{"gene":"PMP22","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1993,"finding":"PMP22 encodes a peripheral myelin protein; a point mutation (Ser→Cys) in a putative transmembrane domain causes CMT1A in an autosomal dominant pattern, establishing a causative role for PMP22 in peripheral nerve myelination.","method":"PCR, heteroduplex analysis, direct nucleotide sequencing of patient DNA; co-segregation analysis","journal":"The New England journal of medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct mutation identification with functional co-segregation; replicated across multiple independent studies identifying PMP22 point mutations","pmids":["8510709"],"is_preprint":false},{"year":1993,"finding":"In cultured Schwann cells, PMP22 is synthesized from an 18-kDa precursor and post-translationally modified by N-linked glycosylation, yielding the mature ~22 kDa glycoprotein; PMP22 mRNA (1.8 kb) is upregulated by forskolin (cAMP pathway activation).","method":"Metabolic labeling, immunoprecipitation with anti-PMP22 antibodies, N-glycosylation analysis, Northern blot, Western blot of purified myelin after deglycosylation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with multiple orthogonal methods (pulse-chase, immunoprecipitation, deglycosylation), single lab","pmids":["8486695"],"is_preprint":false},{"year":1993,"finding":"PMP22 mRNA expression in peripheral nerve is restricted to Schwann cells of myelinated fibers and is co-expressed with MBP and P0 during developmental myelination and nerve regeneration; in cultured Schwann cells PMP22 expression is not strictly growth-arrest-specific (unlike in fibroblasts).","method":"In situ hybridization, immunohistochemistry, Northern blot of cultured Schwann cells under different growth conditions","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple detection methods but primarily localization/expression; single lab","pmids":["7691737"],"is_preprint":false},{"year":1995,"finding":"Retroviral-mediated overexpression of PMP22 in Schwann cells decreases DNA synthesis to ~60% of control and delays G0/G1→S+G2/M entry by ~8 h; antisense-mediated reduction of PMP22 increases DNA synthesis to ~150%, demonstrating that PMP22 directly regulates Schwann cell proliferation.","method":"Retroviral transduction (sense/antisense), BrdU incorporation, flow cytometry cell cycle analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and gain-of-function with defined cellular proliferation phenotype, replicated across multiple assays in same study","pmids":["7720703"],"is_preprint":false},{"year":1995,"finding":"Overexpression of wild-type Gas3/PMP22 in NIH-3T3 cells induces an apoptotic-like phenotype (membrane blebbing, rounding, chromatin condensation without DNA fragmentation) suppressible by antioxidants. CMT1A dominant point mutants (L16P, S79C) behave as dominant negatives for this apoptotic activity; the recessive mutant T118M behaves recessively, establishing PMP22 as a regulator of apoptosis.","method":"Transient transfection overexpression in NIH-3T3 cells; morphological analysis; antioxidant rescue; co-expression dominant-negative experiments","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with multiple mutant alleles and rescue; single lab","pmids":["7649472"],"is_preprint":false},{"year":1995,"finding":"Mice homozygously deleted for Pmp22 show delayed onset of myelination, formation of tomacula (sausage-like hypermyelination), severe demyelination, axonal loss, and functional impairment; heterozygous Pmp22+/- mice exhibit focal tomacula resembling HNPP, establishing Pmp22 as required for correct peripheral nerve development, myelin thickness determination, and myelin stability.","method":"Targeted gene disruption (knockout mice), histopathology, morphometry, electrophysiology","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined cellular and functional phenotypes, widely replicated","pmids":["7581450"],"is_preprint":false},{"year":1997,"finding":"Altered PMP22 expression (over- or under-expression via retroviral transduction) in Schwann cells co-cultured with DRG neurons does not impair early myelination or membrane compaction but affects myelin thickness and stability, indicating PMP22's role is in controlling myelin thickness rather than initiation of myelination.","method":"Retroviral transduction of Schwann cells, co-culture with DRG neurons, RT-PCR, immunohistochemistry, confocal microscopy, electron microscopy","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in myelination assay with ultrastructural readout; single lab","pmids":["9086179"],"is_preprint":false},{"year":1999,"finding":"Gas3/PMP22 overexpression modulates cell spreading through the small GTPase RhoA: active RhoA counteracts Gas3/PMP22-dependent morphological changes but not apoptosis; C3 exoenzyme (Rho inhibitor) renders otherwise unresponsive REF52 cells susceptible to Gas3/PMP22-induced shape changes; Gas3/PMP22 impairs LPA-induced stress fiber and focal adhesion assembly.","method":"Transfection with active/dominant-negative Rho constructs, C3 exoenzyme treatment, cytotoxic necrotizing factor 1 activation of endogenous Rho, time-lapse imaging, Bcl-2 co-expression","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via Rho constructs and pharmacological tools; single lab, multiple orthogonal approaches","pmids":["10397775"],"is_preprint":false},{"year":1999,"finding":"Inhibition of the proteasome pathway causes accumulation of PMP22 in perinuclear aggresomes (co-labeled with ubiquitin); overexpression of PMP22 in Schwann cells alone can induce perinuclear accumulation, establishing that the proteasome pathway is critical for regulating PMP22 protein levels.","method":"Proteasome inhibitor treatment, immunofluorescence double-labeling with anti-ubiquitin and organelle markers, confocal microscopy","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization tied to protein quality control function; single lab with two orthogonal approaches","pmids":["10527811"],"is_preprint":false},{"year":2000,"finding":"Trembler (Tr) and Trembler-J (Tr-J) point-mutant PMP22 proteins are retained in the