{"gene":"CYP4F22","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":2015,"finding":"CYP4F22 is an ultra-long-chain fatty acid ω-hydroxylase that preferentially hydroxylates fatty acids with carbon chain lengths of ≥C28, producing the ω-hydroxylated fatty acid precursor required for acylceramide biosynthesis and skin permeability barrier formation.","method":"Enzyme activity assays with fatty acid substrates of varying chain lengths; lipid analysis of ichthyosis patient samples showing drastic decrease in acylceramide; ichthyosis-associated mutant proteins showing reduced enzyme activity","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro enzyme activity assays with substrate specificity profiling, patient lipid analysis, and disease-mutant functional validation in a single highly-cited study","pmids":["26056268"],"is_preprint":false},{"year":2015,"finding":"CYP4F22 is a type I membrane protein localized 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 localization experiments establishing ER membrane topology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiment with mechanistic implication, reported in a rigorous, highly-cited study with multiple orthogonal methods","pmids":["26056268"],"is_preprint":false},{"year":2015,"finding":"Ichthyosis-causing mutations in CYP4F22 reduce enzyme ω-hydroxylase activity, establishing a direct genotype-phenotype correlation between loss of catalytic function and acylceramide deficiency.","method":"Enzyme activity assays on ichthyosis-mutant CYP4F22 proteins combined with lipid analysis of patient-derived samples","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — multiple mutant proteins tested in activity assays corroborated by patient lipid data; highly-cited study","pmids":["26056268"],"is_preprint":false},{"year":2022,"finding":"Two pathogenic CYP4F22 missense mutations (p.R282W and p.R397C) significantly reduce CYP4F22 protein levels, and this reduction can be rescued by treatment with the deacetylase inhibitor trichostatin A (TSA), implicating deacetylation-dependent protein stability regulation.","method":"In vitro functional study with mutant protein expression; TSA treatment rescue experiment","journal":"The Journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2–3 — in vitro mutant protein stability assay with pharmacological rescue, single lab, moderate mechanistic follow-up","pmids":["35014717"],"is_preprint":false}],"current_model":"CYP4F22 is a type I endoplasmic reticulum membrane protein that functions as an ultra-long-chain fatty acid (≥C28) ω-hydroxylase on the cytoplasmic face of the ER, catalyzing a key step in acylceramide biosynthesis required for skin permeability barrier formation; loss-of-function mutations reduce this enzymatic activity, abolish acylceramide production, and cause autosomal recessive congenital ichthyosis, while mutant protein levels are regulated in part by deacetylation-dependent stability mechanisms."},"narrative":{"teleology":[{"year":2015,"claim":"Resolving the long-standing question of which enzyme performs ω-hydroxylation in the acylceramide pathway, this work demonstrated that CYP4F22 is an ultra-long-chain fatty acid ω-hydroxylase with preference for ≥C28 substrates, localized as a type I ER membrane protein with its catalytic face in the cytoplasm, and that ichthyosis-causing mutations directly reduce this activity — thereby linking enzymatic function, subcellular topology, and disease causation in a single framework.","evidence":"In vitro enzyme activity assays with varying chain-length fatty acids, subcellular fractionation/ER localization, lipid analysis of ichthyosis patient samples, and functional testing of disease-associated mutant proteins","pmids":["26056268"],"confidence":"High","gaps":["No crystal or cryo-EM structure of CYP4F22 to explain substrate chain-length selectivity","The electron-donor partner (cytochrome P450 reductase or other) and its interaction interface are not characterized","Whether CYP4F22 also hydroxylates non-fatty-acid substrates has not been tested"]},{"year":2022,"claim":"Beyond catalytic loss, pathogenic CYP4F22 missense mutations were shown to reduce protein stability, and rescue by the deacetylase inhibitor trichostatin A implicated acetylation/deacetylation balance as a post-translational regulatory mechanism governing CYP4F22 turnover.","evidence":"In vitro expression of p.R282W and p.R397C mutant proteins with quantification of protein levels ± TSA treatment","pmids":["35014717"],"confidence":"Medium","gaps":["The specific lysine residue(s) whose acetylation state controls CYP4F22 stability