{"gene":"PRX","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2018,"finding":"Periaxin (PRX) is expressed specifically in human cerebral endothelial cells (but not in brain endothelium of other mammalian species). In endothelial cells, PRX is predominantly localized to the nucleus. When expressed in mouse endothelial cells, PRX strengthens barrier function, significantly increases transendothelial electrical resistance (~35%), and reduces permeability. The PDZ domain of PRX is necessary and sufficient for barrier-enhancing properties, as the S-PRX splice variant containing only the PDZ domain also increases barrier function. Transcriptome analysis showed that PRX expression suppresses a panel of inflammatory markers, predominantly Type I interferon response genes.","method":"Overexpression in mouse endothelial cells, transendothelial electrical resistance measurement, permeability assays, transcriptome analysis, immunofluorescence localization, splice variant functional comparison","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO/OE with defined cellular phenotype and PDZ domain dissection; single lab study","pmids":["29968755"],"is_preprint":false},{"year":2025,"finding":"PRX encodes two major isoforms: L-PRX (PRXb, 1461 amino acids) and S-PRX (PRXa, 147 amino acids), which differ in their final exon(s) due to intron 6 retention in the S-PRX isoform introducing an earlier stop codon. Loss-of-function variants affecting L-PRX (or both isoforms) cause autosomal recessive neurological phenotypes without cataract. Dominant splicing variants in the intron 6 splice region cause congenital cataract by replacing L-PRX with S-PRX and/or producing aberrant L-PRX through in-frame deletions, likely via a gain-of-function or dominant-negative mechanism affecting lens development. RNA sequencing confirmed aberrant splicing for all identified variants.","method":"Exome and genome sequencing, RNA sequencing confirming aberrant splicing, isoform analysis","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 — RNA-seq validation of splicing mechanism; single study, multiple families","pmids":["41230902"],"is_preprint":false},{"year":2011,"finding":"Mutations in the PRX gene cause autosomal recessive demyelinating Charcot-Marie-Tooth disease type 4F (CMT4F). A novel homozygous PRX mutation (A700PfsX17) was identified in a family with prominent sensory abnormalities and sensory ataxia from early childhood, establishing that PRX loss-of-function disrupts peripheral nerve myelin stability.","method":"Genetic analysis of consanguineous families, sequencing of PRX gene","journal":"Neuropediatrics","confidence":"Medium","confidence_rationale":"Tier 3 — genetic loss-of-function with defined neuropathy phenotype; replicated across multiple independent families and studies","pmids":["18504680","21741241","16534116","25628743","37470010","35810435","36833258"],"is_preprint":false}],"current_model":"Periaxin (PRX) is a PDZ-domain containing protein with two major isoforms (L-PRX and S-PRX) whose PDZ domain is necessary and sufficient for strengthening endothelial barrier function and suppressing Type I interferon response genes in human cerebral endothelial cells; loss-of-function mutations in L-PRX cause autosomal recessive peripheral nerve demyelination (CMT4F) by disrupting myelin stability, while dominant splicing defects that replace L-PRX with S-PRX or produce aberrant L-PRX cause congenital cataract through a likely gain-of-function or dominant-negative mechanism affecting lens cortex adherens junction organization."},"narrative":{"teleology":[{"year":2011,"claim":"Establishing that PRX loss-of-function causes peripheral demyelination resolved the gene's essential role in myelin maintenance and defined CMT4F as a PRX-linked neuropathy.","evidence":"Genetic analysis and sequencing of PRX in consanguineous families with demyelinating neuropathy","pmids":["18504680","21741241","16534116","25628743"],"confidence":"Medium","gaps":["Molecular mechanism by which L-PRX stabilizes peripheral myelin is undefined","Whether S-PRX contributes to peripheral nerve function is unknown","No structural model of full-length L-PRX exists"]},{"year":2018,"claim":"Demonstrating that the PDZ domain alone is necessary and sufficient for endothelial barrier enhancement identified the minimal functional unit and revealed a previously unknown role for PRX in vascular biology and innate immune suppression.","evidence":"Overexpression of full-length PRX and S-PRX (PDZ-only) in mouse endothelial cells with transendothelial electrical resistance, permeability assays, and transcriptome profiling","pmids":["29968755"],"confidence":"Medium","gaps":["Endothelial barrier function was tested only by heterologous overexpression; loss-of-function in human cerebral endothelium not examined","Direct transcriptional targets mediating Type I interferon suppression are unidentified","Nuclear binding partners of PRX in endothelial cells are unknown"]},{"year":2025,"claim":"RNA-seq-validated splicing variants showed that dominant shifts in isoform balance—replacement of L-PRX by S-PRX or production of aberrant L-PRX—cause congenital cataract, establishing isoform-specific pathomechanisms distinct from the recessive neuropathy.","evidence":"Exome/genome sequencing and RNA sequencing of multiple families with congenital cataract confirming aberrant intron 6 splicing","pmids":["41230902"],"confidence":"Medium","gaps":["Whether the cataract mechanism is gain-of-function versus dominant-negative has not been distinguished experimentally","L-PRX interaction partners at lens adherens junctions are uncharacterized","Animal models recapitulating the dominant cataract phenotype are lacking"]},{"year":null,"claim":"The biochemical activities of L-PRX beyond scaffolding—its direct binding partners in myelin, endothelium, and lens, the structural basis of PDZ-domain-mediated barrier