{"gene":"WDR83OS","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2002,"finding":"PAT-10 (WDR83OS) is a novel ER translocon-associated component that remains adjacent to the first transmembrane domain (TM1) of the polytopic membrane protein opsin throughout its biogenesis and membrane integration, but does not associate with TM2, indicating it selectively chaperones specific TM segments during co-translational insertion.","method":"Site-specific cross-linking of nascent opsin chains at the ER translocon; co-immunoprecipitation with Sec61 subunits; N-glycosylation-independence assay; topology-independent TM1 association test","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-specific cross-linking reconstitution at ER translocon with multiple orthogonal controls (glycosylation independence, TM1 sequence variants, co-IP with Sec61), replicated and extended in a follow-up 2008 study","pmids":["12475939"],"is_preprint":false},{"year":2008,"finding":"PAT-10 (WDR83OS) shows a pronounced and prolonged association with TM5 of opsin at the ER translocon, suggesting it facilitates assembly of distinct opsin subdomains; TM4 exits the translocon rapidly without PAT-10 association, demonstrating selective TM-segment engagement by PAT-10.","method":"Site-specific cross-linking of nascent opsin polypeptides at the ER translocon during biosynthesis; extension and substitution of TM7 with more hydrophobic segment as control","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-specific cross-linking with structural controls (TM7 hydrophobicity substitution), consistent with and extending the 2002 study from the same lab","pmids":["18248332"],"is_preprint":false},{"year":2019,"finding":"WDR83OS protein expression is necessary for normal TRPC6 protein expression; WDR83OS physically interacts with both TRPC6 and TMEM208, placing it in a protein complex required for ER translocation/expression of multipass transmembrane proteins.","method":"Genome-wide CRISPR/Cas9 loss-of-function screen; co-immunoprecipitation (WDR83OS with TRPC6 and TMEM208); TRPC6 protein level measurement upon WDR83OS deletion","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus co-IP showing physical interaction, single lab, two orthogonal methods","pmids":["31266804"],"is_preprint":false},{"year":2024,"finding":"WDR83OS encodes the 106-amino-acid protein Asterix, which heterodimerizes with CCDC47 to form the PAT (protein associated with ER translocon) complex; this complex functions as a chaperone for large transmembrane-domain-containing proteins to ensure proper folding. Biallelic loss-of-function variants in WDR83OS cause a neurodevelopmental disorder with hypercholanemia in humans, and zebrafish lacking Wdr83os show defects in nervous system development, craniofacial development, and lipid absorption.","method":"Family-based rare variant analysis with exome sequencing; case matching (GeneMatcher); zebrafish loss-of-function model with phenotypic readouts (nervous system, craniofacial, lipid absorption); biochemical characterization of Asterix–CCDC47 heterodimer (PAT complex)","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetics plus zebrafish KO with defined phenotypic readouts and biochemical complex characterization, single publication","pmids":["39471804"],"is_preprint":false},{"year":2018,"finding":"A homozygous truncating variant in WDR83OS (C19orf56) segregates with a syndrome of intractable itching, hypercholanemia, short stature, and intellectual disability in a family with three affected siblings; WDR83OS is described as known to interact with ATP13A2 and BSEP, implicating it in bile homeostasis.","method":"Exome sequencing and positional mapping in consanguineous family; segregation analysis","journal":"Genetics in medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic mapping only; the ATP13A2/BSEP interaction is stated as previously known but not experimentally demonstrated in this paper; no direct mechanistic experiment performed","pmids":["30250217"],"is_preprint":false}],"current_model":"WDR83OS encodes the small protein Asterix, which heterodimerizes with CCDC47 to form the PAT (protein associated with ER translocon) complex at the endoplasmic reticulum, where it selectively and persistently associates with specific transmembrane segments of polytopic membrane proteins (including opsin TM1/TM5 and TRPC6) during co-translational membrane integration, acting as a chaperone to ensure proper folding and expression of large multi-pass transmembrane proteins; biallelic loss-of-function in humans causes a neurodevelopmental disorder with hypercholanemia."