{"gene":"CYP4F22","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2015,"finding":"CYP4F22 is an ultra-long-chain fatty acid ω-hydroxylase with a preferred substrate of fatty acids with carbon chain length ≥C28, and is required for acylceramide production in skin.","method":"In vitro enzyme activity assay with ichthyosis-mutant proteins showing reduced activity; lipid analysis of patient skin showing drastic decrease in acylceramide","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct enzymatic activity assay, substrate specificity determination, corroborated by patient lipid analysis and disease-linked loss-of-function mutations","pmids":["26056268"],"is_preprint":false},{"year":2015,"finding":"CYP4F22 is a type I membrane protein that localizes to the endoplasmic reticulum (ER), indicating that ω-hydroxylation of ultra-long-chain fatty acids occurs on the cytoplasmic side of the ER.","method":"Subcellular fractionation and membrane topology determination (direct localization experiment)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct localization experiment in single study; topology assignment inferred from ER membrane protein characterization","pmids":["26056268"],"is_preprint":false},{"year":2015,"finding":"Ichthyosis-associated missense mutations in CYP4F22 result in reduced ω-hydroxylase enzyme activity, demonstrating a direct correlation between enzymatic activity loss and disease pathology.","method":"In vitro enzyme activity assay of wild-type vs. ichthyosis-mutant CYP4F22 proteins","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic assay comparing wild-type and multiple disease-associated mutant proteins with patient lipid correlation","pmids":["26056268"],"is_preprint":false},{"year":2022,"finding":"Two pathogenic missense mutations (p.R282W and p.R397C) in CYP4F22 significantly reduce the amount of CYP4F22 protein in vitro, and this reduction can be rescued by trichostatin A (TSA) treatment, implicating deacetylation factors in regulating mutant CYP4F22 protein stability.","method":"In vitro functional studies measuring mutant CYP4F22 protein levels; TSA (HDAC inhibitor) rescue experiment","journal":"The Journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab in vitro study with functional protein quantification and pharmacological rescue, but mechanism of deacetylation-mediated regulation not fully elucidated","pmids":["35014717"],"is_preprint":false}],"current_model":"CYP4F22 is a type I ER-resident cytochrome P450 that functions as an ultra-long-chain fatty acid (≥C28) ω-hydroxylase, catalyzing a key step in acylceramide biosynthesis required for skin permeability barrier formation; loss-of-function mutations reduce enzymatic activity and acylceramide production, causing autosomal recessive congenital ichthyosis, and mutant protein levels can be partially restored by HDAC inhibition."},"narrative":{"mechanistic_narrative":"CYP4F22 is an endoplasmic reticulum-resident cytochrome P450 that catalyzes the ω-hydroxylation of ultra-long-chain fatty acids (preferred substrate ≥C28), a step required for acylceramide production and skin permeability barrier formation [PMID:26056268]. It is a type I membrane protein anchored in the ER, positioning ω-hydroxylation of ultra-long-chain fatty acids on the cytoplasmic face of the ER membrane [PMID:26056268]. Ichthyosis-associated missense mutations directly reduce ω-hydroxylase activity, correlating enzymatic loss with the drastic depletion of acylceramide observed in patient skin and establishing CYP4F22 deficiency as a cause of autosomal recessive congenital ichthyosis [PMID:26056268]. Certain pathogenic mutations (p.R282W, p.R397C) destabilize the protein, and mutant protein levels are partially restored by the HDAC inhibitor trichostatin A, implicating deacetylation-dependent regulation in mutant protein stability [PMID:35014717]. Beyond these findings, the structural basis of substrate recognition and the regulatory mechanism linking acetylation to CYP4F22 stability have not been characterized in the available corpus.","teleology":[{"year":2015,"claim":"Established the enzymatic identity and physiological role of CYP4F22 by showing it is an ω-hydroxylase selective for ultra-long-chain fatty acids (≥C28) required for skin acylceramide synthesis, resolving why its loss disrupts the epidermal barrier.","evidence":"In vitro enzyme activity assays of wild-type and ichthyosis-mutant proteins plus lipid analysis of patient skin","pmids":["26056268"],"confidence":"High","gaps":["No structural model of substrate binding or chain-length selectivity","Cofactor/redox partner requirements not defined","Full in vivo reconstitution of the acylceramide pathway not demonstrated"]},{"year":2015,"claim":"Defined the subcellular site of catalysis by localizing CYP4F22 as a type I ER membrane protein, placing ultra-long-chain fatty acid ω-hydroxylation on the cytoplasmic side of the ER.","evidence":"Subcellular fractionation and membrane