function, and the mechanism linking isoform imbalance to dominant cataract—remain open questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No reconstituted biochemical assay for PRX activity exists","Structural basis for PDZ domain function in barrier integrity is unknown","Comprehensive interactome in disease-relevant tissues has not been determined"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":[],"other_free_text":[]},"mechanistic_narrative":"Periaxin (PRX) is a PDZ-domain-containing scaffolding protein expressed as two major isoforms—L-PRX (1461 aa) and S-PRX (147 aa)—that differ by intron 6 retention, and functions in myelin stability, endothelial barrier integrity, and lens development. Loss-of-function mutations affecting L-PRX cause autosomal recessive demyelinating Charcot-Marie-Tooth disease type 4F (CMT4F), characterized by peripheral nerve demyelination with prominent sensory abnormalities [PMID:21741241, PMID:16534116]. In human cerebral endothelial cells, PRX localizes predominantly to the nucleus, strengthens barrier function, and suppresses Type I interferon response genes through a mechanism that requires only its PDZ domain [PMID:29968755]. Dominant splicing variants in the intron 6 region that replace L-PRX with S-PRX or produce aberrant L-PRX cause congenital cataract through a likely gain-of-function or dominant-negative mechanism disrupting lens cortex organization [PMID:41230902]."},"prefetch_data":{"uniprot":{"accession":"Q9BXM0","full_name":"Periaxin","aliases":[],"length_aa":1461,"mass_kda":154.9,"function":"Scaffolding protein that functions as part of a dystroglycan complex in Schwann cells, and as part of EZR and AHNAK-containing complexes in eye lens fiber cells. Required for the maintenance of the peripheral myelin sheath that is essential for normal transmission of nerve impulses and normal perception of sensory stimuli. Required for normal transport of MBP mRNA from the perinuclear to the paranodal regions. Required for normal remyelination after nerve injury. Required for normal elongation of Schwann cells and normal length of the internodes between the nodes of Ranvier. The demyelinated nodes of Ranvier permit saltatory transmission of nerve impulses; shorter internodes cause slower transmission of nerve impulses. Required for the formation of appositions between the abaxonal surface of the myelin sheath and the Schwann cell plasma membrane; the Schwann cell cytoplasm is restricted to regions between these appositions. Required for the formation of Cajal bands and of Schmidt-Lanterman incisures that correspond to short, cytoplasm-filled regions on myelinated nerves. Recruits DRP2 to the Schwann cell plasma membrane. Required for normal protein composition of the eye lens fiber cell plasma membrane and normal eye lens fiber cell morphology","subcellular_location":"Cell membrane; Cell junction","url":"https://www.uniprot.org/uniprotkb/Q9BXM0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRX","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PRX","total_profiled":1310},"omim":[{"mim_id":"619862","title":"SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 32; SCAR32","url":"https://www.omim.org/entry/619862"},{"mim_id":"617583","title":"SULFIREDOXIN 1; SRXN1","url":"https://www.omim.org/entry/617583"},{"mim_id":"614895","title":"CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4F; CMT4F","url":"https://www.omim.org/entry/614895"},{"mim_id":"605725","title":"PERIAXIN; PRX","url":"https://www.omim.org/entry/605725"},{"mim_id":"604769","title":"PEROXIREDOXIN 3; PRDX3","url":"https://www.omim.org/entry/604769"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lung","ntpm":33.7}],"url":"https://www.proteinatlas.org/search/PRX"},"hgnc":{"alias_symbol":["KIAA1620"],"prev_symbol":[]},"alphafold":{"accession":"Q9BXM0","domains":[{"cath_id":"2.30.42.10","chopping":"17-103","consensus_level":"medium","plddt":77.761,"start":17,"end":103}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXM0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXM0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BXM0-F1-predicted_aligned_error_v6.png","plddt_mean":35.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRX","jax_strain_url":"https://www.jax.org/strain/search?query=PRX"},"sequence":{"accession":"Q9BXM0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BXM0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BXM0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BXM0"}},"corpus_meta":[{"pmid":"18501712","id":"PMC_18501712","title":"A novel 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their up-regulation by radiation.","date":"2002","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12163022","citation_count":54,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23186333","id":"PMC_23186333","title":"Prx I suppresses K-ras-driven lung tumorigenesis by opposing redox-sensitive ERK/cyclin D1 pathway.","date":"2013","source":"Antioxidants & redox signaling","url":"https://pubmed.ncbi.nlm.nih.gov/23186333","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11399772","id":"PMC_11399772","title":"Characterization of glutathione amide reductase from Chromatium gracile. 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neurology","url":"https://pubmed.ncbi.nlm.nih.gov/32812023","citation_count":290,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10893423","id":"PMC_10893423","title":"1-Cys peroxiredoxin, a bifunctional enzyme with glutathione peroxidase and phospholipase A2 activities.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10893423","citation_count":283,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28611215","id":"PMC_28611215","title":"Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28611215","citation_count":282,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15941719","id":"PMC_15941719","title":"Oxidative stress-dependent structural and functional switching of a human 2-Cys peroxiredoxin isotype II that enhances HeLa cell resistance to H2O2-induced cell death.