{"gene":"PEX7","run_date":"2026-04-29T11:37:58","timeline":{"discoveries":[{"year":1997,"finding":"Human PEX7 encodes the cytosolic receptor for peroxisomal matrix proteins bearing the type-2 peroxisome targeting signal (PTS2). Expression of human or murine PEX7 in RCDP patient fibroblasts corrects the PTS2-import defect, demonstrating its role as the PTS2 receptor required for peroxisomal matrix protein import.","method":"Complementation assay in RCDP fibroblasts; PTS2 import rescue; homology cloning","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1-2 — two independent labs simultaneously demonstrated complementation of PTS2 import defect in patient cells, strong replication","pmids":["9090381","9090383"],"is_preprint":false},{"year":1997,"finding":"Mutations in PEX7 (e.g., L292ter, A218V, G217R) cause rhizomelic chondrodysplasia punctata (RCDP), establishing PEX7 as the gene responsible for PBD complementation group 11. Loss-of-function alleles result in mislocalisation of PTS2-targeted enzymes (including thiolase and DHAP-AT) to the cytoplasm.","method":"Mutation identification in 36 RCDP probands; functional complementation in patient fibroblasts; PTS2 import and DHAP-AT activity assays","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1-2 — two independent studies with functional complementation assays and patient mutation data","pmids":["9090381","9090383"],"is_preprint":false},{"year":2002,"finding":"Disease severity in RCDP correlates with residual PEX7 protein activity: alleles that completely abolish PTS2 import cause severe phenotype, while alleles retaining partial PTS2 import capacity (detectable upon overexpression) are associated with milder phenotypes. Reduced amounts of normal Pex7p also associate with milder phenotype.","method":"Expression of 24 mutant PEX7 alleles in RCDP fibroblasts; PTS2 marker protein import assay; Northern/RT-PCR analysis of RNA; phenotype-genotype correlation in 60 probands","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1-2 — functional complementation of multiple alleles with phenotypic correlation, two independent studies","pmids":["12325024","11781871"],"is_preprint":false},{"year":2003,"finding":"PEX7 mutations can produce a broad clinical spectrum beyond severe RCDP, including a milder Refsum disease phenotype. PEX7 mutations cause defects in phytanic acid alpha-oxidation, plasmalogen synthesis, and peroxisomal thiolase processing, identifying PEX7 as a second gene responsible for Refsum disease.","method":"Linkage analysis; biochemical analysis of peroxisomal functions; PEX7 mutation identification in Refsum disease patients without PHYH mutations","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic and biochemical evidence linking PEX7 to a second disease entity, replicated in multiple patients","pmids":["12522768"],"is_preprint":false},{"year":2003,"finding":"Pex7 knockout mice recapitulate the human RCDP phenotype: severe plasmalogen depletion, impaired phytanic acid alpha-oxidation, impaired VLCFA beta-oxidation, delayed neuronal migration in the developing cortex, and defects in endochondral ossification of distal limb bones, establishing PEX7's necessity for normal brain development and skeletogenesis.","method":"Pex7 mouse knockout generation; biochemical assays (plasmalogens, phytanic acid, VLCFA); in vivo neuronal birthdating; bone ossification analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — rigorous KO mouse model with multiple biochemical and cellular phenotypic readouts","pmids":["12915479"],"is_preprint":false},{"year":2011,"finding":"The PTS2 signal forms an amphipathic helix with all conserved residues on one face. 3D structural modeling of PEX7 reveals a complementary groove for PTS2 binding. Mammalian two-hybrid assays and cross-complementation of a PTS2 mutation by a compensatory PEX7 mutation confirm this interaction interface, enabling identification of novel PTS2 proteins including KChIP4.","method":"Sequence/physical property analysis; 3D structural modeling; site-directed mutagenesis; mammalian two-hybrid; cross-complementation assays; PTS2 prediction algorithm","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — structural modeling combined with mutagenesis and functional cross-complementation in a single study","pmids":["22057399"],"is_preprint":false},{"year":2014,"finding":"PEX7 is transported to the peroxisome as a PEX5-PEX7-PTS2 cargo complex in a PEX5- and cargo-dependent manner. PEX7 becomes protease-resistant (fully entering the peroxisomal lumen) upstream of PEX5 monoubiquitination, and cargo release occurs at the trans-side of the membrane. Export of PEX7 back to the cytosol requires PEX5 export but the two export events are not strictly coupled, indicating they leave separately.","method":"In vitro co-import/export assays; protease protection assays; biochemical fractionation; dominant-negative