endoplasmic reticulum (ER) of myelinating Schwann cells in vivo, while wild-type epitope-tagged PMP22 is successfully transported to compact myelin, demonstrating that missense mutations cause pathogenesis through ER retention.","method":"Adenoviral microinjection into sciatic nerve of live rats; immunohistochemistry with ER marker colocalization in myelinating Schwann cells","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct in vivo subcellular localization with functional consequence established; multiple mutant alleles tested","pmids":["11114256"],"is_preprint":false},{"year":2000,"finding":"Wild-type Gas3/PMP22 is exposed at the cell surface, whereas disease-causing point mutants are intracellularly retained co-localizing with ER. Cell-surface exposure is required for Gas3/PMP22 to regulate both cell death and cell spreading; addition of a retrieval signal to wild-type prevents surface exposure and abolishes both functions. N-glycosylation (Asn41) is required for full cell-spreading effect but not for cell death induction.","method":"Immunofluorescence surface staining, ER co-localization, mutagenesis of ER-retrieval motif and N-glycosylation site, cell death and spreading assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with subcellular localization and functional readouts; multiple orthogonal approaches in single study","pmids":["10982389"],"is_preprint":false},{"year":2001,"finding":"Increased Schwann cell proliferation and apoptosis appear in later postnatal development in all PMP22 mutant mouse models (overexpression, deletion, point mutation), but not at P1, demonstrating that PMP22 dosage and point mutations affect Schwann cell proliferation and survival primarily in later development.","method":"BrdU labeling (proliferation), TUNEL/cleaved caspase (apoptosis), cell density quantification in postnatal sciatic nerve of Pmp22 null, heterozygous, and overexpressing mice","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss- and gain-of-function with defined cellular phenotype; single lab","pmids":["11673320"],"is_preprint":false},{"year":2003,"finding":"Progesterone directly regulates Pmp22 and Mpz mRNA levels in Schwann cells: progesterone administration elevates Pmp22 and Mpz mRNA in sciatic nerve and worsens CMT1A phenotype; a progesterone receptor antagonist (onapristone) reduces Pmp22 overexpression and improves the neuropathy phenotype in transgenic CMT1A rats, demonstrating progesterone receptor-mediated transcriptional regulation of PMP22 in Schwann cells.","method":"Pharmacological treatment in transgenic rats; qRT-PCR of Pmp22/Mpz mRNA; electrophysiology; clinical phenotype assessment","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain- and loss-of-pharmacological-function in vivo with molecular and functional readouts; progesterone receptor pathway mechanistically established","pmids":["14608378"],"is_preprint":false},{"year":2004,"finding":"Calnexin interacts with misfolded transmembrane domains of Gas3/PMP22 in a glycan-independent manner, retaining mutant PMP22 in the ER; FRAP experiments show PMP22 disease mutants are mobile but diffuse at ~half the diffusion coefficient of wild-type, consistent with chaperone-mediated retention.","method":"Co-immunoprecipitation of calnexin with PMP22 transmembrane domain-GFP fusions; FRAP (fluorescence recovery after photobleaching) in live cells; glycan-independent interaction confirmed by mutation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus live-cell FRAP; single lab with two orthogonal methods","pmids":["15537650"],"is_preprint":false},{"year":2003,"finding":"Gas3/PMP22 overexpression alters membrane traffic through the Arf6 plasma membrane-endosomal recycling pathway: overexpressed PMP22 accumulates in late endosomes and induces formation of actin/PIP2-positive vacuoles trapping Arf6-pathway membrane proteins; dominant-negative Arf6-T27N blocks vacuole formation; a CMT1A point mutant fails to trigger PIP2-positive vacuole accumulation.","method":"Live-cell imaging of GFP-tagged proteins, dominant-negative and constitutively active Arf6 constructs, transferrin receptor trafficking assay, immunofluorescence co-localization","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via dominant-negative mutant; live imaging with multiple marker comparisons; single lab","pmids":["12584243"],"is_preprint":false},{"year":2005,"finding":"In CMT1A (C22) mice overexpressing PMP22, newly synthesized PMP22 shows slowed turnover, cytoplasmic protein aggregates form with reduced proteasome activity, accumulation of detergent-insoluble ubiquitinated substrates, and a fraction of aggregates associates with autophagosomes and lysosomes, indicating that dysregulation of both proteasomal and autophagic degradation pathways underlies PMP22 aggregate pathology.","method":"Pulse-chase metabolic labeling, proteasome activity assay, detergent fractionation/Western blot for ubiquitinated proteins, immunofluorescence with autophagosome/lysosome markers","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods in disease model; single lab","pmids":["16326107"],"is_preprint":false},{"year":2011,"finding":"The Egr2/Krox20 transcription factor binds a conserved intronic enhancer (~250 bp) within the largest intron of the Pmp22 gene; Sox10 is required for optimal activity of this intronic site and for PMP22 expression; mouse transgenic analysis confirms tissue-specific (peripheral nerve) activity of this intronic sequence.","method":"Chromatin immunoprecipitation (ChIP) of rat Pmp22 locus, luciferase reporter assays, Sox10 knockdown/expression assays, mouse transgenic analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP plus reporter assay plus in vivo transgenic validation; multiple orthogonal methods in single study","pmids":["21411665"],"is_preprint":false},{"year":2014,"finding":"PMP22 interacts physically with junctional adhesion molecule-C (JAM-C) and myelin-associated glycoprotein (MAG); PMP22 deficiency disrupts multiple myelin junction complexes, causing increased myelin permeability and impaired action potential propagation. Deletion of Jam-c or Mag individually