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15941719","citation_count":247,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16815975","id":"PMC_16815975","title":"HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFN-induced ISGylation of protein targets.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16815975","citation_count":242,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12650976","id":"PMC_12650976","title":"Aberrant expression of peroxiredoxin subtypes in neurodegenerative disorders.","date":"2003","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/12650976","citation_count":232,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17207965","id":"PMC_17207965","title":"hORFeome v3.1: a resource of human 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[\"16534116\", \"21741241\", \"18504680\", \"25628743\", \"37470010\", \"36833258\", \"35810435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Periaxin (PRX) is expressed specifically in human cerebral endothelial cells (not detected in other mammalian species' brain endothelium) and is predominantly localized to the nucleus; its PDZ domain is necessary and sufficient to strengthen endothelial barrier function, increase transendothelial electrical resistance, reduce permeability, and suppress inflammatory/interferon response genes.\",\n      \"method\": \"Transcriptome analysis, transendothelial electrical resistance measurement, permeability assays, and PDZ domain truncation (S-PRX splice variant) experiments in mouse endothelial cells expressing human PRX\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (TEER, permeability, transcriptomics, domain truncation) in single study\",\n      \"pmids\": [\"29968755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRX has two major isoforms (L-PRX/PRXb and S-PRX/PRXa) differing in their final exon; splice-site mutations in the final intron of PRX cause aberrant splicing of L-PRX (intron retention or small in-frame deletions), effectively switching expression to S-PRX, and this dominant splicing defect results in congenital cataract without neurological phenotype, distinct from the recessive neurological CMT4F phenotype caused by loss of L-PRX.\",\n      \"method\": \"Exome/genome sequencing, RNA sequencing confirming aberrant splicing in affected individuals from four families\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-seq validation of splicing defect across multiple families, functional isoform distinction established\",\n      \"pmids\": [\"41230902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A missense variant (p.V1225M) in the PRX gene was identified in a Chinese family with congenital cataract, broadening the phenotypic spectrum of PRX-associated disease beyond neuropathy.\",\n      \"method\": \"Exome sequencing and Sanger sequencing validation in a four-generation family\",\n      \"journal\": \"QJM : monthly journal of the Association of Physicians\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genetic association only, no direct functional/mechanistic validation of PRX in lens\",\n      \"pmids\": [\"27081207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PRX-1 (paired-related homeobox 1) acts cooperatively with PRX-2 to maintain cell fates within the craniofacial mesenchyme; double prx-1;prx-2 mutant mice display novel phenotypes (absent mandibular incisor, absent Meckel's cartilage, hyoid arch cells adopting first branchial arch identity) not seen in single mutants, and both genes regulate pax9 and patched expression in mandibular arch mesenchyme.\",\n      \"method\": \"Genetic epistasis via double-mutant mice, lacZ fate-mapping, transgene reporter, marker gene expression analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple orthogonal readouts (fate mapping, marker genes, transgenic reporter), replicated finding\",\n      \"pmids\": [\"9876178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The PRX-1/PRX-2 homeobox transcription factor complex binds an ATTA-sequence-containing element near the PDGFRA transcription initiation site together with PBX, controlling PDGFRA promoter activity during differentiation; mutation of these binding sites strongly impairs promoter activity.\",\n      \"method\": \"Promoter-reporter assay, mutagenesis of transcription factor binding sites, EMSA/transcriptional complex identification in Tera-2 embryonal carcinoma cells\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter mutagenesis and reporter assay establishing PRX as transcriptional regulator of PDGFRA\",\n      \"pmids\": [\"12393181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PRX-2 (paired-related homeobox 2) regulates fetal but not adult fibroblast wound healing responses; Prx-2-/- fetal fibroblasts show altered cellular proliferation, extracellular matrix reorganization, MMP2 and hyaluronic acid production compared to wild-type, while adult fibroblast behavior is unaffected.\",\n      \"method\": \"Knockout mouse fibroblasts (Prx-2-/- vs. wild-type), RNase protection analysis, functional assays (proliferation, ECM reorganization, MMP2 and HA production)\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular phenotypes with multiple functional readouts from KO fibroblasts\",\n      \"pmids\": [\"12535210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Maturation of mitochondrially targeted Prx V (peroxiredoxin 5) involves sequential cleavage: first by mitochondrial processing peptidase (MPP) generating an unstable intermediate (I-Prx V) with a destabilizing N-terminal phenylalanine, then by mitochondrial intermediate peptidase (MIP) to produce the stable mature form. Elevated mitochondrial H2O2 inhibits MIP, causing accumulation and subsequent degradation of I-Prx V, thus reducing mature Prx V levels.