topology determination","pmids":["26056268"],"confidence":"Medium","gaps":["Topology inferred from a single study","Spatial coupling to downstream acylceramide enzymes not mapped"]},{"year":2015,"claim":"Linked CYP4F22 dysfunction to disease by demonstrating that ichthyosis-associated missense mutations reduce ω-hydroxylase activity, establishing a direct genotype–enzyme–phenotype chain for autosomal recessive congenital ichthyosis.","evidence":"Comparative in vitro enzyme activity assays of wild-type vs. multiple disease-associated mutant proteins with patient lipid correlation","pmids":["26056268"],"confidence":"High","gaps":["Does not address mutations acting via protein stability rather than catalysis","Variant-specific severity not systematically resolved"]},{"year":2022,"claim":"Revealed a stability-based mechanism of pathogenicity by showing that p.R282W and p.R397C reduce CYP4F22 protein levels and are rescued by HDAC inhibition, implicating deacetylation factors in mutant protein turnover.","evidence":"In vitro protein quantification with trichostatin A (HDAC inhibitor) rescue","pmids":["35014717"],"confidence":"Medium","gaps":["Mechanism of deacetylation-mediated regulation not elucidated","Single-lab in vitro study without endogenous validation","Acetylation site(s) and responsible enzymes unidentified"]},{"year":null,"claim":"How CYP4F22 recognizes ultra-long-chain substrates structurally and how acetylation/deacetylation controls its stability and activity remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure","Redox partner and electron-transfer requirements undefined","Direct acetylation of CYP4F22 not demonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6NT55","full_name":"Ultra-long-chain fatty acid omega-hydroxylase","aliases":["Cytochrome P450 4F22"],"length_aa":531,"mass_kda":62.0,"function":"A cytochrome P450 monooxygenase involved in epidermal ceramide biosynthesis. Hydroxylates the terminal carbon (omega-hydroxylation) of ultra-long-chain fatty acyls (C28-C36) prior to ceramide synthesis (PubMed:26056268). Contributes to the synthesis of three classes of omega-hydroxy-ultra-long chain fatty acylceramides having sphingosine, 6-hydroxysphingosine and phytosphingosine bases, all major lipid components that underlie the permeability barrier of the stratum corneum (PubMed:26056268). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:26056268)","subcellular_location":"Endoplasmic reticulum membrane; Microsome membrane","url":"https://www.uniprot.org/uniprotkb/Q6NT55/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CYP4F22","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CYP4F22","total_profiled":1310},"omim":[{"mim_id":"611495","title":"CYTOCHROME P450, FAMILY 4, SUBFAMILY F, POLYPEPTIDE 22; CYP4F22","url":"https://www.omim.org/entry/611495"},{"mim_id":"604777","title":"ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 5; ARCI5","url":"https://www.omim.org/entry/604777"},{"mim_id":"242300","title":"ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 1; ARCI1","url":"https://www.omim.org/entry/242300"},{"mim_id":"190195","title":"TRANSGLUTAMINASE 1; TGM1","url":"https://www.omim.org/entry/190195"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":18.7},{"tissue":"skin 1","ntpm":55.8},{"tissue":"vagina","ntpm":21.5}],"url":"https://www.proteinatlas.org/search/CYP4F22"},"hgnc":{"alias_symbol":["FLJ39501"],"prev_symbol":[]},"alphafold":{"accession":"Q6NT55","domains":[{"cath_id":"-","chopping":"5-58","consensus_level":"high","plddt":89.9296,"start":5,"end":58},{"cath_id":"1.10.630.10","chopping":"61-527","consensus_level":"medium","plddt":93.9957,"start":61,"end":527}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NT55","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NT55-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6NT55-F1-predicted_aligned_error_v6.png","plddt_mean":93.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CYP4F22","jax_strain_url":"https://www.jax.org/strain/search?query=CYP4F22"},"sequence":{"accession":"Q6NT55","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6NT55.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6NT55/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6NT55"}},"corpus_meta":[{"pmid":"26056268","id":"PMC_26056268","title":"Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26056268","citation_count":138,"is_preprint":false},{"pmid":"21540472","id":"PMC_21540472","title":"Finding homes for orphan cytochrome P450s: CYP4V2 and CYP4F22 in disease states.","date":"2011","source":"Molecular interventions","url":"https://pubmed.ncbi.nlm.nih.gov/21540472","citation_count":44,"is_preprint":false},{"pmid":"30011118","id":"PMC_30011118","title":"Mutation update for CYP4F22 variants associated with autosomal recessive congenital ichthyosis.","date":"2018","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/30011118","citation_count":24,"is_preprint":false},{"pmid":"26646773","id":"PMC_26646773","title":"Two Cases of Autosomal Recessive Congenital Ichthyosis due to CYP4F22 Mutations: Expanding the Genotype of Self-Healing Collodion Baby.","date":"2015","source":"Pediatric dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/26646773","citation_count":15,"is_preprint":false},{"pmid":"32069299","id":"PMC_32069299","title":"Novel CYP4F22 mutations associated with autosomal recessive congenital ichthyosis (ARCI). Study of the CYP4F22 c.1303C>T founder mutation.