and time-course analyses","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — reconstitution-style in vitro import/export assays with rigorous biochemical controls","pmids":["24865970"],"is_preprint":false},{"year":2015,"finding":"The export competence of peroxisomal PEX7 is determined by the specific PEX5 molecule that transported it to the peroxisome, implying PEX7 is retained at the docking/translocation machinery (DTM) during peroxisomal steps. Cargo (PTS2 protein) is released into the organelle matrix by DTM-embedded PEX7, and PTS2 cleavage is not required for cargo release.","method":"In vitro co-import/export assays with pre-assembled trimeric PEX5-PEX7-PTS2 complexes; biochemical fractionation","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro assays with defined complexes","pmids":["26138649"],"is_preprint":false},{"year":2000,"finding":"PEX7 spans 102 kb on chromosome 6q21-q22.2 and contains at least 10 exons. Alternative splicing produces eight smaller PEX7 transcripts, but none of these splice forms can restore PTS2 protein import in RCDP fibroblasts, indicating they are non-functional for the canonical receptor role.","method":"Gene structure characterization; expression of alternative splice variants in RCDP fibroblasts; PTS2 import assay","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — functional complementation assay for splice variants, single study","pmids":["10673331"],"is_preprint":false},{"year":2009,"finding":"A Pex7 hypomorphic mouse model (Pex7 transcript <5% of wild-type) develops early cataracts, skeletal abnormalities (delayed endochondral ossification, abnormal lens fibers), tissue plasmalogen deficiency, phytanic acid accumulation, and reduced PTS2 cargo import, identifying the lens and skeleton as particularly sensitive to plasmalogen deficiency.","method":"Hypomorphic mouse engineering; biochemical assays (plasmalogens, phytanic acid); PTS2 import assay; histology; dietary supplementation experiments","journal":"Molecular genetics and metabolism","confidence":"High","confidence_rationale":"Tier 2 — well-characterized hypomorphic model with multiple biochemical and histological readouts","pmids":["20060764"],"is_preprint":false},{"year":2007,"finding":"In Trypanosoma brucei, PEX7 depletion by RNAi causes mislocalization of PTS2-containing proteins to the cytosol in bloodstream-form trypanosomes, and mislocalization of both PTS1, PTS2, and I-PTS proteins in procyclic cells. T. brucei PEX7 can bind PEX5, and both receptors are essential for parasite viability.","method":"RNA interference; immunofluorescence; subcellular fractionation; growth assays","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi knockdown with direct localization readouts, single study in a non-mammalian organism (relevant ortholog)","pmids":["17320990"],"is_preprint":false},{"year":2018,"finding":"Drosophila Pex7, despite no identified PTS2 cargo in flies, functions as a bona fide PTS2 receptor: it can rescue PTS2 protein (thiolase) targeting to peroxisomes in human PEX7-mutant fibroblasts. Pex7 fly mutants show lipid processing defects with mild brain developmental effects, distinct from the severe Pex5 mutant phenotype.","method":"Drosophila Pex7 mutant characterization; rescue of human RCDP fibroblasts by Drosophila Pex7 expression; lipid analysis; developmental phenotyping","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — cross-species complementation assay with biochemical phenotyping, single study","pmids":["30389805"],"is_preprint":false}],"current_model":"PEX7 is the cytosolic PTS2 receptor that forms a trimeric complex with PEX5 and PTS2-containing cargo proteins, shuttles into the peroxisomal lumen in a PEX5- and cargo-dependent manner upstream of PEX5 monoubiquitination, releases cargo at the trans-side of the membrane (independent of PTS2 cleavage) while retained at the docking/translocation machinery, and is then exported back to the cytosol separately from but dependent on PEX5 export; loss-of-function mutations in PEX7 cause rhizomelic chondrodysplasia punctata (RCDP) and a subset of Refsum disease by preventing peroxisomal import of plasmalogens biosynthesis enzymes, thiolase, and phytanoyl-CoA hydroxylase."