recapitulates HNPP pathology, establishing PMP22 as a component of myelin junction complexes.","method":"Co-immunoprecipitation of PMP22 with JAM-C and MAG from nerve lysates; morphological analysis of junction complexes; electrophysiological assays; Jam-c and Mag knockout mouse genetic epistasis","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic epistasis via knockout mice, electrophysiology; multiple orthogonal methods","pmids":["24339129"],"is_preprint":false},{"year":2014,"finding":"PMP22 is localized to cholesterol-enriched lipid raft membrane domains; PMP22-deficient Schwann cells show impaired migration and adhesion, shortened myelin internodes, collapsed lamellipodia, and failure of F-actin-enriched Schmidt-Lanterman incisures to form properly; expression and localization of flotillin-1, cholesterol, and GM1 ganglioside are altered. Cholesterol supplementation rescues elongation and migration deficits, linking PMP22 to actin cytoskeleton-plasma membrane linkage via lipid raft cholesterol regulation.","method":"Schwann cell migration/adhesion assays with PMP22 KO cells, phalloidin staining of F-actin, lipid raft fractionation, immunofluorescence for flotillin-1/GM1/cholesterol; cholesterol supplementation rescue","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple functional readouts and pharmacological rescue; multiple orthogonal methods in single study","pmids":["25429154"],"is_preprint":false},{"year":2015,"finding":"The conformational stability of PMP22 (assessed by Zn(II)-mediated folding equilibrium) is proportional to the efficiency of its cellular trafficking through the secretory pathway; disease-causing mutations destabilize PMP22 and reduce trafficking efficiency proportionally to reductions in motor nerve conduction velocity in patients, establishing that misfolding-driven ER retention is the molecular basis for CMT from PMP22 point mutations.","method":"Quantitative Zn(II)-mediated conformational stability assay for 12 PMP22 variants, flow-cytometry-based cellular trafficking assay, correlation with patient NCV data","journal":"Journal of the American Chemical Society","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biophysical assay + cell-based trafficking quantification + clinical correlation; multiple orthogonal methods","pmids":["26102530"],"is_preprint":false},{"year":2015,"finding":"Inducible HSP70 (HSP70.1/3) is critical for preventing aggregation of misfolded PMP22 (especially Trembler-J PMP22) under proteotoxic stress; HSP70 aids processing of Tr-J PMP22 through the Golgi and delivery to lysosomes via Rab7-positive vesicles; HSP70 KO cells show increased PMP22 aggregation and proteasome dysfunction.","method":"HSP70.1/3 knockout mouse-derived cells, pharmacological induction of HSP70 (FDA-approved small molecule), immunofluorescence co-localization with Golgi/Rab7 markers, proteasome activity assay, Western blot","journal":"ASN neuro","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cell model with multiple readouts; single lab","pmids":["25694550"],"is_preprint":false},{"year":2016,"finding":"In Pmp22+/- (HNPP model) nerves, increased F-actin levels correlate with enhanced PAK1 activity; pharmacological PAK inhibition normalizes F-actin, prevents progression of myelin junction disruption, and prevents nerve conduction failure, positioning PAK1-mediated actin polymerization upstream of myelin junction disruption in HNPP.","method":"Immunofluorescence quantification of F-actin in nerve sections, PAK kinase activity assay, pharmacological PAK inhibitor treatment in Pmp22+/- mice, electrophysiology","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis in disease model with biochemical and functional readouts; single lab","pmids":["27583434"],"is_preprint":false},{"year":2018,"finding":"A distal super-enhancer (~90-130 kb upstream of Pmp22 TSS) is required for full Pmp22 expression; CRISPR deletion of this super-enhancer significantly decreases Pmp22 transcript levels, with the Schwann cell-specific P1 promoter being disproportionately more sensitive than the P2 promoter.","method":"Genome editing (CRISPR) deletion of super-enhancer, allele-specific RT-qPCR, H3K27ac ChIP-seq chromatin mark identification","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — CRISPR deletion with allele-specific expression quantification; multiple methods in single study","pmids":["29771329"],"is_preprint":false},{"year":2019,"finding":"PMP22 co-immunoprecipitates with ABCA1 from Schwann cell and nerve lysates, and both proteins co-localize at the Schwann cell plasma membrane; PMP22 absence reduces ABCA1 membrane localization and impairs ABCA1-mediated cholesterol efflux. Conversely, ABCA1 KO mice show elevated PMP22 expression with aberrant subcellular processing, establishing a reciprocal functional interaction between PMP22 and ABCA1 in cholesterol homeostasis.","method":"Co-immunoprecipitation from Schwann cell/nerve lysates, immunofluorescence co-localization, cholesterol efflux assay, whole-cell patch-clamp (membrane capacitance/resistance), Western blot in PMP22 KO and ABCA1 KO mice","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus KO functional assays in two genetic models plus electrophysiology; multiple orthogonal methods","pmids":["31061090"],"is_preprint":false},{"year":2020,"finding":"As the expression level of PMP22 (wild-type or disease variants) is increased in individual cells, the fraction of intracellularly retained (misfolded) PMP22 increases disproportionately relative to surface-trafficked protein, demonstrating that overexpression per se saturates ER quality control to produce mistrafficking.","method":"Single-cell flow-cytometry trafficking assay distinguishing surface vs. intracellular PMP22; stable and transient expression systems","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative single-cell trafficking assay with two expression systems; single lab","pmids":["32647009"],"is_preprint":false},{"year":2021,"finding":"N-glycosylation at Asn41 is a limiting factor for forward trafficking of PMP22: N41Q mutation increases wild-type trafficking efficiency ~3-fold and L16P ~10-fold in HEK293 and Schwann cells. WT PMP22 is glycosylated post-translationally by OST-B; L16P is co-translationally glycosylated by OST-A. CRISPR KO studies identify RER1 as limiting for all PMP22 forms, UGGT1 as limiting for WT and L16P but not N41Q, and calnexin as limiting for WT and N41Q but not L16P.","method":"N41Q mutagenesis, flow-cytometry trafficking assay, OST-A/B depletion, CRISPR KO of RER1/UGGT1/calnexin, quantitative proteomics interactome screens","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis, CRISPR KO of quality-control components, quantitative trafficking assay, proteomics interactome; multiple orthogonal methods in single study","pmids":["33933451"],"is_preprint":false}],"current_model":"PMP22 is a tetraspan N-glycosylated integral membrane glycoprotein of Schwann cell compact myelin whose precise level is critical: it is transcriptionally induced in Schwann cells via Egr2/Sox10-bound intronic and distal super-enhancer elements and progesterone receptor signaling; only ~20% of newly synthesized PMP22 traffics efficiently to the cell surface, with N-glycosylation, calnexin, UGGT1, and RER1 limiting forward trafficking and the proteasome/HSP70/autophagy network degrading the misfolded majority; wild-type PMP22 at the plasma membrane regulates Schwann cell proliferation, apoptosis, actin-cytoskeleton linkage, lipid raft integrity, cholesterol homeostasis (through physical interaction with ABCA1), and myelin junction permeability (through interaction with JAM-C and MAG); disease-causing point mutations destabilize PMP22 fold proportionally to their clinical severity, causing ER retention (aided by glycan-independent calnexin binding) and aggresome formation, while PMP22 overexpression saturates ER quality control producing disproportionate mistrafficking and CMT1A-like demyelination, and haploinsufficiency disrupts myelin junctions and impairs PAK1/actin-regulated myelin permeability causing the HNPP phenotype."},"narrative":{"mechanistic_narrative":"PMP22 is an N-glycosylated tetraspan integral membrane glycoprotein of Schwann cells whose dosage and folding fidelity are critical determinants of peripheral nerve myelination, with point mutations causing dominant CMT1A and gene-dosage imbalance underlying CMT1A and HNPP [PMID:8510709, PMID:7581450]. The protein is synthesized as an 18-kDa precursor and matured to ~22 kDa by N-linked glycosylation, and its expression is restricted to myelinating Schwann cells where it is induced by cAMP signaling [PMID:8486695, PMID:7691737], by Egr2/Sox10 acting through a conserved intronic enhancer and a distal super-enhancer that drives the Schwann cell-specific promoter [PMID:21411665, PMID:29771329], and by progesterone receptor signaling [PMID:14608378]. Functionally, surface-resident wild-type PMP22 restrains Schwann cell proliferation and regulates apoptosis and cell spreading through RhoA, and controls myelin thickness and stability rather than myelin initiation [PMID:7720703, PMID:7581450, PMID:9086179, PMID:10397775, PMID:10982389]. At the plasma membrane PMP22 resides in cholesterol-enriched lipid rafts and links the actin cytoskeleton to the membrane, physically partnering with ABCA1 to govern cholesterol efflux and homeostasis, and with JAM-C and MAG to maintain myelin junction integrity and permeability [PMID:24339129, PMID:25429154, PMID:31061090]. PMP22 trafficking is intrinsically inefficient: conformational stability is rate-limiting for forward trafficking, with N-glycosylation at Asn41 and the ER quality-control factors calnexin, UGGT1, and RER1 acting as restraints, such that destabilizing point mutations are retained in the ER in proportion to their clinical severity, while overexpression disproportionately saturates this quality control to produce mistrafficking [PMID:15537650, PMID:26102530, PMID:32647009, PMID:33933451]. Misfolded PMP22 is cleared by the proteasome, HSP70 chaperones, and autophagy, and its failure produces ubiquitinated perinuclear aggresomes [PMID:10527811, PMID:16326107, PMID:25694550]. In HNPP, PMP22 haploinsufficiency disrupts myelin junctions via PAK1-driven F-actin dysregulation, impairing action potential propagation [PMID:24339129, PMID:27583434].","teleology":[{"year":1993,"claim":"Established that PMP22 is a peripheral myelin gene whose mutation causes inherited neuropathy, defining the gene's clinical and tissue relevance.","evidence":"Point-mutation identification and co-segregation in CMT1A families; biochemical characterization of the glycoprotein in cultured Schwann cells","pmids":["8510709","8486695","7691737"],"confidence":"High","gaps":["Did not define the cellular function of PMP22","Mechanism linking mutation to demyelination unknown","Trafficking and folding behavior uncharacterized"]},{"year":1995,"claim":"Showed that PMP22 dosage actively regulates Schwann cell proliferation, apoptosis, and myelin thickness/stability, moving it from a structural marker to a functional regulator.","evidence":"Retroviral gain/loss-of-function with BrdU and cell-cycle analysis; NIH-3T3 apoptosis assay with dominant/recessive mutant alleles; Pmp22 knockout mouse histopathology","pmids":["7720703","7649472","7581450"],"confidence":"High","gaps":["Molecular partners mediating proliferation/apoptosis effects not identified","Whether effects require surface localization unresolved at this stage"]},{"year":1997,"claim":"Refined PMP22's role to control of myelin thickness and stability rather than myelin initiation or compaction.","evidence":"Retroviral over/under-expression in Schwann cell-DRG co-culture with EM ultrastructure","pmids":["9086179"],"confidence":"Medium","gaps":["Single lab","Mechanism of thickness control not defined"]},{"year":1999,"claim":"Linked PMP22's effects on cell shape to RhoA signaling and Arf6-dependent membrane recycling, indicating cytoskeletal and trafficking-pathway engagement.","evidence":"Rho construct epistasis and C3 exoenzyme treatment; dominant-negative Arf6 and live-cell trafficking imaging","pmids":["10397775","12584243"],"confidence":"Medium","gaps":["Direct biochemical interaction