\",\n      \"method\": \"Cell fractionation, Western blot, deletion of Prx III and Srx in mouse tissues to elevate mitochondrial H2O2, rotenone treatment of HeLa cells\",\n      \"journal\": \"Antioxidants (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and pharmacological interventions with consistent mechanistic outcome\",\n      \"pmids\": [\"33669127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mutagenesis and NMR-based modeling of the sulfiredoxin (hSrx)–Prx I complex identified Asp187 of Prx I as the catalytic residue responsible for ATP hydrolysis during sulfiredoxin-mediated reduction of hyperoxidized Prx cysteinesulfinic acid; D187A mutant retains hSrx binding but abolishes ATP hydrolysis and reduction, while D187N retains both.\",\n      \"method\": \"Site-directed mutagenesis (D187A, D187N), NMR structure of ATP-bound hSrx, EMAP-CHARMM docking of hSrx-Prx complex, binding and activity assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure plus mutagenesis with catalytic mechanism defined in single rigorous study\",\n      \"pmids\": [\"17176052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Peroxiredoxin-1 (Prx-1) interacts with ASK1 via the thioredoxin-binding domain of ASK1 in a H2O2-inducible and redox-sensitive manner; catalytic cysteine mutants (C52A, C173A, C52A/C173A) of Prx-1 cannot undergo H2O2-induced interaction with ASK1. Prx-1 overexpression inhibits ASK1 activation and downstream MKK3/6 and p38 signaling; Prx-1 knockdown leads to rapid ASK1, p38, and JNK activation and apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, catalytic cysteine mutagenesis, overexpression and siRNA knockdown with kinase activation readouts (Western blot, apoptosis assay)\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with mutagenesis plus gain/loss-of-function with multiple orthogonal readouts\",\n      \"pmids\": [\"18501712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PRX 1 (peroxiredoxin 1) is upregulated by laminar shear stress (LS) in bovine aortic endothelial cells and functions as a mechanosensitive antioxidant; PRX 1 knockdown via siRNA attenuated LS-dependent reduction of reactive oxygen species, while PRX 5 knockdown did not, establishing PRX 1 as the specific mediator of shear-dependent ROS reduction.\",\n      \"method\": \"Western blot, immunofluorescence, siRNA knockdown of PRX 1 and PRX 5 in endothelial cells under defined laminar/oscillatory shear conditions, ROS measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA KD with specific functional readout (ROS) distinguishing PRX1 from PRX5 isoform\",\n      \"pmids\": [\"18024958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Absence of PrxI activates the DNA damage-dependent apoptosis pathway in response to TNF-α-induced H2O2 via interaction with H2AX, while absence of PrxII activates the RIPK1-dependent apoptosis pathway by allowing H2O2-mediated oxidation of Cys308 in cIAP1-BIR3 domain, inducing cIAP1 dimerization and E3 ligase activation leading to cIAP1 destruction; these distinct routes are mediated by differential interaction of PrxI with H2AX and PrxII with cIAP1.\",\n      \"method\": \"PrxI/II knockout cell lines, TNF-α treatment, cysteine mutagenesis (Cys308 of cIAP1), co-immunoprecipitation of PrxI-H2AX and PrxII-cIAP1, cell death assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO cells, mutagenesis, reciprocal Co-IP, multiple pathway readouts establishing mechanistic distinction between two Prx isoforms\",\n      \"pmids\": [\"30784599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Nicotinamide nucleotide transhydrogenase (Nnt) provides the critical link between mitochondrial respiration and H2O2 detoxification via the thioredoxin/peroxiredoxin (Trx/Prx) system in brain mitochondria by generating NADPH from NADH using the proton gradient; Nnt inhibition increases oxidized mitochondrial Prx levels, decreases H2O2 catabolism, and renders dopaminergic cells more susceptible to oxidative stress.\",\n      \"method\": \"Pharmacological inhibition and lentiviral knockdown of Nnt, isolated brain mitochondria H2O2 consumption assays, NADPH/NADP+ measurement, oxidized Prx immunoblotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (pharmacological + genetic KD) with defined mechanistic pathway linking Nnt-NADPH to Trx/Prx activity\",\n      \"pmids\": [\"24722990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Mouse Prx-IV (peroxiredoxin 4) is localized to the cytoplasm/organellar compartment (nucleus-excluded region), not secreted into conditioned media of cultured cells; overexpression of mouse Prx-IV prevents ROS production induced by epidermal growth factor or p53.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, conditioned media analysis, ROS measurement after EGF or p53 overexpression with Prx-IV co-expression\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct localization with functional overexpression ROS readout, single lab\",\n      \"pmids\": [\"11229364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Prx I suppresses K-ras(G12D)-driven lung adenocarcinogenesis by opposing the ROS-dependent ERK/cyclin D1 pathway; Prx I null mutation in K-ras(G12D) transgenic mice greatly increased lung tumor number and size via ROS-dependent ERK/cyclin D1 pathway activation; Prx I is induced via Nrf2 transcription in tumor regions.\",\n      \"method\": \"Prx I null/K-ras(G12D) double mutant mice, tumor quantification, ROS measurement, ERK/cyclin D1 pathway analysis by Western blot, Nrf2 transcriptional analysis\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vivo with pathway analysis, single lab\",\n      \"pmids\": [\"23186333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cisplatin selectively induces autophagic degradation of PrxI (not other Prx isoforms) in kidney proximal tubular cells via cisplatin-induced ER stress and CYP2E1-generated ROS on the ER surface; 3-methyladenine (autophagy inhibitor) and ATG7 KO block PrxI degradation; PrxI ablation exacerbates cisplatin nephrotoxicity.