},"narrative":{"mechanistic_narrative":"WDR83OS encodes Asterix (originally PAT-10), an endoplasmic reticulum translocon-associated chaperone that engages specific transmembrane segments of polytopic membrane proteins during their co-translational membrane integration [PMID:12475939]. Site-specific cross-linking of nascent opsin chains established that Asterix remains selectively and persistently adjacent to particular TM segments — the first transmembrane domain and, with prolonged engagement, TM5 — while ignoring others such as TM2 and TM4, demonstrating that it discriminates among TM helices rather than acting indiscriminately [PMID:12475939, PMID:18248332]. Asterix heterodimerizes with CCDC47 to form the PAT (protein associated with the ER translocon) complex, which functions to ensure proper folding of large transmembrane-domain-containing client proteins [PMID:39471804]; consistent with this chaperone role, loss of WDR83OS reduces expression of the multipass channel TRPC6, with which it physically interacts alongside TMEM208 [PMID:31266804]. Biallelic loss-of-function variants in WDR83OS cause a human neurodevelopmental disorder with hypercholanemia, and zebrafish lacking the gene show defects in nervous system development, craniofacial development, and lipid absorption [PMID:39471804].","teleology":[{"year":2002,"claim":"Established that an uncharacterized translocon-associated factor (PAT-10/WDR83OS) selectively engages defined transmembrane segments of a nascent polytopic protein, framing it as a segment-specific component of membrane protein biogenesis rather than a general translocon subunit.","evidence":"Site-specific cross-linking of nascent opsin at the ER translocon with Sec61 co-IP and glycosylation-independence controls","pmids":["12475939"],"confidence":"High","gaps":["Did not identify the molecular identity of the chaperone activity or its binding partners","Limited to opsin TM1; generality across other substrates untested","Functional consequence of the association for folding not measured"]},{"year":2008,"claim":"Extended the selectivity model by showing prolonged engagement with opsin TM5 but rapid TM4 exit, demonstrating that segment discrimination follows the substrate's folding subdomains.","evidence":"Site-specific cross-linking of nascent opsin with TM7 hydrophobicity-substitution controls","pmids":["18248332"],"confidence":"High","gaps":["Determinants of which TM segments are engaged remain undefined","No structural model of the engagement","Did not connect the activity to a named protein complex"]},{"year":2019,"claim":"Linked WDR83OS to a functional outcome by showing it is required for expression of a client multipass channel and physically associates with that client and TMEM208, embedding it in an ER translocation complex.","evidence":"Genome-wide CRISPR/Cas9 screen plus co-IP of WDR83OS with TRPC6 and TMEM208, with TRPC6 protein-level readout","pmids":["31266804"],"confidence":"Medium","gaps":["Single lab, two orthogonal methods without reciprocal validation","Whether interaction is direct vs. complex-mediated not resolved","Stoichiometry and architecture of the complex not defined"]},{"year":2024,"claim":"Resolved the molecular identity and clinical relevance: WDR83OS encodes the 106-aa Asterix protein that heterodimerizes with CCDC47 as the PAT complex, and biallelic loss causes a human neurodevelopmental disorder with hypercholanemia recapitulated in zebrafish.","evidence":"Family-based exome sequencing with GeneMatcher case matching, zebrafish loss-of-function model, and biochemical characterization of the Asterix–CCDC47 heterodimer","pmids":["39471804"],"confidence":"Medium","gaps":["Single publication for the disease association","Mechanistic link between PAT chaperone defect and hypercholanemia/lipid phenotype not established at molecular level","Full client repertoire of the PAT complex in vivo undefined"]},{"year":null,"claim":"How Asterix recognizes specific transmembrane segments and how its chaperone failure produces the tissue-specific phenotypes (neurodevelopment, bile/lipid homeostasis) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural basis for TM-segment selectivity","Causal chain from chaperone loss to hypercholanemia unmapped","Comprehensive client substrate list not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3]}],"complexes":["PAT complex (Asterix–CCDC47)"],"partners":["CCDC47","TRPC6","TMEM208","SEC61"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y284","full_name":"PAT complex subunit Asterix","aliases":["Protein associated with the ER translocon of 10kDa","PAT-10","PAT10","WD repeat domain 83 opposite strand","WDR83 opposite