},"narrative":{"teleology":[{"year":1997,"claim":"Identification of PEX7 as the PTS2 receptor resolved the molecular basis of RCDP and revealed how PTS2-bearing matrix proteins are recognized for peroxisomal import.","evidence":"Complementation cloning and expression of PEX7 in RCDP patient fibroblasts rescued PTS2 protein import; mutations identified in 36 probands","pmids":["9090381","9090383"],"confidence":"High","gaps":["Mechanism by which PEX7 delivers cargo to the peroxisomal membrane was unknown","Structural basis of PTS2 recognition by PEX7 was not determined","Relationship between PEX7 and PEX5 during import was undefined"]},{"year":2000,"claim":"Characterization of PEX7 gene structure and alternative splice forms established that only the full-length transcript encodes a functional PTS2 receptor.","evidence":"Expression of eight alternative PEX7 splice variants in RCDP fibroblasts; none rescued PTS2 import","pmids":["10673331"],"confidence":"Medium","gaps":["Single study; biological role of non-functional splice forms remains unclear","Whether alternative transcripts have dominant-negative effects was not tested"]},{"year":2002,"claim":"Genotype-phenotype correlation across dozens of RCDP alleles demonstrated that residual PEX7 activity is the primary determinant of clinical severity, establishing a functional continuum from null to hypomorphic alleles.","evidence":"Expression of 24 mutant PEX7 alleles in RCDP fibroblasts with PTS2 import quantification; correlation with clinical phenotype in 60 probands","pmids":["12325024","11781871"],"confidence":"High","gaps":["Molecular basis of partial activity for mild alleles not structurally resolved","Tissue-specific thresholds of PEX7 activity for normal function were unknown"]},{"year":2003,"claim":"Discovery that PEX7 mutations also cause Refsum disease broadened the phenotypic spectrum and linked PEX7 to phytanic acid metabolism, while the Pex7 knockout mouse confirmed the gene's requirement for plasmalogen synthesis, neuronal migration, and endochondral ossification in vivo.","evidence":"Genetic linkage and mutation analysis in Refsum patients lacking PHYH mutations; Pex7-null mice with biochemical, neuronal birthdating, and skeletal analyses","pmids":["12522768","12915479"],"confidence":"High","gaps":["Whether plasmalogen deficiency alone or combined metabolite disruption drives each tissue phenotype was not resolved","No therapeutic rescue demonstrated in the mouse model"]},{"year":2007,"claim":"Conservation of PEX7 function in Trypanosoma brucei demonstrated that PTS2 receptor activity is an ancestral eukaryotic feature and revealed unexpected cross-talk between PTS1 and PTS2 import pathways in some organisms.","evidence":"RNAi knockdown of T. brucei PEX7; immunofluorescence and fractionation showing mislocalization of PTS2 and (in procyclic cells) PTS1 proteins","pmids":["17320990"],"confidence":"Medium","gaps":["Mechanism of PTS1 pathway disruption upon PEX7 depletion not clarified","Single-organism RNAi study; not confirmed by complementation"]},{"year":2009,"claim":"A Pex7 hypomorphic mouse producing <5% normal transcript identified the lens and skeleton as tissues most sensitive to reduced PEX7 activity, linking plasmalogen deficiency to cataract formation.","evidence":"Hypomorphic Pex7 mouse with biochemical, histological, and dietary intervention analyses","pmids":["20060764"],"confidence":"High","gaps":["Whether dietary plasmalogen supplementation can prevent cataracts was not conclusively shown","Threshold level of PEX7 activity sufficient for each tissue was not quantified"]},{"year":2011,"claim":"Structural modeling of PEX7 and characterization of the PTS2 signal as an amphipathic helix, validated by compensatory mutagenesis, defined the molecular recognition interface and enabled prediction of novel PTS2 cargo proteins.","evidence":"3D modeling of PEX7 WD40 domain; site-directed mutagenesis and mammalian two-hybrid cross-complementation; computational PTS2 prediction","pmids":["22057399"],"confidence":"High","gaps":["No experimentally determined crystal or cryo-EM structure of the PEX7-PTS2 complex","Predicted novel cargoes (e.g., KChIP4) not confirmed by in vivo import assays"]},{"year":2014,"claim":"Reconstituted import/export assays resolved the PEX7 shuttling cycle: PEX7 enters the peroxisomal lumen as part of a trimeric PEX5-PEX7-cargo complex upstream of PEX5 ubiquitination and is exported back to the cytosol in a PEX5-dependent but temporally uncoupled manner.","evidence":"In vitro co-import/export assays with protease protection, dominant-negative blocks, and time-course fractionation","pmids":["24865970"],"confidence":"High","gaps":["Identity of machinery mediating PEX7-specific export step unknown","Whether PEX7 is ubiquitinated during cycling was not addressed"]},{"year":2015,"claim":"Demonstration that PEX7 export competence depends on the specific PEX5 molecule that co-imported it established that PEX7 remains tethered to the docking/translocation machinery during the intra-peroxisomal phase, and that PTS2 cleavage is dispensable for cargo release.","evidence":"In vitro assays with pre-assembled trimeric complexes; biochemical fractionation showing PEX7 retention at DTM","pmids":["26138649"],"confidence":"High","gaps":["Structural basis of PEX7 retention at the DTM not determined","How PEX7 releases cargo at the trans-side mechanistically is unresolved"]},{"year":2018,"claim":"Drosophila Pex7 cross-complements human PEX7-deficient cells despite