have not been identified","Whether TSA acts directly on CYP4F22 acetylation or indirectly through chaperone or proteasomal pathways is unresolved","Rescue of enzyme activity (not just protein level) by TSA was not demonstrated"]},{"year":null,"claim":"Key unresolved questions include the structural basis of CYP4F22's ultra-long-chain substrate selectivity, the identity of its redox partner(s), whether pharmacological stabilization of mutant protein can restore barrier function in vivo, and the full spectrum of post-translational modifications regulating its activity and turnover.","evidence":"","pmids":[],"confidence":"Low","gaps":["No in vivo animal model recapitulating CYP4F22-dependent ichthyosis with functional rescue","Structural model for substrate binding and chain-length selectivity is absent","Relationship between CYP4F22 and other acylceramide pathway enzymes (e.g., PNPLA1, CERS3) at the protein complex level is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,2]}],"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]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2]}],"complexes":[],"partners":[],"other_free_text":[]},"mechanistic_narrative":"CYP4F22 is a type I endoplasmic reticulum membrane protein that functions as an ultra-long-chain fatty acid (≥C28) ω-hydroxylase, catalyzing the production of ω-hydroxylated fatty acid precursors essential for acylceramide biosynthesis and skin permeability barrier formation [PMID:26056268]. The enzyme's active site faces the cytoplasmic side of the ER, and ichthyosis-causing mutations directly reduce its ω-hydroxylase activity, establishing a genotype–phenotype link between loss of catalytic function, acylceramide deficiency, and autosomal recessive congenital ichthyosis [PMID:26056268]. Pathogenic missense variants (e.g., p.R282W, p.R397C) also destabilize the protein, and this instability can be rescued by trichostatin A, implicating deacetylation-dependent mechanisms in CYP4F22 protein turnover [PMID:35014717]."},"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":136,"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":"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":"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":"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5866,"output_tokens":1006,"usd":0.016344},"stage2":{"model":"claude-opus-4-6","input_tokens":4231,"output_tokens":1215,"usd":0.077295},"total_usd":0.093639,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","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 that preferentially hydroxylates fatty acids with carbon chain lengths of ≥C28, producing the ω-hydroxylated fatty acid precursor required for acylceramide biosynthesis and skin permeability barrier formation.\",\n      \"method\": \"Enzyme activity assays with fatty acid substrates of varying chain lengths; lipid analysis of ichthyosis patient samples showing drastic decrease in acylceramide; ichthyosis-associated mutant proteins showing reduced enzyme activity\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro enzyme activity assays with substrate specificity profiling, patient lipid analysis, and disease-mutant functional validation in a single highly-cited study\",\n      \"pmids\": [\"26056268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CYP4F22 is a type I membrane protein localized 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 localization experiments establishing ER membrane topology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with mechanistic implication, reported in a rigorous, highly-cited study with multiple orthogonal methods\",\n      \"pmids\": [\"26056268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ichthyosis-causing mutations in CYP4F22 reduce enzyme ω-hydroxylase activity, establishing a direct genotype-phenotype correlation between loss of catalytic function and acylceramide deficiency.\",\n      \"method\": \"Enzyme activity assays on ichthyosis-mutant CYP4F22 proteins combined with lipid analysis of patient-derived samples\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple mutant proteins tested in activity assays corroborated by patient lipid data; highly-cited study\",\n      \"pmids\": [\"26056268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Two pathogenic CYP4F22 missense mutations (p.R282W and p.R397C) significantly reduce CYP4F22 protein levels, and this reduction can be rescued by treatment with the deacetylase inhibitor trichostatin A (TSA), implicating deacetylation-dependent protein stability regulation.