strand"],"length_aa":106,"mass_kda":12.1,"function":"Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes (PubMed:12475939, PubMed:32814900, PubMed:36261522). The MPT complex takes over after the SEC61 complex: following membrane insertion of the first few transmembrane segments of proteins by the SEC61 complex, the MPT complex occludes the lateral gate of the SEC61 complex to promote insertion of subsequent transmembrane regions (PubMed:32814900, PubMed:36261522). Within the MPT complex, the PAT subcomplex sequesters any highly polar regions in the transmembrane domains away from the non-polar membrane environment until they can be buried in the interior of the fully assembled protein (By similarity). Within the PAT subcomplex, WDR83OS/Asterix binds to and redirects the substrate to a location behind the SEC61 complex (By similarity)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y284/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR83OS","classification":"Not Classified","n_dependent_lines":127,"n_total_lines":1165,"dependency_fraction":0.10901287553648069},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/WDR83OS","total_profiled":1310},"omim":[{"mim_id":"621016","title":"NEURODEVELOPMENTAL DISORDER WITH VARIABLE FAMILIAL HYPERCHOLANEMIA; NEDFHCA","url":"https://www.omim.org/entry/621016"},{"mim_id":"619662","title":"CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC, 8; PFIC8","url":"https://www.omim.org/entry/619662"},{"mim_id":"619658","title":"CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC, 7, WITH OR WITHOUT HEARING LOSS; PFIC7","url":"https://www.omim.org/entry/619658"},{"mim_id":"619309","title":"PROTEIN PHOSPHATASE, MAGNESIUM/MANGANESE-DEPENDENT, 1F; PPM1F","url":"https://www.omim.org/entry/619309"},{"mim_id":"618474","title":"WDR83 OPPOSITE STRAND; WDR83OS","url":"https://www.omim.org/entry/618474"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDR83OS"},"hgnc":{"alias_symbol":["PTD008","PAT10"],"prev_symbol":["C19orf56"]},"alphafold":{"accession":"Q9Y284","domains":[{"cath_id":"-","chopping":"31-67","consensus_level":"medium","plddt":65.4035,"start":31,"end":67}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y284","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y284-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y284-F1-predicted_aligned_error_v6.png","plddt_mean":62.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR83OS","jax_strain_url":"https://www.jax.org/strain/search?query=WDR83OS"},"sequence":{"accession":"Q9Y284","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y284.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y284/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y284"}},"corpus_meta":[{"pmid":"25324391","id":"PMC_25324391","title":"HSF-1-mediated cytoskeletal integrity determines thermotolerance and life span.","date":"2014","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/25324391","citation_count":140,"is_preprint":false},{"pmid":"30250217","id":"PMC_30250217","title":"Identification of novel loci for pediatric cholestatic liver disease defined by KIF12, PPM1F, USP53, LSR, and WDR83OS pathogenic variants.","date":"2018","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30250217","citation_count":88,"is_preprint":false},{"pmid":"12475939","id":"PMC_12475939","title":"Different transmembrane domains associate with distinct endoplasmic reticulum components during membrane integration of a polytopic protein.","date":"2002","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/12475939","citation_count":77,"is_preprint":false},{"pmid":"28559361","id":"PMC_28559361","title":"Adaptor Protein-3-Dependent Vacuolar Trafficking Involves a Subpopulation of COPII and HOPS Tethering Proteins.","date":"2017","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28559361","citation_count":53,"is_preprint":false},{"pmid":"29898977","id":"PMC_29898977","title":"A Tonoplast-Associated Calcium-Signaling Module Dampens ABA Signaling during Stomatal Movement.","date":"2018","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29898977","citation_count":44,"is_preprint":false},{"pmid":"23201220","id":"PMC_23201220","title":"Gene silencing in root lesion nematodes (Pratylenchus spp.) significantly reduces reproduction in a plant host.","date":"2012","source":"Experimental parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/23201220","citation_count":42,"is_preprint":false},{"pmid":"28837672","id":"PMC_28837672","title":"Cardiac transcriptome profiling of diabetic Akita mice using microarray and next generation sequencing.