{"gene":"PHETA2","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2020,"finding":"PHETA2 (FAM109B/IPIP27B) functions as an endocytic adaptor protein that interacts with the OCRL protein product (mutated in Lowe syndrome) and is required for endocytosis and ciliogenesis in renal tissues, as well as craniofacial development including chondrocyte differentiation. Loss of both zebrafish pheta1 and pheta2 orthologs caused dysregulation of cathepsin K, leading to increased abundance of type II collagen (immature cartilage ECM marker) in craniofacial cartilages; cathepsin K inhibition rescued the craniofacial phenotype in double mutants.","method":"Zebrafish genetic knockouts of pheta1 and pheta2 orthologs; endocytosis assays in renal tissue; ciliogenesis assays; immunostaining for type II collagen and cathepsin K; pharmacological rescue with cathepsin K inhibitor; expression of patient-specific PHETA1 R6C variant in zebrafish","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic KO, biochemical assays, pharmacological rescue, patient variant expression) in a single rigorous in vivo study with specific mechanistic pathway placement","pmids":["32152089"],"is_preprint":false}],"current_model":"PHETA2 (FAM109B/IPIP27B) is an endocytic adaptor protein that interacts with the OCRL phosphatase and is required for endosomal trafficking, renal endocytosis, ciliogenesis, and craniofacial chondrocyte differentiation; mechanistically, its loss dysregulates cathepsin K activity leading to accumulation of immature type II collagen in cartilage extracellular matrix."},"narrative":{"mechanistic_narrative":"PHETA2 (FAM109B/IPIP27B) is an endocytic adaptor protein that interacts with the OCRL phosphatase and is required for endosomal endocytosis, ciliogenesis, and craniofacial development in renal and cartilage tissues [PMID:32152089]. Loss of both zebrafish pheta1 and pheta2 orthologs dysregulates cathepsin K activity, leading to accumulation of type II collagen, an immature cartilage extracellular matrix marker, in craniofacial cartilages; pharmacological inhibition of cathepsin K rescues this craniofacial phenotype [PMID:32152089]. Beyond this single in vivo study, no further mechanistic detail for PHETA2 has been characterized in the available corpus.","teleology":[{"year":2020,"claim":"Established PHETA2 as an OCRL-interacting endocytic adaptor whose loss links impaired endocytosis and ciliogenesis to a defined cathepsin K–collagen axis in craniofacial cartilage, placing it in a mechanistic pathway rather than mere association.","evidence":"Zebrafish pheta1/pheta2 double knockouts with renal endocytosis and ciliogenesis assays, type II collagen and cathepsin K immunostaining, cathepsin K inhibitor rescue, and patient-variant expression","pmids":["32152089"],"confidence":"High","gaps":["Direct biochemical demonstration of how PHETA2 binding to OCRL regulates cathepsin K activity is not resolved","Functional separation of PHETA2 from its paralog pheta1 is not established, as phenotypes derive from double knockouts","Subcellular localization and structural basis of the PHETA2–OCRL interaction are not characterized"]},{"year":null,"claim":"How PHETA2 mechanistically couples endosomal trafficking to cathepsin K regulation, and whether it acts non-redundantly with pheta1 in mammals, remains unresolved.","evidence":"No further experimental evidence in the available corpus","pmids":[],"confidence":"High","gaps":["No mammalian loss-of-function or rescue data","No direct substrate or trafficking-cargo identification","No structural model of the adaptor function"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0]}],"complexes":[],"partners":["OCRL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6ICB4","full_name":"Sesquipedalian-2","aliases":["27 kDa inositol polyphosphate phosphatase interacting protein B","IPIP27B","PH domain-containing endocytic trafficking adaptor 2"],"length_aa":259,"mass_kda":28.3,"function":"Plays a role in endocytic trafficking. Required for receptor recycling from endosomes, both to the trans-Golgi network and the plasma membrane","subcellular_location":"Early endosome; Recycling endosome; Golgi apparatus, trans-Golgi network; Cytoplasmic vesicle, clathrin-coated vesicle","url":"https://www.uniprot.org/uniprotkb/Q6ICB4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PHETA2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PHETA2","total_profiled":1310},"omim":[{"mim_id":"614240","title":"PH DOMAIN-CONTAINING ENDOCYTIC TRAFFICKING ADAPTOR 2; PHETA2","url":"https://www.omim.org/entry/614240"},{"mim_id":"614239","title":"PH DOMAIN-CONTAINING ENDOCYTIC TRAFFICKING ADAPTOR 1; PHETA1","url":"https://www.omim.org/entry/614239"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PHETA2"},"hgnc":{"alias_symbol":["DKFZp686J07229","SES2","IPIP27B"],"prev_symbol":["FAM109B"]},"alphafold":{"accession":"Q6ICB4","domains":[{"cath_id":"2.30.29.30","chopping":"6-120","consensus_level":"high","plddt":91.0809,"start":6,"end":120}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ICB4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ICB4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ICB4-F1-predicted_aligned_error_v6.png","plddt_mean":75.