the absence of identified PTS2 cargo in flies, confirming deep evolutionary conservation of PTS2 receptor mechanism.","evidence":"Expression of Drosophila Pex7 in human RCDP fibroblasts rescues thiolase import; Drosophila Pex7 mutant lipid and developmental phenotyping","pmids":["30389805"],"confidence":"Medium","gaps":["No PTS2 cargo identified in Drosophila; endogenous substrates remain unknown","Whether fly Pex7 forms a trimeric complex with fly Pex5 analogous to the mammalian system was not tested"]},{"year":null,"claim":"An experimentally determined high-resolution structure of the PEX7-PTS2 complex, the identity of the machinery that mediates PEX7-specific export from the peroxisomal membrane, and the full complement of PTS2 cargo proteins in different organisms remain to be established.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of PEX7 bound to PTS2 cargo","Mechanism and components of PEX7 export from peroxisomal membrane unknown","Complete PTS2 proteome not validated in any organism"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,5,6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,6,7]},{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[6,7]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,6,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,6]}],"complexes":["PEX5-PEX7-PTS2 cargo trimeric import complex"],"partners":["PEX5"],"other_free_text":[]},"mechanistic_narrative":"PEX7 is the cytosolic receptor for peroxisomal matrix proteins bearing the type-2 peroxisome targeting signal (PTS2), essential for importing enzymes required for plasmalogen biosynthesis, phytanic acid alpha-oxidation, and fatty acid beta-oxidation into peroxisomes. PEX7 recognizes the amphipathic helical PTS2 motif via a complementary binding groove on its WD40-repeat surface, forms a trimeric complex with PEX5 and PTS2 cargo, and shuttles into the peroxisomal lumen in a PEX5- and cargo-dependent manner upstream of PEX5 monoubiquitination; cargo is released at the trans-side of the membrane while PEX7 remains at the docking/translocation machinery and is subsequently exported back to the cytosol in a process dependent on, but not strictly coupled to, PEX5 recycling [PMID:24865970, PMID:26138649, PMID:22057399]. Loss-of-function mutations in PEX7 cause rhizomelic chondrodysplasia punctata (RCDP) and a subset of Refsum disease, with disease severity correlating with residual PEX7 activity; knockout and hypomorphic mouse models confirm that PEX7 is required for normal brain development, endochondral ossification, and lens integrity [PMID:9090381, PMID:12522768, PMID:12915479, PMID:20060764]. The PTS2-receptor function of PEX7 is evolutionarily conserved from trypanosomes and Drosophila to humans [PMID:17320990, PMID:30389805]."},"prefetch_data":{"uniprot":{"accession":"O00628","full_name":"Peroxisomal targeting signal 2 receptor","aliases":["Peroxin-7"],"length_aa":323,"mass_kda":35.9,"function":"Receptor required for the peroxisomal import of proteins containing a C-terminal PTS2-type peroxisomal targeting signal (PubMed:11931631, PubMed:22057399, PubMed:25538232, PubMed:9090381). Specifically binds to cargo proteins containing a PTS2 peroxisomal targeting signal in the cytosol (PubMed:11931631, PubMed:22057399, PubMed:25538232). Cargo protein-binding triggers interaction with PEX5 and formation of a ternary complex composed of PEX5 and PEX7 along with PTS2-containing cargo proteins, which is tranlocated into peroxisomes by passing through the PEX13-PEX14 docking complex (PubMed:11546814, PubMed:25538232)","subcellular_location":"Cytoplasm, cytosol; Peroxisome matrix","url":"https://www.uniprot.org/uniprotkb/O00628/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PEX7","classification":"Not Classified","n_dependent_lines":19,"n_total_lines":1208,"dependency_fraction":0.015728476821192054},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PEX7","total_profiled":1310},"omim":[{"mim_id":"621410","title":"PEROXISOME BIOGENESIS FACTOR 39; PEX39","url":"https://www.omim.org/entry/621410"},{"mim_id":"616716","title":"RHIZOMELIC CHONDRODYSPLASIA PUNCTATA, TYPE 5; RCDP5","url":"https://www.omim.org/entry/616716"},{"mim_id":"614879","title":"PEROXISOME BIOGENESIS DISORDER 9B; PBD9B","url":"https://www.omim.org/entry/614879"},{"mim_id":"608666","title":"PEROXISOME BIOGENESIS FACTOR 26; PEX26","url":"https://www.omim.org/entry/608666"},{"mim_id":"607622","title":"PHOSPHOMEVALONATE KINASE; PMVK","url":"https://www.omim.org/entry/607622"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PEX7"},"hgnc":{"alias_symbol":["PTS2R","RD"],"prev_symbol":[]},"alphafold":{"accession":"O00628","domains":[{"cath_id":"2.130.10.10","chopping":"11-321","consensus_level":"high","plddt":96.7364,"start":11,"end":321}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00628","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00628-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00628-F1-predicted_aligned_error_v6.png","plddt_mean":95.