\",\n      \"method\": \"Cisplatin treatment of mice and MEF cells, ATG7 KO MEF, autophagy inhibitor (3-methyladenine), CYP2E1 overexpression, Western blot for PrxI isoform selectivity\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO plus pharmacological inhibition with mechanistic pathway placement, single lab\",\n      \"pmids\": [\"39366472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Prx II (peroxiredoxin 2) physically associates with brain-type creatine kinase (CKBB) under normal conditions and this interaction is enhanced by heat stress; temperature-induced oligomerization of Prx II promotes association with CKBB and may protect CKBB enzyme activity during heat-induced stress.\",\n      \"method\": \"Co-immunoprecipitation with HA-Prx II and Flag-CKBB in A549 and HeLa cell lysates under normal and heat stress conditions\",\n      \"journal\": \"Ukrainian biochemical journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 + Weak — single Co-IP experiment, limited mechanistic follow-up\",\n      \"pmids\": [\"29227081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Prx II deletion in MEF cells accelerates cellular senescence via ROS-mediated activation of the Ras-ERK-NFκB pathway; elevated ERK activity (not NFκB) mediates the senescent phenotype as demonstrated by ERK inhibitor PD98059 reversal of SA-β-galactosidase-positive cell formation and increased p16 and cell cycle arrest.\",\n      \"method\": \"Prx II-/- MEF, SA-β-galactosidase assay, pharmacological ERK inhibition (PD98059), NFκB inhibition (TPCK), cell cycle analysis, p16/p21/p53 Western blot\",\n      \"journal\": \"Free radical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with multiple signaling pathway readouts and pharmacological epistasis, single lab\",\n      \"pmids\": [\"17050172\", \"16109412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Prx II preserves mitochondrial integrity by facilitating the formation of endoplasmic reticulum–mitochondria contact sites (EMCSs); Prx II regulates a novel axis (Prx II → ATF3 → miR-181b-5p) that modulates expression of Armcx3, a protein involved in mitochondrial transport, and maintains mitochondrial Ca2+ homeostasis to prevent mitochondria-dependent apoptosis.\",\n      \"method\": \"Prx II KD and overexpression in HT22 cells, transmission electron microscopy, RNA sequencing, bioinformatic analysis of EMCS length, miR-181b-5p pathway validation\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD/OE with TEM, RNA-seq, and pathway identification, single lab\",\n      \"pmids\": [\"38637880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Xenopus prx-1 (ortholog of mammalian PRX-1 homeobox gene) is expressed in mononuclear cells under the epidermis of skin wounds and regenerating limbs; the mouse prx1 limb-specific enhancer is active during scarless wound healing in Xenopus froglets but not during adult mouse wound healing, suggesting that prx1 enhancer activation is required for scarless wound healing and epimorphic regeneration.\",\n      \"method\": \"Transgenic Xenopus expressing mouse prx1 limb-specific enhancer reporter, in situ hybridization, immunostaining, skin excision wound healing model\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic enhancer reporter in vivo with direct functional context, single lab\",\n      \"pmids\": [\"21776009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PrxI silencing in bladder cancer T24 cells suppresses growth, promotes apoptosis, and reduces phospho-NF-κB p50 and p65 expression, placing PrxI upstream of the NF-κB signaling pathway in bladder cancer cell survival.\",\n      \"method\": \"Prx-I shRNA transfection in T24 cells, NF-κB phosphorylation Western blot, cell growth and apoptosis assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA KD with defined pathway placement (NF-κB), single lab\",\n      \"pmids\": [\"24904997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Prx I knockout mice demonstrate reduced tissue reducing activity in liver and kidney and greater susceptibility to Fe-NTA-induced oxidative damage (elevated serum AST/ALT), demonstrating that Prx I functions as a key cytoplasmic peroxidase for intracellular hydroperoxide reduction in vivo.\",\n      \"method\": \"Prx I-/- mice (gene trap), Fe-NTA oxidative stress model, real-time EPR imaging of nitroxyl radical reduction in vivo, serum transaminase measurement\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with direct EPR imaging of redox activity plus biochemical readouts, strong mechanistic demonstration\",\n      \"pmids\": [\"16297875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Prx II-deficient bone marrow cells and splenocytes, constitutive endogenous ROS production is elevated, leading to enhanced T lymphocyte and dendritic cell activation, increased splenocyte proliferation, and augmented dendritic cell differentiation; Prx II functions to inhibit immune cell responsiveness by scavenging low levels of ROS.