mutations to a biochemical sterol defect, confirming that the disease arises specifically from loss of delta8-delta7 isomerase activity.\",\n      \"evidence\": \"EBP sequencing in CDP patients combined with sterol profile analysis showing accumulation of dehydrocholesterol and 8(9)-cholestenol\",\n      \"pmids\": [\"11038443\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish structural basis of catalysis\", \"Missense severity correlation not mechanistically explained\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed that single-gene somatic mosaicism for an EBP mutation is sufficient to produce the CDPX2 phenotype even in males, clarifying how the X-linked dominant condition can manifest in hemizygous individuals.\",\n      \"evidence\": \"Biochemical sterol analysis and molecular mutation analysis in a single male patient\",\n      \"pmids\": [\"12503102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case without independent replication\", \"Extent of tissue mosaicism not quantified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved the catalytic determinant of EBP by identifying residue Y111 as critical for isomerase activity and distinguishing EBP from its inactive paralog EBPL.\",\n      \"evidence\": \"Heterologous expression in yeast with isomerase and sigma-ligand binding assays, site-directed mutagenesis (Y111W), chimeric constructs, and cross-linking for homodimerization\",\n      \"pmids\": [\"12760743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of the active site\", \"Mechanism of sigma-ligand binding relative to catalysis unclear\", \"Functional significance of homodimerization not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Validated additional patient mutations as pathogenic by demonstrating the in vivo sterol biochemical signature, reinforcing the enzymatic loss-of-function model.\",\n      \"evidence\": \"EBP sequencing, gas chromatography-mass spectroscopy of serum sterols, and X-inactivation studies in CDPX2 patients\",\n      \"pmids\": [\"17949453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Small patient series from a single lab\", \"No in vitro enzymatic assay of the new variants\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of EBP catalysis and the physiological role of its sigma-ligand binding and homodimerization remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No atomic structure of EBP\", \"Functional purpose of sigma-ligand binding within cholesterol biosynthesis unknown\", \"Role of homodimerization in activity undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}