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PEX7","jax_strain_url":"https://www.jax.org/strain/search?query=PEX7"},"sequence":{"accession":"O00628","fasta_url":"https://rest.uniprot.org/uniprotkb/O00628.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00628/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00628"}},"corpus_meta":[{"pmid":"7542800","id":"PMC_7542800","title":"Whole-genome random sequencing and assembly of Haemophilus influenzae Rd.","date":"1995","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/7542800","citation_count":4048,"is_preprint":false},{"pmid":"8398150","id":"PMC_8398150","title":"Apoptosis: final common pathway of photoreceptor death in rd, rds, and rhodopsin mutant mice.","date":"1993","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/8398150","citation_count":559,"is_preprint":false},{"pmid":"659071","id":"PMC_659071","title":"Differential effect of the rd mutation on rods and cones in the mouse retina.","date":"1978","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/659071","citation_count":461,"is_preprint":false},{"pmid":"1941717","id":"PMC_1941717","title":"Circadian photoreception in the retinally degenerate mouse (rd/rd).","date":"1991","source":"Journal of comparative physiology. 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Expression of human or murine PEX7 in RCDP patient fibroblasts corrects the PTS2-import defect, demonstrating its role as the PTS2 receptor required for peroxisomal matrix protein import.\",\n      \"method\": \"Complementation assay in RCDP fibroblasts; PTS2 import rescue; homology cloning\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — two independent labs simultaneously demonstrated complementation of PTS2 import defect in patient cells, strong replication\",\n      \"pmids\": [\"9090381\", \"9090383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Mutations in PEX7 (e.g., L292ter, A218V, G217R) cause rhizomelic chondrodysplasia punctata (RCDP), establishing PEX7 as the gene responsible for PBD complementation group 11. Loss-of-function alleles result in mislocalisation of PTS2-targeted enzymes (including thiolase and DHAP-AT) to the cytoplasm.\",\n      \"method\": \"Mutation identification in 36 RCDP probands; functional complementation in patient fibroblasts; PTS2 import and DHAP-AT activity assays\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — two independent studies with functional complementation assays and patient mutation data\",\n      \"pmids\": [\"9090381\", \"9090383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Disease severity in RCDP correlates with residual PEX7 protein activity: alleles that completely abolish PTS2 import cause severe phenotype, while alleles retaining partial PTS2 import capacity (detectable upon overexpression) are associated with milder phenotypes. Reduced amounts of normal Pex7p also associate with milder phenotype.\",\n      \"method\": \"Expression of 24 mutant PEX7 alleles in RCDP fibroblasts; PTS2 marker protein import assay; Northern/RT-PCR analysis of RNA; phenotype-genotype correlation in 60 probands\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional complementation of multiple alleles with phenotypic correlation, two independent studies\",\n      \"pmids\": [\"12325024\", \"11781871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PEX7 mutations can produce a broad clinical spectrum beyond severe RCDP, including a milder Refsum disease phenotype. PEX7 mutations cause defects in phytanic acid alpha-oxidation, plasmalogen synthesis, and peroxisomal thiolase processing, identifying PEX7 as a second gene responsible for Refsum disease.\",\n      \"method\": \"Linkage analysis; biochemical analysis of peroxisomal functions; PEX7 mutation identification in Refsum disease patients without PHYH mutations\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and biochemical evidence linking PEX7 to a second disease entity, replicated in multiple patients\",\n      \"pmids\": [\"12522768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Pex7 knockout mice recapitulate the human RCDP phenotype: severe plasmalogen depletion, impaired phytanic acid alpha-oxidation, impaired VLCFA beta-oxidation, delayed neuronal migration in the developing cortex, and defects in endochondral ossification of distal limb bones, establishing PEX7's necessity for normal brain development and skeletogenesis.