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28837672","citation_count":41,"is_preprint":false},{"pmid":"10402470","id":"PMC_10402470","title":"Genomic organization, expression, and analysis of the troponin C gene pat-10 of Caenorhabditis elegans.","date":"1999","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10402470","citation_count":40,"is_preprint":false},{"pmid":"31266804","id":"PMC_31266804","title":"Transmembrane insertases and N-glycosylation critically determine synthesis, trafficking, and activity of the nonselective cation channel TRPC6.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31266804","citation_count":37,"is_preprint":false},{"pmid":"18248332","id":"PMC_18248332","title":"Specific transmembrane segments are selectively delayed at the ER translocon during opsin biogenesis.","date":"2008","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18248332","citation_count":33,"is_preprint":false},{"pmid":"9113409","id":"PMC_9113409","title":"Mutations and expressions of the tropomyosin gene and the troponin C gene of Caenorhabditis elegans.","date":"1997","source":"Cell structure and function","url":"https://pubmed.ncbi.nlm.nih.gov/9113409","citation_count":29,"is_preprint":false},{"pmid":"29523712","id":"PMC_29523712","title":"The ADAPTOR PROTEIN-3 Complex Mediates Pollen Tube Growth by Coordinating Vacuolar Targeting and Organization.","date":"2018","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29523712","citation_count":27,"is_preprint":false},{"pmid":"23043990","id":"PMC_23043990","title":"RNA interference in Pratylenchus coffeae: knock down of Pc-pat-10 and Pc-unc-87 impedes migration.","date":"2012","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/23043990","citation_count":21,"is_preprint":false},{"pmid":"31441225","id":"PMC_31441225","title":"S-acylation of CBL10/SCaBP8 by PAT10 is crucial for its tonoplast association and function in salt tolerance.","date":"2019","source":"Journal of integrative plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/31441225","citation_count":19,"is_preprint":false},{"pmid":"23095951","id":"PMC_23095951","title":"The Corynebacterium pseudotuberculosis in silico predicted pan-exoproteome.","date":"2012","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/23095951","citation_count":11,"is_preprint":false},{"pmid":"36293134","id":"PMC_36293134","title":"Identification of the Extracellular Nuclease Influencing Soaking RNA Interference Efficiency in Bursaphelenchus xylophilus.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36293134","citation_count":5,"is_preprint":false},{"pmid":"37569502","id":"PMC_37569502","title":"Transgenic East African Highland Banana Plants Are Protected against Radopholus similis through Host-Delivered RNAi.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37569502","citation_count":5,"is_preprint":false},{"pmid":"40061802","id":"PMC_40061802","title":"Integrative analysis of genome-wide association studies of polyphenols in apple fruits identifies the MdDof2.4-MdPAT10 module that promotes procyanidin accumulation.","date":"2024","source":"Horticulture research","url":"https://pubmed.ncbi.nlm.nih.gov/40061802","citation_count":2,"is_preprint":false},{"pmid":"39471804","id":"PMC_39471804","title":"Homozygous variants in WDR83OS lead to a neurodevelopmental disorder with hypercholanemia.","date":"2024","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39471804","citation_count":1,"is_preprint":false},{"pmid":"40959459","id":"PMC_40959459","title":"Single-Cell Transcriptomic Atlas of Peripheral Blood Reveals B-Cell-Driven Signature Predictive of Acute Pancreatitis Severity.","date":"2025","source":"MedComm","url":"https://pubmed.ncbi.nlm.nih.gov/40959459","citation_count":1,"is_preprint":false},{"pmid":"17134856","id":"PMC_17134856","title":"A novel non-coding DNA family in Caenorhabditis elegans.","date":"2006","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/17134856","citation_count":0,"is_preprint":false},{"pmid":"41007306","id":"PMC_41007306","title":"Nematicidal Efficacy of a dsRNA-Chitosan Formulation Against Acrobeloides nanus Estimated by a Soil Drenching Application.","date":"2025","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41007306","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13073,"output_tokens":1470,"usd":0.030634,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8148,"output_tokens":1970,"usd":0.044995,"stage2_stop_reason":"end_turn"},"total_usd":0.075629,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"PAT-10 (WDR83OS) is a novel ER translocon-associated component that remains adjacent to the first transmembrane domain (TM1) of the polytopic membrane protein opsin throughout its biogenesis and membrane integration, but does not associate with TM2, indicating it selectively chaperones specific TM segments during co-translational insertion.