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32069299","citation_count":13,"is_preprint":false},{"pmid":"27449533","id":"PMC_27449533","title":"Morphological alterations in two siblings with autosomal recessive congenital ichthyosis associated with CYP4F22 mutations.","date":"2017","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/27449533","citation_count":10,"is_preprint":false},{"pmid":"31020658","id":"PMC_31020658","title":"A Tunisian family with a novel mutation in the gene CYP4F22 for lamellar ichthyosis and co-occurrence of hearing loss in a child due to mutation in the SLC26A4 gene.","date":"2019","source":"International journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/31020658","citation_count":6,"is_preprint":false},{"pmid":"35350521","id":"PMC_35350521","title":"CYP4F22-Related Autosomal Recessive Congenital Ichthyosis: Clinical Presentation.","date":"2022","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/35350521","citation_count":3,"is_preprint":false},{"pmid":"34917360","id":"PMC_34917360","title":"Novel compound heterozygous mutations in the CYP4F22 gene in a patient with autosomal recessive congenital ichthyosis.","date":"2021","source":"Clinical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/34917360","citation_count":3,"is_preprint":false},{"pmid":"35014717","id":"PMC_35014717","title":"Whole-exome sequencing identified a novel pathogenic mutation of the CYP4F22 gene in a Chinese patient with autosomal recessive congenital ichthyosis and in vitro study of the mutant CYP4F22 protein.","date":"2022","source":"The Journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/35014717","citation_count":2,"is_preprint":false},{"pmid":"38196085","id":"PMC_38196085","title":"Autosomal recessive congenital ichthyosis due to novel CYP4F22 mutation presenting with a collodion membrane and ocular manifestations.","date":"2024","source":"Pediatric dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/38196085","citation_count":0,"is_preprint":false},{"pmid":"42196615","id":"PMC_42196615","title":"Identification of Pathogenic Variants in CYP4F22, FLG, ALOX12B, and NIPAL4 in a Case Series of Inherited Ichthyosis.","date":"2026","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/42196615","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7175,"output_tokens":982,"usd":0.018128,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7523,"output_tokens":1805,"usd":0.04137,"stage2_stop_reason":"end_turn"},"total_usd":0.059498,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"CYP4F22 is an ultra-long-chain fatty acid ω-hydroxylase with a preferred substrate of fatty acids with carbon chain length ≥C28, and is required for acylceramide production in skin.\",\n      \"method\": \"In vitro enzyme activity assay with ichthyosis-mutant proteins showing reduced activity; lipid analysis of patient skin showing drastic decrease in acylceramide\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct enzymatic activity assay, substrate specificity determination, corroborated by patient lipid analysis and disease-linked loss-of-function mutations\",\n      \"pmids\": [\"26056268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CYP4F22 is a type I membrane protein that localizes to the endoplasmic reticulum (ER), indicating that ω-hydroxylation of ultra-long-chain fatty acids occurs on the cytoplasmic side of the ER.\",\n      \"method\": \"Subcellular fractionation and membrane topology determination (direct localization experiment)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct localization experiment in single study; topology assignment inferred from ER membrane protein characterization\",\n      \"pmids\": [\"26056268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ichthyosis-associated missense mutations in CYP4F22 result in reduced ω-hydroxylase enzyme activity, demonstrating a direct correlation between enzymatic activity loss and disease pathology.\",\n      \"method\": \"In vitro enzyme activity assay of wild-type vs. ichthyosis-mutant CYP4F22 proteins\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic assay comparing wild-type and multiple disease-associated mutant proteins with patient lipid correlation\",\n      \"pmids\": [\"26056268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Two pathogenic missense mutations (p.R282W and p.R397C) in CYP4F22 significantly reduce the amount of CYP4F22 protein in vitro, and this reduction can be rescued by trichostatin A (TSA) treatment, implicating deacetylation factors in regulating mutant CYP4F22 protein stability.