with Rho/Arf6 not shown","Relevance to in vivo myelination not established"]},{"year":2000,"claim":"Demonstrated that disease-causing missense mutants are retained in the ER and that cell-surface exposure is required for PMP22 function, establishing mislocalization as the pathogenic mechanism.","evidence":"Adenoviral expression in live rat sciatic nerve with ER marker colocalization; surface staining, ER-retrieval and N-glycosylation site mutagenesis with functional assays","pmids":["11114256","10982389"],"confidence":"High","gaps":["Chaperones mediating retention not yet identified","Quantitative relationship between retention and severity not defined"]},{"year":2001,"claim":"Showed that PMP22 dosage and point mutations affect Schwann cell proliferation and survival specifically in later postnatal development, timing the cellular phenotype.","evidence":"BrdU, TUNEL, and density quantification across Pmp22 null, heterozygous, and overexpressing mouse nerves","pmids":["11673320"],"confidence":"Medium","gaps":["Single lab","Molecular trigger of late-developmental effect unknown"]},{"year":2003,"claim":"Identified progesterone receptor signaling as a transcriptional regulator of Pmp22, providing a pharmacologically tractable node modulating disease severity.","evidence":"Progesterone and onapristone treatment of CMT1A transgenic rats with qRT-PCR, electrophysiology, and phenotype scoring","pmids":["14608378"],"confidence":"High","gaps":["Direct PR binding to Pmp22 regulatory elements not mapped","Interaction with other transcriptional inputs unclear"]},{"year":2004,"claim":"Defined calnexin as a glycan-independent chaperone retaining misfolded PMP22 transmembrane domains in the ER, providing a molecular mechanism for mutant retention.","evidence":"Co-IP of calnexin with TMD-GFP fusions and live-cell FRAP","pmids":["15537650"],"confidence":"Medium","gaps":["Single lab","Other quality-control factors not yet defined"]},{"year":2005,"claim":"Showed both proteasomal and autophagic degradation pathways are engaged and dysregulated in PMP22 aggregate pathology, expanding the disposal network for misfolded protein.","evidence":"Pulse-chase, proteasome activity assay, detergent fractionation, and autophagosome/lysosome immunofluorescence in CMT1A mice; earlier proteasome/aggresome study","pmids":["16326107","10527811"],"confidence":"Medium","gaps":["Single lab","Causal contribution of each pathway to disease not separated"]},{"year":2011,"claim":"Mapped the transcriptional control of Pmp22 to an Egr2/Krox20-bound intronic enhancer requiring Sox10, defining the core Schwann cell-specific regulatory logic.","evidence":"ChIP, luciferase reporters, Sox10 manipulation, and mouse transgenic validation","pmids":["21411665"],"confidence":"High","gaps":["Distal regulatory elements not yet identified","Contribution to gene-dosage disease unclear"]},{"year":2014,"claim":"Established PMP22 as a component of myelin junction complexes and lipid-raft membrane organization, identifying JAM-C, MAG, and ABCA1-relevant cholesterol pathways as effectors.","evidence":"Reciprocal Co-IP with JAM-C and MAG plus Jam-c/Mag knockout epistasis; lipid raft fractionation, F-actin staining, and cholesterol rescue in PMP22 KO Schwann cells","pmids":["24339129","25429154"],"confidence":"High","gaps":["Stoichiometry and architecture of the junction complex unresolved","Direct binding interfaces not mapped"]},{"year":2015,"claim":"Quantitatively linked PMP22 conformational stability to trafficking efficiency and clinical severity, and identified HSP70 as a key chaperone preventing mutant aggregation.","evidence":"Zn(II)-mediated stability assay across 12 variants with trafficking and patient NCV correlation; HSP70 KO cells with Golgi/Rab7 colocalization and proteasome assays","pmids":["26102530","25694550"],"confidence":"High","gaps":["Structural basis of destabilization not defined","HSP70 study single lab"]},{"year":2016,"claim":"Positioned PAK1-mediated actin polymerization upstream of myelin junction disruption in HNPP, defining a targetable effector of PMP22 haploinsufficiency.","evidence":"F-actin and PAK activity quantification with pharmacological PAK inhibition and electrophysiology in Pmp22+/- mice","pmids":["27583434"],"confidence":"Medium","gaps":["Single lab","How PMP22 loss activates PAK1 not defined"]},{"year":2018,"claim":"Identified a distal super-enhancer required for full Pmp22 expression with promoter-specific sensitivity, refining the dosage-sensitive transcriptional architecture relevant to CMT1A/HNPP.","evidence":"CRISPR deletion of super-enhancer with allele-specific RT-qPCR and H3K27ac ChIP-seq","pmids":["29771329"],"confidence":"High","gaps":["Transcription factors binding the super-enhancer not fully defined","Interaction with intronic enhancer unresolved"]},{"year":2019,"claim":"Established a reciprocal physical and functional partnership between PMP22 and ABCA1 governing Schwann cell cholesterol efflux and homeostasis.","evidence":"Reciprocal Co-IP, colocalization, cholesterol efflux and patch-clamp assays in PMP22 KO and ABCA1 KO mice","pmids":["31061090"],"confidence":"High","gaps":["Direct binding interface unmapped","Whether the interaction is altered by disease mutants untested"]},{"year":2021,"claim":"Dissected the ER quality-control machinery restraining PMP22 trafficking and showed overexpression saturates this control, unifying point-mutation and gene-dosage mechanisms.","evidence":"Single-cell flow trafficking assays, N41Q mutagenesis, OST-A/B depletion, CRISPR KO of RER1/UGGT1/calnexin, and interactome proteomics","pmids":["32647009","33933451"],"confidence":"High","gaps":["In vivo relevance of glycosylation-limited trafficking not tested","Structural reason for inherent inefficiency unknown"]},{"year":null,"claim":"How the distinct PMP22 partner complexes (ABCA1, JAM-C/MAG, lipid rafts) are coordinated at the Schwann cell membrane and whether modulating trafficking efficiency can therapeutically rescue myelination remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of PMP22 membrane complexes","Whether enhancing forward trafficking corrects