\",\n      \"method\": \"Site-specific cross-linking of nascent opsin chains at the ER translocon; co-immunoprecipitation with Sec61 subunits; N-glycosylation-independence assay; topology-independent TM1 association test\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-specific cross-linking reconstitution at ER translocon with multiple orthogonal controls (glycosylation independence, TM1 sequence variants, co-IP with Sec61), replicated and extended in a follow-up 2008 study\",\n      \"pmids\": [\"12475939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PAT-10 (WDR83OS) shows a pronounced and prolonged association with TM5 of opsin at the ER translocon, suggesting it facilitates assembly of distinct opsin subdomains; TM4 exits the translocon rapidly without PAT-10 association, demonstrating selective TM-segment engagement by PAT-10.\",\n      \"method\": \"Site-specific cross-linking of nascent opsin polypeptides at the ER translocon during biosynthesis; extension and substitution of TM7 with more hydrophobic segment as control\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-specific cross-linking with structural controls (TM7 hydrophobicity substitution), consistent with and extending the 2002 study from the same lab\",\n      \"pmids\": [\"18248332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WDR83OS protein expression is necessary for normal TRPC6 protein expression; WDR83OS physically interacts with both TRPC6 and TMEM208, placing it in a protein complex required for ER translocation/expression of multipass transmembrane proteins.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 loss-of-function screen; co-immunoprecipitation (WDR83OS with TRPC6 and TMEM208); TRPC6 protein level measurement upon WDR83OS deletion\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus co-IP showing physical interaction, single lab, two orthogonal methods\",\n      \"pmids\": [\"31266804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WDR83OS encodes the 106-amino-acid protein Asterix, which heterodimerizes with CCDC47 to form the PAT (protein associated with ER translocon) complex; this complex functions as a chaperone for large transmembrane-domain-containing proteins to ensure proper folding. Biallelic loss-of-function variants in WDR83OS cause a neurodevelopmental disorder with hypercholanemia in humans, and zebrafish lacking Wdr83os show defects in nervous system development, craniofacial development, and lipid absorption.\",\n      \"method\": \"Family-based rare variant analysis with exome sequencing; case matching (GeneMatcher); zebrafish loss-of-function model with phenotypic readouts (nervous system, craniofacial, lipid absorption); biochemical characterization of Asterix–CCDC47 heterodimer (PAT complex)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetics plus zebrafish KO with defined phenotypic readouts and biochemical complex characterization, single publication\",\n      \"pmids\": [\"39471804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A homozygous truncating variant in WDR83OS (C19orf56) segregates with a syndrome of intractable itching, hypercholanemia, short stature, and intellectual disability in a family with three affected siblings; WDR83OS is described as known to interact with ATP13A2 and BSEP, implicating it in bile homeostasis.\",\n      \"method\": \"Exome sequencing and positional mapping in consanguineous family; segregation analysis\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic mapping only; the ATP13A2/BSEP interaction is stated as previously known but not experimentally demonstrated in this paper; no direct mechanistic experiment performed\",\n      \"pmids\": [\"30250217\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR83OS encodes the small protein Asterix, which heterodimerizes with CCDC47 to form the PAT (protein associated with ER translocon) complex at the endoplasmic reticulum, where it selectively and persistently associates with specific transmembrane segments of polytopic membrane proteins (including opsin TM1/TM5 and TRPC6) during co-translational membrane integration, acting as a chaperone to ensure proper folding and expression of large multi-pass transmembrane proteins; biallelic loss-of-function in humans causes a neurodevelopmental disorder with hypercholanemia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDR83OS encodes Asterix (originally PAT-10), an endoplasmic reticulum translocon-associated chaperone that engages specific transmembrane segments of