\",\n      \"method\": \"Prx II-/- mice, splenocyte/PBMC counts, CD3+ T cell and CD11c+ DC quantification, MLR assay, ConA-induced proliferation, bone marrow transplantation\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mice with multiple immunological readouts and bone marrow transplant epistasis, single lab\",\n      \"pmids\": [\"16290204\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRX (periaxin) is a PDZ domain-containing protein essential for peripheral nerve myelin maintenance (loss-of-function causing CMT4F), whose PDZ domain also strengthens endothelial barrier function and suppresses inflammatory gene programs in human cerebral endothelium; the gene's two isoforms (L-PRX and S-PRX) have distinct functions, with splice defects causing dominant congenital cataract. Separately, the peroxiredoxin (Prx) family members (Prx I–VI) are thiol-based peroxidases that reduce H2O2 and organic peroxides using thioredoxin as electron donor, regulated by sulfiredoxin-mediated ATP-dependent repair of hyperoxidized cysteinesulfinic acid (requiring Asp187 of Prx I for ATP hydrolysis), and they modulate diverse signaling pathways including ASK1/p38/JNK apoptosis, Ras-ERK-NFκB senescence, RIPK1-dependent and DNA damage-dependent apoptosis, and Nrf2-dependent tumor suppression, with their subcellular localization and proteolytic maturation (particularly mitochondrial Prx V) subject to redox-dependent regulation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI need to carefully classify each paper before extracting discoveries. The gene PRX here refers to **periaxin (PRX)**, a human gene encoding a PDZ-domain containing protein involved in peripheral nerve myelin maintenance and lens development, with mutations causing CMT4F (Charcot-Marie-Tooth type 4F).\n\nLet me classify the papers:\n\n**KEEP (canonical periaxin PRX protein):**\n- [26] Wang MM 2018 (PMID:29968755) - PRX/periaxin in cerebral endothelial cells, PDZ domain, barrier function ✓\n- [28] Nouioua S 2011 (PMID:21741241) - PRX gene mutations, CMT4F ✓\n- [29] Kabzinska D 2006 (PMID:16534116) - PRX gene mutations, CMT4F ✓\n- [33] Auer-Grumbach M 2008 (PMID:18504680) - PRX mutations, CMT ✓\n- [41] Yuan L 2016 (PMID:27081207) - PRX variant, congenital cataract ✓\n- [45] Zaman Q 2023 (PMID:36833258) - PRX variants, CMT4F ✓\n- [53] Choi YJ 2014 (PMID:25628743) - PRX mutations, DSN ✓\n- [65] Ma X 2023 (PMID:37470010) - PRX mutations, CMT4F, periaxin ✓\n- [79] Yang Y 2022 (PMID:35810435) - PRX gene variants, CMT4F ✓\n- [86] Reis LM 2025 (PMID:41230902) - PRX splicing, cataract, isoforms of periaxin ✓\n- [100] Hall S 2024 preprint (bio_10.1101_2024.05.21.595255) - periaxin/Prx used as myelinating glial marker ✓\n\n**EXCLUDE (alias collision - these \"Prx\" papers are about peroxiredoxins, not periaxin):**\n- [1]-[13], [16]-[17], [19]-[25], [27], [30]-[32], [34]-[40], [42]-[44], [46]-[48], [51]-[52], [54]-[58], [60]-[61], [63]-[64], [66]-[75], [77]-[78], [80]-[82], [84]-[85], [87]-[90], [92]-[98] — all about peroxiredoxins (Prx family antioxidant enzymes), NOT periaxin\n\n**EXCLUDE (other symbol collisions or unrelated):**\n- [2] prx-1/prx-2 homeobox genes - these are paired-related homeobox genes PRX1/PRX2, not periaxin PRX\n- [3] PRX-00023 - drug compound, not the gene\n- [5] PRX-2 homeobox - paired-related homeobox, not periaxin\n- [10] Xenopus prx1 homeobox - homeobox gene, not periaxin\n- [15] PRX-03140 - drug\n- [18] PRX-07034 - drug\n- [23] PRX-08066 - drug\n- [34] PRX-2 homeobox - paired-related homeobox\n- [35] Ol-Prx3 - homeobox gene in medaka\n- [37] PRX-00023 - drug\n- [44] PRX-00023 - drug\n- [46] Xenopus prx-1 homeobox - homeobox gene\n- [47] PRX-00023 - drug\n- [48] PRX homeobox transcription factors - paired-related homeobox\n- [49] PRX-102 - enzyme replacement therapy for Fabry disease\n- [50] PRX gene family in pears - plant class III peroxidases\n- [59] PRX genes in cucumber - plant peroxidases\n- [62] PRX-07034 - drug\n- [66] GhPRXR1-A in cotton - plant class III peroxidase\n- [67] PRX sports drink - nutritional supplement\n- [74] PRX-119 - PEGylated DNase I\n- [76] PRX-P4-003 - prodrug\n- [83] PRx (pressure reactivity index) - clinical monitoring index, not the gene\n- [91] PRX-rs3814290 - genomic variant mention in population genetics paper\n- [92] PRX-11/PEX11 in C. elegans - peroxisome fission protein, not periaxin\n- [93] PRX+ alveolar microvasculature - mentions periaxin as marker but no mechanism\n- [95] PRX-3140 - drug\n- [96] Prx (paratox) in Streptococcus - bacterial protein, symbol collision\n- [99] PRx (pressure reactivity index) - clinical monitoring\n- [78] PRX-11 in C. elegans - peroxisome fission protein\n\n**Additional gene2pubmed papers:**\n- Most are generic proteomics/interactome papers with no specific periaxin mechanism\n- [19] Crystal structure of hORF6 (peroxiredoxin) - EXCLUDE, peroxiredoxin\n- [15] Prx 1-Cys characterization - EXCLUDE, peroxiredoxin  \n- [24] 1-Cys peroxiredoxin bifunctional - EXCLUDE, peroxiredoxin\n- [26] 2-Cys peroxiredoxin - EXCLUDE, peroxiredoxin\n- [28] Peroxiredoxin subtypes in neurodegeneration - EXCLUDE, peroxiredoxins\n\nNow extracting discoveries only from KEPT periaxin papers:\n\n**Paper [26] PMID:29968755** - Wang MM 2018: PRX (periaxin) expressed specifically in human cerebral endothelial cells; localized to nucleus; PDZ domain necessary and sufficient for barrier-enhancing function; S-PRX (PDZ domain only splice variant) also increases barrier; PRX suppresses inflammatory/IFN response genes; strengthens transendothelial electrical resistance ~35%.\n\n**Paper [86] PMID:41230902** - Reis LM 2025: PRX has two major isoforms (L-PRX/PRXb, 1461 aa; S-PRX/PRXa, 147 aa) differing in final exon(s). Intron 6 retention switches L-PRX to S-PRX. Loss-of-function affecting L-PRX causes recessive neurological phenotypes; dominant splicing variants causing cataract by replacing L-PRX with S-PRX or producing aberrant L-PRX, possibly gain-of-function/dominant-negative. RNA sequencing confirmed aberrant splicing.\n\n**Papers [28], [29], [33], [45], [53], [65], [79]** - Clinical genetics papers reporting PRX mutations causing CMT4F/DSN - these describe genotype-phenotype but not molecular mechanism per se. However, they establish periaxin's role in peripheral nerve myelin maintenance through loss-of-function.\n\n**Paper [100] preprint** - Hall S 2024: periaxin/Prx used as marker for myelinating glial cells; spatial analysis of selectively expressed myelinating (periaxin/Prx, claudin 19/Cldn19) glial cell genes by scRNA-seq - this identifies PRX expression as a marker but no new mechanism.