disease phenotypes in vivo untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[17]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[18,21]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[5,17]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[10,18,23]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[9,10,13]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[15,19,25]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[16,22,12]}],"complexes":["myelin junction complex"],"partners":["ABCA1","JAM-C","MAG","CALNEXIN","UGGT1","RER1","HSP70"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NR77","full_name":"Peroxisomal membrane protein 2","aliases":["22 kDa peroxisomal membrane protein"],"length_aa":195,"mass_kda":22.3,"function":"Seems to be involved in pore-forming activity and may contribute to the unspecific permeability of the peroxisomal membrane","subcellular_location":"Peroxisome membrane","url":"https://www.uniprot.org/uniprotkb/Q9NR77/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PMP22","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PMP22","total_profiled":1310},"omim":[{"mim_id":"619209","title":"ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 7; 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with Increasing Dosage of the PLP Gene: Implications for CMT1A Due to PMP22 Gene Duplication.","date":"1999","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29086937","citation_count":26,"is_preprint":false},{"pmid":"10625337","id":"PMC_10625337","title":"Tetraspan myelin protein PMP22 and demyelinating peripheral neuropathies: new facts and hypotheses.","date":"2000","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/10625337","citation_count":25,"is_preprint":false},{"pmid":"17464210","id":"PMC_17464210","title":"Rapid diagnosis of CMT1A duplications and HNPP deletions by multiplex microsatellite PCR.","date":"2007","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/17464210","citation_count":24,"is_preprint":false},{"pmid":"26076881","id":"PMC_26076881","title":"Molecular and clinical features of inherited neuropathies due to PMP22 duplication.","date":"2015","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26076881","citation_count":24,"is_preprint":false},{"pmid":"25694550","id":"PMC_25694550","title":"Inducible HSP70 is critical in preventing the aggregation and enhancing the processing of PMP22.","date":"2015","source":"ASN neuro","url":"https://pubmed.ncbi.nlm.nih.gov/25694550","citation_count":24,"is_preprint":false},{"pmid":"36571339","id":"PMC_36571339","title":"CMT1A current gene therapy approaches and promising biomarkers.","date":"2023","source":"Neural regeneration research","url":"https://pubmed.ncbi.nlm.nih.gov/36571339","citation_count":23,"is_preprint":false},{"pmid":"32647009","id":"PMC_32647009","title":"Direct relationship between increased expression and mistrafficking of the Charcot-Marie-Tooth-associated protein PMP22.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32647009","citation_count":23,"is_preprint":false},{"pmid":"24812204","id":"PMC_24812204","title":"PMP22 messenger RNA levels in skin biopsies: testing the effectiveness of a Charcot-Marie-Tooth 1A biomarker.","date":"2014","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24812204","citation_count":23,"is_preprint":false},{"pmid":"24819634","id":"PMC_24819634","title":"Mutation analysis of MFN2, GJB1, MPZ and PMP22 in Italian patients with axonal Charcot-Marie-Tooth disease.","date":"2014","source":"Neuromolecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24819634","citation_count":23,"is_preprint":false},{"pmid":"28812050","id":"PMC_28812050","title":"Caveats in the Established Understanding of CMT1A.","date":"2017","source":"Annals of clinical and translational 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(Ser→Cys) in a putative transmembrane domain causes CMT1A in an autosomal dominant pattern, establishing a causative role for PMP22 in peripheral nerve myelination.\",\n      \"method\": \"PCR, heteroduplex analysis, direct nucleotide sequencing of patient DNA; co-segregation analysis\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct mutation identification with functional co-segregation; replicated across multiple independent studies identifying PMP22 point mutations\",\n      \"pmids\": [\"8510709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"In cultured Schwann cells, PMP22 is synthesized from an 18-kDa precursor and post-translationally modified by N-linked glycosylation, yielding the mature ~22 kDa glycoprotein; PMP22 mRNA (1.8 kb) is upregulated by forskolin (cAMP pathway activation).\",\n      \"method\": \"Metabolic labeling, immunoprecipitation with anti-PMP22 antibodies, N-glycosylation analysis, Northern blot, Western blot of purified myelin after deglycosylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with multiple orthogonal methods (pulse-chase, immunoprecipitation, deglycosylation), single lab\",\n      \"pmids\": [\"8486695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"PMP22 mRNA expression in peripheral nerve is restricted to Schwann cells of myelinated fibers and is co-expressed with MBP and P0 during developmental myelination and nerve regeneration; in cultured Schwann cells PMP22 expression is not strictly growth-arrest-specific (unlike in fibroblasts).\",\n      \"method\": \"In situ hybridization, immunohistochemistry, Northern blot of cultured Schwann cells under different growth conditions\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple detection methods but primarily localization/expression; single lab\",\n      \"pmids\": [\"7691737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Retroviral-mediated overexpression of PMP22 in Schwann cells decreases DNA synthesis to ~60% of control and delays G0/G1→S+G2/M entry by ~8 h; antisense-mediated reduction of PMP22 increases DNA synthesis to ~150%, demonstrating that PMP22 directly regulates Schwann cell proliferation.