\",\n      \"method\": \"In vitro functional studies measuring mutant CYP4F22 protein levels; TSA (HDAC inhibitor) rescue experiment\",\n      \"journal\": \"The Journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab in vitro study with functional protein quantification and pharmacological rescue, but mechanism of deacetylation-mediated regulation not fully elucidated\",\n      \"pmids\": [\"35014717\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CYP4F22 is a type I ER-resident cytochrome P450 that functions as an ultra-long-chain fatty acid (≥C28) ω-hydroxylase, catalyzing a key step in acylceramide biosynthesis required for skin permeability barrier formation; loss-of-function mutations reduce enzymatic activity and acylceramide production, causing autosomal recessive congenital ichthyosis, and mutant protein levels can be partially restored by HDAC inhibition.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CYP4F22 is an endoplasmic reticulum-resident cytochrome P450 that catalyzes the ω-hydroxylation of ultra-long-chain fatty acids (preferred substrate ≥C28), a step required for acylceramide production and skin permeability barrier formation [#0]. It is a type I membrane protein anchored in the ER, positioning ω-hydroxylation of ultra-long-chain fatty acids on the cytoplasmic face of the ER membrane [#1]. Ichthyosis-associated missense mutations directly reduce ω-hydroxylase activity, correlating enzymatic loss with the drastic depletion of acylceramide observed in patient skin and establishing CYP4F22 deficiency as a cause of autosomal recessive congenital ichthyosis [#0, #2]. Certain pathogenic mutations (p.R282W, p.R397C) destabilize the protein, and mutant protein levels are partially restored by the HDAC inhibitor trichostatin A, implicating deacetylation-dependent regulation in mutant protein stability [#3]. Beyond these findings, the structural basis of substrate recognition and the regulatory mechanism linking acetylation to CYP4F22 stability have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established the enzymatic identity and physiological role of CYP4F22 by showing it is an ω-hydroxylase selective for ultra-long-chain fatty acids (≥C28) required for skin acylceramide synthesis, resolving why its loss disrupts the epidermal barrier.\",\n      \"evidence\": \"In vitro enzyme activity assays of wild-type and ichthyosis-mutant proteins plus lipid analysis of patient skin\",\n      \"pmids\": [\"26056268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of substrate binding or chain-length selectivity\", \"Cofactor/redox partner requirements not defined\", \"Full in vivo reconstitution of the acylceramide pathway not demonstrated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the subcellular site of catalysis by localizing CYP4F22 as a type I ER membrane protein, placing ultra-long-chain fatty acid ω-hydroxylation on the cytoplasmic side of the ER.\",\n      \"evidence\": \"Subcellular fractionation and membrane topology determination\",\n      \"pmids\": [\"26056268\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Topology inferred from a single study\", \"Spatial coupling to downstream acylceramide enzymes not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked CYP4F22 dysfunction to disease by demonstrating that ichthyosis-associated missense mutations reduce ω-hydroxylase activity, establishing a direct genotype–enzyme–phenotype chain for autosomal recessive congenital ichthyosis.\",\n      \"evidence\": \"Comparative in vitro enzyme activity assays of wild-type vs. multiple disease-associated mutant proteins with patient lipid correlation\",\n      \"pmids\": [\"26056268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address mutations acting via protein stability rather than catalysis\", \"Variant-specific severity not systematically resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a stability-based mechanism of pathogenicity by showing that p.R282W and p.R397C reduce CYP4F22 protein levels and are rescued by HDAC inhibition, implicating deacetylation factors in mutant protein turnover.\",\n      \"evidence\": \"In vitro protein quantification with trichostatin A (HDAC inhibitor) rescue\",\n      \"pmids\": [\"35014717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of deacetylation-mediated regulation not elucidated\", \"Single-lab in vitro study without endogenous validation\", \"Acetylation site(s) and responsible enzymes unidentified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CYP4F22 recognizes ultra-long-chain substrates structurally and how acetylation/deacetylation controls its stability and activity remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure\", \"Redox partner and electron-transfer requirements undefined\", \"Direct acetylation of CYP4F22 not demonstrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}