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"Periaxin (PRX) is expressed specifically in human cerebral endothelial cells (but not in brain endothelium of other mammalian species). In endothelial cells, PRX is predominantly localized to the nucleus. When expressed in mouse endothelial cells, PRX strengthens barrier function, significantly increases transendothelial electrical resistance (~35%), and reduces permeability. The PDZ domain of PRX is necessary and sufficient for barrier-enhancing properties, as the S-PRX splice variant containing only the PDZ domain also increases barrier function. Transcriptome analysis showed that PRX expression suppresses a panel of inflammatory markers, predominantly Type I interferon response genes.\",\n      \"method\": \"Overexpression in mouse endothelial cells, transendothelial electrical resistance measurement, permeability assays, transcriptome analysis, immunofluorescence localization, splice variant functional comparison\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/OE with defined cellular phenotype and PDZ domain dissection; single lab study\",\n      \"pmids\": [\"29968755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRX encodes two major isoforms: L-PRX (PRXb, 1461 amino acids) and S-PRX (PRXa, 147 amino acids), which differ in their final exon(s) due to intron 6 retention in the S-PRX isoform introducing an earlier stop codon. Loss-of-function variants affecting L-PRX (or both isoforms) cause autosomal recessive neurological phenotypes without cataract. Dominant splicing variants in the intron 6 splice region cause congenital cataract by replacing L-PRX with S-PRX and/or producing aberrant L-PRX through in-frame deletions, likely via a gain-of-function or dominant-negative mechanism affecting lens development. RNA sequencing confirmed aberrant splicing for all identified variants.\",\n      \"method\": \"Exome and genome sequencing, RNA sequencing confirming aberrant splicing, isoform analysis\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-seq validation of splicing mechanism; single study, multiple families\",\n      \"pmids\": [\"41230902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mutations in the PRX gene cause autosomal recessive demyelinating Charcot-Marie-Tooth disease type 4F (CMT4F). A novel homozygous PRX mutation (A700PfsX17) was identified in a family with prominent sensory abnormalities and sensory ataxia from early childhood, establishing that PRX loss-of-function disrupts peripheral nerve myelin stability.\",\n      \"method\": \"Genetic analysis of consanguineous families, sequencing of PRX gene\",\n      \"journal\": \"Neuropediatrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic loss-of-function with defined neuropathy phenotype; replicated across multiple independent families and studies\",\n      \"pmids\": [\"18504680\", \"21741241\", \"16534116\", \"25628743\", \"37470010\", \"35810435\", \"36833258\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Periaxin (PRX) is a PDZ-domain containing protein with two major isoforms (L-PRX and S-PRX) whose PDZ domain is necessary and sufficient for strengthening endothelial barrier function and suppressing Type I interferon response genes in human cerebral endothelial cells; loss-of-function mutations in L-PRX cause autosomal recessive peripheral nerve demyelination (CMT4F) by disrupting myelin stability, while dominant splicing defects that replace L-PRX with S-PRX or produce aberrant L-PRX cause congenital cataract through a likely gain-of-function or dominant-negative mechanism affecting lens cortex adherens junction organization.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"The PRX gene encodes periaxin, a PDZ domain-containing scaffolding protein essential for peripheral nerve myelin maintenance, whose loss-of-function mutations cause autosomal recessive Charcot-Marie-Tooth type 4F (CMT4F) demyelinating neuropathy [PMID:16534116, PMID:21741241]. PRX produces two major isoforms (L-PRX and S-PRX) with distinct tissue functions: L-PRX is required for peripheral myelination, while dominant splice-site mutations that shift expression toward S-PRX cause congenital cataract without neuropathy [PMID:41230902]. In human cerebral endothelial cells, periaxin localizes predominantly to the nucleus, where its PDZ domain strengthens the endothelial barrier, increases transendothelial electrical resistance, and suppresses inflammatory and interferon-response gene programs [PMID:29968755]. Note: multiple timeline entries concern the peroxiredoxin (PRDX) family and the paired-related homeobox (PRRX) genes, which are distinct loci from periaxin PRX.\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing that PRX is a peripheral myelin maintenance gene whose loss causes CMT4F resolved the molecular basis of this demyelinating neuropathy and identified periaxin as a structural/scaffolding component of Schwann cell biology.\",\n      \"evidence\": \"Identification of homozygous nonsense and frameshift mutations in PRX across multiple independent CMT4F families with consistent severe demyelination phenotype\",\n      \"pmids\": [\"16534116\", \"21741241\", \"18504680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise molecular mechanism by which periaxin maintains myelin compaction is not defined\",\n        \"Direct binding partners of PRX in Schwann cells beyond DRP2 are incompletely characterized in the timeline\",\n        \"No structural model of full-length L-PRX\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that PRX is expressed in human (but not other mammalian) cerebral endothelium and that its PDZ domain strengthens barrier function and suppresses inflammatory gene programs established a novel, species-specific vascular role for periaxin beyond myelination.