\",\n      \"method\": \"Retroviral transduction (sense/antisense), BrdU incorporation, flow cytometry cell cycle analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and gain-of-function with defined cellular proliferation phenotype, replicated across multiple assays in same study\",\n      \"pmids\": [\"7720703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Overexpression of wild-type Gas3/PMP22 in NIH-3T3 cells induces an apoptotic-like phenotype (membrane blebbing, rounding, chromatin condensation without DNA fragmentation) suppressible by antioxidants. CMT1A dominant point mutants (L16P, S79C) behave as dominant negatives for this apoptotic activity; the recessive mutant T118M behaves recessively, establishing PMP22 as a regulator of apoptosis.\",\n      \"method\": \"Transient transfection overexpression in NIH-3T3 cells; morphological analysis; antioxidant rescue; co-expression dominant-negative experiments\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with multiple mutant alleles and rescue; single lab\",\n      \"pmids\": [\"7649472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Mice homozygously deleted for Pmp22 show delayed onset of myelination, formation of tomacula (sausage-like hypermyelination), severe demyelination, axonal loss, and functional impairment; heterozygous Pmp22+/- mice exhibit focal tomacula resembling HNPP, establishing Pmp22 as required for correct peripheral nerve development, myelin thickness determination, and myelin stability.\",\n      \"method\": \"Targeted gene disruption (knockout mice), histopathology, morphometry, electrophysiology\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined cellular and functional phenotypes, widely replicated\",\n      \"pmids\": [\"7581450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Altered PMP22 expression (over- or under-expression via retroviral transduction) in Schwann cells co-cultured with DRG neurons does not impair early myelination or membrane compaction but affects myelin thickness and stability, indicating PMP22's role is in controlling myelin thickness rather than initiation of myelination.\",\n      \"method\": \"Retroviral transduction of Schwann cells, co-culture with DRG neurons, RT-PCR, immunohistochemistry, confocal microscopy, electron microscopy\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in myelination assay with ultrastructural readout; single lab\",\n      \"pmids\": [\"9086179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Gas3/PMP22 overexpression modulates cell spreading through the small GTPase RhoA: active RhoA counteracts Gas3/PMP22-dependent morphological changes but not apoptosis; C3 exoenzyme (Rho inhibitor) renders otherwise unresponsive REF52 cells susceptible to Gas3/PMP22-induced shape changes; Gas3/PMP22 impairs LPA-induced stress fiber and focal adhesion assembly.\",\n      \"method\": \"Transfection with active/dominant-negative Rho constructs, C3 exoenzyme treatment, cytotoxic necrotizing factor 1 activation of endogenous Rho, time-lapse imaging, Bcl-2 co-expression\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via Rho constructs and pharmacological tools; single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"10397775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Inhibition of the proteasome pathway causes accumulation of PMP22 in perinuclear aggresomes (co-labeled with ubiquitin); overexpression of PMP22 in Schwann cells alone can induce perinuclear accumulation, establishing that the proteasome pathway is critical for regulating PMP22 protein levels.\",\n      \"method\": \"Proteasome inhibitor treatment, immunofluorescence double-labeling with anti-ubiquitin and organelle markers, confocal microscopy\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization tied to protein quality control function; single lab with two orthogonal approaches\",\n      \"pmids\": [\"10527811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Trembler (Tr) and Trembler-J (Tr-J) point-mutant PMP22 proteins are retained in the endoplasmic reticulum (ER) of myelinating Schwann cells in vivo, while wild-type epitope-tagged PMP22 is successfully transported to compact myelin, demonstrating that missense mutations cause pathogenesis through ER retention.\",\n      \"method\": \"Adenoviral microinjection into sciatic nerve of live rats; immunohistochemistry with ER marker colocalization in myelinating Schwann cells\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct in vivo subcellular localization with functional consequence established; multiple mutant alleles tested\",\n      \"pmids\": [\"11114256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Wild-type Gas3/PMP22 is exposed at the cell surface, whereas disease-causing point mutants are intracellularly retained co-localizing with ER. Cell-surface exposure is required for Gas3/PMP22 to regulate both cell death and cell spreading; addition of a retrieval signal to wild-type prevents surface exposure and abolishes both functions. N-glycosylation (Asn41) is required for full cell-spreading effect but not for cell death induction.\",\n      \"method\": \"Immunofluorescence surface staining, ER co-localization, mutagenesis of ER-retrieval motif and N-glycosylation site, cell death and spreading assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with subcellular localization and functional readouts; multiple orthogonal approaches in single study\",\n      \"pmids\": [\"10982389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Increased Schwann cell proliferation and apoptosis appear in later postnatal development in all PMP22 mutant mouse models (overexpression, deletion, point mutation), but not at P1, demonstrating that PMP22 dosage and point mutations affect Schwann cell proliferation and survival primarily in later development.\",\n      \"method\": \"BrdU labeling (proliferation), TUNEL/cleaved caspase (apoptosis), cell density quantification in postnatal sciatic nerve of Pmp22 null, heterozygous, and overexpressing mice\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss- and gain-of-function with defined cellular phenotype; single lab\",\n      \"pmids\": [\"11673320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Progesterone directly regulates Pmp22 and Mpz mRNA levels in Schwann cells: progesterone administration elevates Pmp22 and Mpz mRNA in sciatic nerve and worsens CMT1A phenotype; a progesterone receptor antagonist (onapristone) reduces Pmp22 overexpression and improves the neuropathy phenotype in transgenic CMT1A rats, demonstrating progesterone receptor-mediated transcriptional regulation of PMP22 in Schwann cells.