\",\n      \"method\": \"In vitro functional study with mutant protein expression; TSA treatment rescue experiment\",\n      \"journal\": \"The Journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — in vitro mutant protein stability assay with pharmacological rescue, single lab, moderate mechanistic follow-up\",\n      \"pmids\": [\"35014717\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CYP4F22 is a type I endoplasmic reticulum membrane protein that functions as an ultra-long-chain fatty acid (≥C28) ω-hydroxylase on the cytoplasmic face of the ER, catalyzing a key step in acylceramide biosynthesis required for skin permeability barrier formation; loss-of-function mutations reduce this enzymatic activity, abolish acylceramide production, and cause autosomal recessive congenital ichthyosis, while mutant protein levels are regulated in part by deacetylation-dependent stability mechanisms.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CYP4F22 is a type I endoplasmic reticulum membrane protein that functions as an ultra-long-chain fatty acid (≥C28) ω-hydroxylase, catalyzing the production of ω-hydroxylated fatty acid precursors essential for acylceramide biosynthesis and skin permeability barrier formation [PMID:26056268]. The enzyme's active site faces the cytoplasmic side of the ER, and ichthyosis-causing mutations directly reduce its ω-hydroxylase activity, establishing a genotype–phenotype link between loss of catalytic function, acylceramide deficiency, and autosomal recessive congenital ichthyosis [PMID:26056268]. Pathogenic missense variants (e.g., p.R282W, p.R397C) also destabilize the protein, and this instability can be rescued by trichostatin A, implicating deacetylation-dependent mechanisms in CYP4F22 protein turnover [PMID:35014717].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolving the long-standing question of which enzyme performs ω-hydroxylation in the acylceramide pathway, this work demonstrated that CYP4F22 is an ultra-long-chain fatty acid ω-hydroxylase with preference for ≥C28 substrates, localized as a type I ER membrane protein with its catalytic face in the cytoplasm, and that ichthyosis-causing mutations directly reduce this activity — thereby linking enzymatic function, subcellular topology, and disease causation in a single framework.\",\n      \"evidence\": \"In vitro enzyme activity assays with varying chain-length fatty acids, subcellular fractionation/ER localization, lipid analysis of ichthyosis patient samples, and functional testing of disease-associated mutant proteins\",\n      \"pmids\": [\"26056268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of CYP4F22 to explain substrate chain-length selectivity\",\n        \"The electron-donor partner (cytochrome P450 reductase or other) and its interaction interface are not characterized\",\n        \"Whether CYP4F22 also hydroxylates non-fatty-acid substrates has not been tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Beyond catalytic loss, pathogenic CYP4F22 missense mutations were shown to reduce protein stability, and rescue by the deacetylase inhibitor trichostatin A implicated acetylation/deacetylation balance as a post-translational regulatory mechanism governing CYP4F22 turnover.\",\n      \"evidence\": \"In vitro expression of p.R282W and p.R397C mutant proteins with quantification of protein levels ± TSA treatment\",\n      \"pmids\": [\"35014717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The specific lysine residue(s) whose acetylation state controls CYP4F22 stability have not been identified\",\n        \"Whether TSA acts directly on CYP4F22 acetylation or indirectly through chaperone or proteasomal pathways is unresolved\",\n        \"Rescue of enzyme activity (not just protein level) by TSA was not demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of CYP4F22's ultra-long-chain substrate selectivity, the identity of its redox partner(s), whether pharmacological stabilization of mutant protein can restore barrier function in vivo, and the full spectrum of post-translational modifications regulating its activity and turnover.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No in vivo animal model recapitulating CYP4F22-dependent ichthyosis with functional rescue\",\n        \"Structural model for substrate binding and chain-length selectivity is absent\",\n        \"Relationship between CYP4F22 and other acylceramide pathway enzymes (e.g., PNPLA1, CERS3) at the protein complex level is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 2]}\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      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```"}