\",\n      \"method\": \"Pex7 mouse knockout generation; biochemical assays (plasmalogens, phytanic acid, VLCFA); in vivo neuronal birthdating; bone ossification analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — rigorous KO mouse model with multiple biochemical and cellular phenotypic readouts\",\n      \"pmids\": [\"12915479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The PTS2 signal forms an amphipathic helix with all conserved residues on one face. 3D structural modeling of PEX7 reveals a complementary groove for PTS2 binding. Mammalian two-hybrid assays and cross-complementation of a PTS2 mutation by a compensatory PEX7 mutation confirm this interaction interface, enabling identification of novel PTS2 proteins including KChIP4.\",\n      \"method\": \"Sequence/physical property analysis; 3D structural modeling; site-directed mutagenesis; mammalian two-hybrid; cross-complementation assays; PTS2 prediction algorithm\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural modeling combined with mutagenesis and functional cross-complementation in a single study\",\n      \"pmids\": [\"22057399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PEX7 is transported to the peroxisome as a PEX5-PEX7-PTS2 cargo complex in a PEX5- and cargo-dependent manner. PEX7 becomes protease-resistant (fully entering the peroxisomal lumen) upstream of PEX5 monoubiquitination, and cargo release occurs at the trans-side of the membrane. Export of PEX7 back to the cytosol requires PEX5 export but the two export events are not strictly coupled, indicating they leave separately.\",\n      \"method\": \"In vitro co-import/export assays; protease protection assays; biochemical fractionation; dominant-negative and time-course analyses\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution-style in vitro import/export assays with rigorous biochemical controls\",\n      \"pmids\": [\"24865970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The export competence of peroxisomal PEX7 is determined by the specific PEX5 molecule that transported it to the peroxisome, implying PEX7 is retained at the docking/translocation machinery (DTM) during peroxisomal steps. Cargo (PTS2 protein) is released into the organelle matrix by DTM-embedded PEX7, and PTS2 cleavage is not required for cargo release.\",\n      \"method\": \"In vitro co-import/export assays with pre-assembled trimeric PEX5-PEX7-PTS2 complexes; biochemical fractionation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro assays with defined complexes\",\n      \"pmids\": [\"26138649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PEX7 spans 102 kb on chromosome 6q21-q22.2 and contains at least 10 exons. Alternative splicing produces eight smaller PEX7 transcripts, but none of these splice forms can restore PTS2 protein import in RCDP fibroblasts, indicating they are non-functional for the canonical receptor role.\",\n      \"method\": \"Gene structure characterization; expression of alternative splice variants in RCDP fibroblasts; PTS2 import assay\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional complementation assay for splice variants, single study\",\n      \"pmids\": [\"10673331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A Pex7 hypomorphic mouse model (Pex7 transcript <5% of wild-type) develops early cataracts, skeletal abnormalities (delayed endochondral ossification, abnormal lens fibers), tissue plasmalogen deficiency, phytanic acid accumulation, and reduced PTS2 cargo import, identifying the lens and skeleton as particularly sensitive to plasmalogen deficiency.\",\n      \"method\": \"Hypomorphic mouse engineering; biochemical assays (plasmalogens, phytanic acid); PTS2 import assay; histology; dietary supplementation experiments\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — well-characterized hypomorphic model with multiple biochemical and histological readouts\",\n      \"pmids\": [\"20060764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Trypanosoma brucei, PEX7 depletion by RNAi causes mislocalization of PTS2-containing proteins to the cytosol in bloodstream-form trypanosomes, and mislocalization of both PTS1, PTS2, and I-PTS proteins in procyclic cells. T. brucei PEX7 can bind PEX5, and both receptors are essential for parasite viability.\",\n      \"method\": \"RNA interference; immunofluorescence; subcellular fractionation; growth assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi knockdown with direct localization readouts, single study in a non-mammalian organism (relevant ortholog)\",\n      \"pmids\": [\"17320990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Drosophila Pex7, despite no identified PTS2 cargo in flies, functions as a bona fide PTS2 receptor: it can rescue PTS2 protein (thiolase) targeting to peroxisomes in human PEX7-mutant fibroblasts. Pex7 fly mutants show lipid processing defects with mild brain developmental effects, distinct from the severe Pex5 mutant phenotype.