polytopic membrane proteins during their co-translational membrane integration [#0]. Site-specific cross-linking of nascent opsin chains established that Asterix remains selectively and persistently adjacent to particular TM segments — the first transmembrane domain and, with prolonged engagement, TM5 — while ignoring others such as TM2 and TM4, demonstrating that it discriminates among TM helices rather than acting indiscriminately [#0, #1]. Asterix heterodimerizes with CCDC47 to form the PAT (protein associated with the ER translocon) complex, which functions to ensure proper folding of large transmembrane-domain-containing client proteins [#3]; consistent with this chaperone role, loss of WDR83OS reduces expression of the multipass channel TRPC6, with which it physically interacts alongside TMEM208 [#2]. Biallelic loss-of-function variants in WDR83OS cause a human neurodevelopmental disorder with hypercholanemia, and zebrafish lacking the gene show defects in nervous system development, craniofacial development, and lipid absorption [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that an uncharacterized translocon-associated factor (PAT-10/WDR83OS) selectively engages defined transmembrane segments of a nascent polytopic protein, framing it as a segment-specific component of membrane protein biogenesis rather than a general translocon subunit.\",\n      \"evidence\": \"Site-specific cross-linking of nascent opsin at the ER translocon with Sec61 co-IP and glycosylation-independence controls\",\n      \"pmids\": [\"12475939\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not identify the molecular identity of the chaperone activity or its binding partners\",\n        \"Limited to opsin TM1; generality across other substrates untested\",\n        \"Functional consequence of the association for folding not measured\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended the selectivity model by showing prolonged engagement with opsin TM5 but rapid TM4 exit, demonstrating that segment discrimination follows the substrate's folding subdomains.\",\n      \"evidence\": \"Site-specific cross-linking of nascent opsin with TM7 hydrophobicity-substitution controls\",\n      \"pmids\": [\"18248332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Determinants of which TM segments are engaged remain undefined\",\n        \"No structural model of the engagement\",\n        \"Did not connect the activity to a named protein complex\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked WDR83OS to a functional outcome by showing it is required for expression of a client multipass channel and physically associates with that client and TMEM208, embedding it in an ER translocation complex.\",\n      \"evidence\": \"Genome-wide CRISPR/Cas9 screen plus co-IP of WDR83OS with TRPC6 and TMEM208, with TRPC6 protein-level readout\",\n      \"pmids\": [\"31266804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab, two orthogonal methods without reciprocal validation\",\n        \"Whether interaction is direct vs. complex-mediated not resolved\",\n        \"Stoichiometry and architecture of the complex not defined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the molecular identity and clinical relevance: WDR83OS encodes the 106-aa Asterix protein that heterodimerizes with CCDC47 as the PAT complex, and biallelic loss causes a human neurodevelopmental disorder with hypercholanemia recapitulated in zebrafish.\",\n      \"evidence\": \"Family-based exome sequencing with GeneMatcher case matching, zebrafish loss-of-function model, and biochemical characterization of the Asterix–CCDC47 heterodimer\",\n      \"pmids\": [\"39471804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single publication for the disease association\",\n        \"Mechanistic link between PAT chaperone defect and hypercholanemia/lipid phenotype not established at molecular level\",\n        \"Full client repertoire of the PAT complex in vivo undefined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Asterix recognizes specific transmembrane segments and how its chaperone failure produces the tissue-specific phenotypes (neurodevelopment, bile/lipid homeostasis) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural basis for TM-segment selectivity\",\n        \"Causal chain from chaperone loss to hypercholanemia unmapped\",\n        \"Comprehensive client substrate list not defined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [\"PAT complex (Asterix–CCDC47)\"],\n    \"partners\": [\"CCDC47\", \"TRPC6\", \"TMEM208\", \"SEC61\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":4,"faith_pct":75.0}}