\",\n      \"evidence\": \"Transcriptomic profiling, TEER measurement, permeability assays, and PDZ domain truncation experiments in mouse endothelial cells expressing human PRX\",\n      \"pmids\": [\"29968755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Endothelial barrier function of PRX has not been validated in vivo or in primary human brain endothelium\",\n        \"Mechanism linking nuclear PRX PDZ domain to transcriptional suppression of interferon-response genes is unknown\",\n        \"Whether PRX interacts with junctional proteins or chromatin remodelers in endothelial cells is not determined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying that splice-site mutations in the final intron of PRX cause dominant congenital cataract by aberrantly shifting L-PRX expression toward S-PRX revealed isoform-specific disease mechanisms and genotype-phenotype distinctions at a single locus.\",\n      \"evidence\": \"Exome/genome sequencing with RNA-seq validation of aberrant splicing in four independent families with congenital cataract\",\n      \"pmids\": [\"41230902\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional role of L-PRX versus S-PRX in lens fiber cells has not been directly demonstrated\",\n        \"Whether S-PRX exerts a dominant-negative effect or whether L-PRX haploinsufficiency alone suffices is unresolved\",\n        \"Animal models recapitulating the cataract phenotype are lacking\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how periaxin's PDZ domain mechanistically connects to both myelin maintenance in Schwann cells and barrier/transcriptional regulation in endothelial cells, and whether the two isoforms have distinct interactomes in each tissue context.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No proteomics-based interactome for L-PRX or S-PRX in relevant cell types\",\n        \"No structural model of the PRX PDZ domain in complex with a physiological ligand\",\n        \"In vivo role of PRX in human blood-brain barrier integrity has not been tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Periaxin (PRX) is a PDZ-domain-containing scaffolding protein expressed as two major isoforms—L-PRX (1461 aa) and S-PRX (147 aa)—that differ by intron 6 retention, and functions in myelin stability, endothelial barrier integrity, and lens development. Loss-of-function mutations affecting L-PRX cause autosomal recessive demyelinating Charcot-Marie-Tooth disease type 4F (CMT4F), characterized by peripheral nerve demyelination with prominent sensory abnormalities [PMID:21741241, PMID:16534116]. In human cerebral endothelial cells, PRX localizes predominantly to the nucleus, strengthens barrier function, and suppresses Type I interferon response genes through a mechanism that requires only its PDZ domain [PMID:29968755]. Dominant splicing variants in the intron 6 region that replace L-PRX with S-PRX or produce aberrant L-PRX cause congenital cataract through a likely gain-of-function or dominant-negative mechanism disrupting lens cortex organization [PMID:41230902].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing that PRX loss-of-function causes peripheral demyelination resolved the gene's essential role in myelin maintenance and defined CMT4F as a PRX-linked neuropathy.\",\n      \"evidence\": \"Genetic analysis and sequencing of PRX in consanguineous families with demyelinating neuropathy\",\n      \"pmids\": [\"18504680\", \"21741241\", \"16534116\", \"25628743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism by which L-PRX stabilizes peripheral myelin is undefined\",\n        \"Whether S-PRX contributes to peripheral nerve function is unknown\",\n        \"No structural model of full-length L-PRX exists\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that the PDZ domain alone is necessary and sufficient for endothelial barrier enhancement identified the minimal functional unit and revealed a previously unknown role for PRX in vascular biology and innate immune suppression.\",\n      \"evidence\": \"Overexpression of full-length PRX and S-PRX (PDZ-only) in mouse endothelial cells with transendothelial electrical resistance, permeability assays, and transcriptome profiling\",\n      \"pmids\": [\"29968755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Endothelial barrier function was tested only by heterologous overexpression; loss-of-function in human cerebral endothelium not examined\",\n        \"Direct transcriptional targets mediating Type I interferon suppression are unidentified\",\n        \"Nuclear binding partners of PRX in endothelial cells are unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"RNA-seq-validated splicing variants showed that dominant shifts in isoform balance—replacement of L-PRX by S-PRX or production of aberrant L-PRX—cause congenital cataract, establishing isoform-specific pathomechanisms distinct from the recessive neuropathy.\",\n      \"evidence\": \"Exome/genome sequencing and RNA sequencing of multiple families with congenital cataract confirming aberrant intron 6 splicing\",\n      \"pmids\": [\"41230902\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the cataract mechanism is gain-of-function versus dominant-negative has not been distinguished experimentally\",\n        \"L-PRX interaction partners at lens adherens junctions are uncharacterized\",\n        \"Animal models recapitulating the dominant cataract phenotype are lacking\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical activities of L-PRX beyond scaffolding—its direct binding partners in myelin, endothelium, and lens, the structural basis of PDZ-domain-mediated barrier function, and the mechanism linking isoform imbalance to dominant cataract—remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No reconstituted biochemical assay for PRX activity exists\",\n        \"Structural basis for PDZ domain function in barrier integrity is unknown\",\n        \"Comprehensive interactome in disease-relevant tissues has not been determined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```"}