\",\n      \"method\": \"Drosophila Pex7 mutant characterization; rescue of human RCDP fibroblasts by Drosophila Pex7 expression; lipid analysis; developmental phenotyping\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cross-species complementation assay with biochemical phenotyping, single study\",\n      \"pmids\": [\"30389805\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PEX7 is the cytosolic PTS2 receptor that forms a trimeric complex with PEX5 and PTS2-containing cargo proteins, shuttles into the peroxisomal lumen in a PEX5- and cargo-dependent manner upstream of PEX5 monoubiquitination, releases cargo at the trans-side of the membrane (independent of PTS2 cleavage) while retained at the docking/translocation machinery, and is then exported back to the cytosol separately from but dependent on PEX5 export; loss-of-function mutations in PEX7 cause rhizomelic chondrodysplasia punctata (RCDP) and a subset of Refsum disease by preventing peroxisomal import of plasmalogens biosynthesis enzymes, thiolase, and phytanoyl-CoA hydroxylase.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PEX7 is the cytosolic receptor for peroxisomal matrix proteins bearing the type-2 peroxisome targeting signal (PTS2), essential for importing enzymes required for plasmalogen biosynthesis, phytanic acid alpha-oxidation, and fatty acid beta-oxidation into peroxisomes. PEX7 recognizes the amphipathic helical PTS2 motif via a complementary binding groove on its WD40-repeat surface, forms a trimeric complex with PEX5 and PTS2 cargo, and shuttles into the peroxisomal lumen in a PEX5- and cargo-dependent manner upstream of PEX5 monoubiquitination; cargo is released at the trans-side of the membrane while PEX7 remains at the docking/translocation machinery and is subsequently exported back to the cytosol in a process dependent on, but not strictly coupled to, PEX5 recycling [PMID:24865970, PMID:26138649, PMID:22057399]. Loss-of-function mutations in PEX7 cause rhizomelic chondrodysplasia punctata (RCDP) and a subset of Refsum disease, with disease severity correlating with residual PEX7 activity; knockout and hypomorphic mouse models confirm that PEX7 is required for normal brain development, endochondral ossification, and lens integrity [PMID:9090381, PMID:12522768, PMID:12915479, PMID:20060764]. The PTS2-receptor function of PEX7 is evolutionarily conserved from trypanosomes and Drosophila to humans [PMID:17320990, PMID:30389805].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of PEX7 as the PTS2 receptor resolved the molecular basis of RCDP and revealed how PTS2-bearing matrix proteins are recognized for peroxisomal import.\",\n      \"evidence\": \"Complementation cloning and expression of PEX7 in RCDP patient fibroblasts rescued PTS2 protein import; mutations identified in 36 probands\",\n      \"pmids\": [\"9090381\", \"9090383\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which PEX7 delivers cargo to the peroxisomal membrane was unknown\",\n        \"Structural basis of PTS2 recognition by PEX7 was not determined\",\n        \"Relationship between PEX7 and PEX5 during import was undefined\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Characterization of PEX7 gene structure and alternative splice forms established that only the full-length transcript encodes a functional PTS2 receptor.\",\n      \"evidence\": \"Expression of eight alternative PEX7 splice variants in RCDP fibroblasts; none rescued PTS2 import\",\n      \"pmids\": [\"10673331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study; biological role of non-functional splice forms remains unclear\",\n        \"Whether alternative transcripts have dominant-negative effects was not tested\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Genotype-phenotype correlation across dozens of RCDP alleles demonstrated that residual PEX7 activity is the primary determinant of clinical severity, establishing a functional continuum from null to hypomorphic alleles.\",\n      \"evidence\": \"Expression of 24 mutant PEX7 alleles in RCDP fibroblasts with PTS2 import quantification; correlation with clinical phenotype in 60 probands\",\n      \"pmids\": [\"12325024\", \"11781871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular basis of partial activity for mild alleles not structurally resolved\",\n        \"Tissue-specific thresholds of PEX7 activity for normal function were unknown\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery that PEX7 mutations also cause Refsum disease broadened the phenotypic spectrum and linked PEX7 to phytanic acid metabolism, while the Pex7 knockout mouse confirmed the gene's requirement for plasmalogen synthesis, neuronal migration, and endochondral ossification in vivo.