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PHETA2","jax_strain_url":"https://www.jax.org/strain/search?query=PHETA2"},"sequence":{"accession":"Q6ICB4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6ICB4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6ICB4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ICB4"}},"corpus_meta":[{"pmid":"36926455","id":"PMC_36926455","title":"Ranking Breast Cancer Drugs and Biomarkers Identification Using Machine Learning and Pharmacogenomics.","date":"2023","source":"ACS pharmacology & translational science","url":"https://pubmed.ncbi.nlm.nih.gov/36926455","citation_count":29,"is_preprint":false},{"pmid":"34637873","id":"PMC_34637873","title":"Identification of genetic variants influencing methylation in brain with pleiotropic effects on psychiatric disorders.","date":"2021","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/34637873","citation_count":17,"is_preprint":false},{"pmid":"25981829","id":"PMC_25981829","title":"Whole exome sequencing in a case of sporadic multiple meningioma reveals shared NF2, FAM109B, and TPRXL mutations, together with unique SMARCB1 alterations in a subset of tumor nodules.","date":"2015","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25981829","citation_count":14,"is_preprint":false},{"pmid":"33659785","id":"PMC_33659785","title":"Longitudinal genetic studies of cognitive characteristics.","date":"2020","source":"Vavilovskii zhurnal genetiki i selektsii","url":"https://pubmed.ncbi.nlm.nih.gov/33659785","citation_count":10,"is_preprint":false},{"pmid":"32152089","id":"PMC_32152089","title":"Deficiency in the endocytic adaptor proteins PHETA1/2 impairs renal and craniofacial development.","date":"2020","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/32152089","citation_count":7,"is_preprint":false},{"pmid":"39256832","id":"PMC_39256832","title":"FAM109B plays a tumorigenic role in low-grade gliomas and is associated with tumor-associated macrophages (TAMs).","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39256832","citation_count":5,"is_preprint":false},{"pmid":"38710118","id":"PMC_38710118","title":"The immune cells have complex causal regulation effects on cancers.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38710118","citation_count":5,"is_preprint":false},{"pmid":"37884875","id":"PMC_37884875","title":"Identification of genetic variants associated with anterior cruciate ligament rupture and AKC standard coat color in the Labrador Retriever.","date":"2023","source":"BMC genomic data","url":"https://pubmed.ncbi.nlm.nih.gov/37884875","citation_count":5,"is_preprint":false},{"pmid":"30193228","id":"PMC_30193228","title":"Modeling, dynamics and phosphoinositide binding of the pleckstrin homology domain of two novel PLCs: η1 and η2.","date":"2018","source":"Journal of molecular graphics & modelling","url":"https://pubmed.ncbi.nlm.nih.gov/30193228","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7281,"output_tokens":495,"usd":0.014634,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6784,"output_tokens":1062,"usd":0.030235,"stage2_stop_reason":"end_turn"},"total_usd":0.044869,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"PHETA2 (FAM109B/IPIP27B) functions as an endocytic adaptor protein that interacts with the OCRL protein product (mutated in Lowe syndrome) and is required for endocytosis and ciliogenesis in renal tissues, as well as craniofacial development including chondrocyte differentiation. Loss of both zebrafish pheta1 and pheta2 orthologs caused dysregulation of cathepsin K, leading to increased abundance of type II collagen (immature cartilage ECM marker) in craniofacial cartilages; cathepsin K inhibition rescued the craniofacial phenotype in double mutants.\",\n      \"method\": \"Zebrafish genetic knockouts of pheta1 and pheta2 orthologs; endocytosis assays in renal tissue; ciliogenesis assays; immunostaining for type II collagen and cathepsin K; pharmacological rescue with cathepsin K inhibitor; expression of patient-specific PHETA1 R6C variant in zebrafish\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic KO, biochemical assays, pharmacological rescue, patient variant expression) in a single rigorous in vivo study with specific mechanistic pathway placement\",\n      \"pmids\": [\"32152089\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PHETA2 (FAM109B/IPIP27B) is an endocytic adaptor protein that interacts with the OCRL phosphatase and is required for endosomal trafficking, renal endocytosis, ciliogenesis, and craniofacial chondrocyte differentiation; mechanistically, its loss dysregulates cathepsin K activity leading to accumulation of immature type II collagen in cartilage extracellular matrix.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PHETA2 (FAM109B/IPIP27B) is an endocytic adaptor protein that interacts with the OCRL phosphatase and is required for endosomal endocytosis, ciliogenesis, and craniofacial development in renal and cartilage tissues [#0]. Loss of both zebrafish pheta1 and pheta2 orthologs dysregulates cathepsin K activity, leading to accumulation of type II collagen, an immature cartilage extracellular matrix marker, in craniofacial cartilages; pharmacological inhibition of cathepsin K rescues this craniofacial phenotype [#0]. Beyond this single in vivo study, no further mechanistic detail for PHETA2 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Established PHETA2 as an OCRL-interacting endocytic adaptor whose loss links impaired endocytosis and ciliogenesis to a defined cathepsin K–collagen axis in craniofacial cartilage, placing it in a mechanistic pathway rather than mere association.\",\n      \"evidence\": \"Zebrafish pheta1/pheta2 double knockouts with renal endocytosis and ciliogenesis assays, type II collagen and cathepsin K immunostaining, cathepsin K inhibitor rescue, and patient-variant expression\",\n      \"pmids\": [\"32152089\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct biochemical demonstration of how PHETA2 binding to OCRL regulates cathepsin K activity is not resolved\",\n        \"Functional separation of PHETA2 from its paralog pheta1 is not established, as phenotypes derive from double knockouts\",\n        \"Subcellular localization and structural basis of the PHETA2–OCRL interaction are not characterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PHETA2 mechanistically couples endosomal trafficking to cathepsin K regulation, and whether it acts non-redundantly with pheta1 in mammals, remains unresolved.\",\n      \"evidence\": \"No further experimental evidence in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No mammalian loss-of-function or rescue data\",\n        \"No direct substrate or trafficking-cargo identification\",\n        \"No structural model of the adaptor function\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"OCRL\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":2,"faith_total":2,"faith_pct":100.0}}