\",\n      \"evidence\": \"Genetic linkage and mutation analysis in Refsum patients lacking PHYH mutations; Pex7-null mice with biochemical, neuronal birthdating, and skeletal analyses\",\n      \"pmids\": [\"12522768\", \"12915479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether plasmalogen deficiency alone or combined metabolite disruption drives each tissue phenotype was not resolved\",\n        \"No therapeutic rescue demonstrated in the mouse model\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Conservation of PEX7 function in Trypanosoma brucei demonstrated that PTS2 receptor activity is an ancestral eukaryotic feature and revealed unexpected cross-talk between PTS1 and PTS2 import pathways in some organisms.\",\n      \"evidence\": \"RNAi knockdown of T. brucei PEX7; immunofluorescence and fractionation showing mislocalization of PTS2 and (in procyclic cells) PTS1 proteins\",\n      \"pmids\": [\"17320990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of PTS1 pathway disruption upon PEX7 depletion not clarified\",\n        \"Single-organism RNAi study; not confirmed by complementation\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"A Pex7 hypomorphic mouse producing <5% normal transcript identified the lens and skeleton as tissues most sensitive to reduced PEX7 activity, linking plasmalogen deficiency to cataract formation.\",\n      \"evidence\": \"Hypomorphic Pex7 mouse with biochemical, histological, and dietary intervention analyses\",\n      \"pmids\": [\"20060764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether dietary plasmalogen supplementation can prevent cataracts was not conclusively shown\",\n        \"Threshold level of PEX7 activity sufficient for each tissue was not quantified\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Structural modeling of PEX7 and characterization of the PTS2 signal as an amphipathic helix, validated by compensatory mutagenesis, defined the molecular recognition interface and enabled prediction of novel PTS2 cargo proteins.\",\n      \"evidence\": \"3D modeling of PEX7 WD40 domain; site-directed mutagenesis and mammalian two-hybrid cross-complementation; computational PTS2 prediction\",\n      \"pmids\": [\"22057399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No experimentally determined crystal or cryo-EM structure of the PEX7-PTS2 complex\",\n        \"Predicted novel cargoes (e.g., KChIP4) not confirmed by in vivo import assays\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Reconstituted import/export assays resolved the PEX7 shuttling cycle: PEX7 enters the peroxisomal lumen as part of a trimeric PEX5-PEX7-cargo complex upstream of PEX5 ubiquitination and is exported back to the cytosol in a PEX5-dependent but temporally uncoupled manner.\",\n      \"evidence\": \"In vitro co-import/export assays with protease protection, dominant-negative blocks, and time-course fractionation\",\n      \"pmids\": [\"24865970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of machinery mediating PEX7-specific export step unknown\",\n        \"Whether PEX7 is ubiquitinated during cycling was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstration that PEX7 export competence depends on the specific PEX5 molecule that co-imported it established that PEX7 remains tethered to the docking/translocation machinery during the intra-peroxisomal phase, and that PTS2 cleavage is dispensable for cargo release.\",\n      \"evidence\": \"In vitro assays with pre-assembled trimeric complexes; biochemical fractionation showing PEX7 retention at DTM\",\n      \"pmids\": [\"26138649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of PEX7 retention at the DTM not determined\",\n        \"How PEX7 releases cargo at the trans-side mechanistically is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Drosophila Pex7 cross-complements human PEX7-deficient cells despite the absence of identified PTS2 cargo in flies, confirming deep evolutionary conservation of PTS2 receptor mechanism.\",\n      \"evidence\": \"Expression of Drosophila Pex7 in human RCDP fibroblasts rescues thiolase import; Drosophila Pex7 mutant lipid and developmental phenotyping\",\n      \"pmids\": [\"30389805\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No PTS2 cargo identified in Drosophila; endogenous substrates remain unknown\",\n        \"Whether fly Pex7 forms a trimeric complex with fly Pex5 analogous to the mammalian system was not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"An experimentally determined high-resolution structure of the PEX7-PTS2 complex, the identity of the machinery that mediates PEX7-specific export from the peroxisomal membrane, and the full complement of PTS2 cargo proteins in different organisms remain to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of PEX7 bound to PTS2 cargo\",\n        \"Mechanism and components of PEX7 export from peroxisomal membrane unknown\",\n        \"Complete PTS2 proteome not validated in any organism\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"complexes\": [\n      \"PEX5-PEX7-PTS2 cargo trimeric import complex\"\n    ],\n    \"partners\": [\n      \"PEX5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}