\",\n      \"method\": \"Pharmacological treatment in transgenic rats; qRT-PCR of Pmp22/Mpz mRNA; electrophysiology; clinical phenotype assessment\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain- and loss-of-pharmacological-function in vivo with molecular and functional readouts; progesterone receptor pathway mechanistically established\",\n      \"pmids\": [\"14608378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Calnexin interacts with misfolded transmembrane domains of Gas3/PMP22 in a glycan-independent manner, retaining mutant PMP22 in the ER; FRAP experiments show PMP22 disease mutants are mobile but diffuse at ~half the diffusion coefficient of wild-type, consistent with chaperone-mediated retention.\",\n      \"method\": \"Co-immunoprecipitation of calnexin with PMP22 transmembrane domain-GFP fusions; FRAP (fluorescence recovery after photobleaching) in live cells; glycan-independent interaction confirmed by mutation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus live-cell FRAP; single lab with two orthogonal methods\",\n      \"pmids\": [\"15537650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Gas3/PMP22 overexpression alters membrane traffic through the Arf6 plasma membrane-endosomal recycling pathway: overexpressed PMP22 accumulates in late endosomes and induces formation of actin/PIP2-positive vacuoles trapping Arf6-pathway membrane proteins; dominant-negative Arf6-T27N blocks vacuole formation; a CMT1A point mutant fails to trigger PIP2-positive vacuole accumulation.\",\n      \"method\": \"Live-cell imaging of GFP-tagged proteins, dominant-negative and constitutively active Arf6 constructs, transferrin receptor trafficking assay, immunofluorescence co-localization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via dominant-negative mutant; live imaging with multiple marker comparisons; single lab\",\n      \"pmids\": [\"12584243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In CMT1A (C22) mice overexpressing PMP22, newly synthesized PMP22 shows slowed turnover, cytoplasmic protein aggregates form with reduced proteasome activity, accumulation of detergent-insoluble ubiquitinated substrates, and a fraction of aggregates associates with autophagosomes and lysosomes, indicating that dysregulation of both proteasomal and autophagic degradation pathways underlies PMP22 aggregate pathology.\",\n      \"method\": \"Pulse-chase metabolic labeling, proteasome activity assay, detergent fractionation/Western blot for ubiquitinated proteins, immunofluorescence with autophagosome/lysosome markers\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods in disease model; single lab\",\n      \"pmids\": [\"16326107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The Egr2/Krox20 transcription factor binds a conserved intronic enhancer (~250 bp) within the largest intron of the Pmp22 gene; Sox10 is required for optimal activity of this intronic site and for PMP22 expression; mouse transgenic analysis confirms tissue-specific (peripheral nerve) activity of this intronic sequence.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) of rat Pmp22 locus, luciferase reporter assays, Sox10 knockdown/expression assays, mouse transgenic analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP plus reporter assay plus in vivo transgenic validation; multiple orthogonal methods in single study\",\n      \"pmids\": [\"21411665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PMP22 interacts physically with junctional adhesion molecule-C (JAM-C) and myelin-associated glycoprotein (MAG); PMP22 deficiency disrupts multiple myelin junction complexes, causing increased myelin permeability and impaired action potential propagation. Deletion of Jam-c or Mag individually recapitulates HNPP pathology, establishing PMP22 as a component of myelin junction complexes.\",\n      \"method\": \"Co-immunoprecipitation of PMP22 with JAM-C and MAG from nerve lysates; morphological analysis of junction complexes; electrophysiological assays; Jam-c and Mag knockout mouse genetic epistasis\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic epistasis via knockout mice, electrophysiology; multiple orthogonal methods\",\n      \"pmids\": [\"24339129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PMP22 is localized to cholesterol-enriched lipid raft membrane domains; PMP22-deficient Schwann cells show impaired migration and adhesion, shortened myelin internodes, collapsed lamellipodia, and failure of F-actin-enriched Schmidt-Lanterman incisures to form properly; expression and localization of flotillin-1, cholesterol, and GM1 ganglioside are altered. Cholesterol supplementation rescues elongation and migration deficits, linking PMP22 to actin cytoskeleton-plasma membrane linkage via lipid raft cholesterol regulation.\",\n      \"method\": \"Schwann cell migration/adhesion assays with PMP22 KO cells, phalloidin staining of F-actin, lipid raft fractionation, immunofluorescence for flotillin-1/GM1/cholesterol; cholesterol supplementation rescue\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple functional readouts and pharmacological rescue; multiple orthogonal methods in single study\",\n      \"pmids\": [\"25429154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The conformational stability of PMP22 (assessed by Zn(II)-mediated folding equilibrium) is proportional to the efficiency of its cellular trafficking through the secretory pathway; disease-causing mutations destabilize PMP22 and reduce trafficking efficiency proportionally to reductions in motor nerve conduction velocity in patients, establishing that misfolding-driven ER retention is the molecular basis for CMT from PMP22 point mutations.\",\n      \"method\": \"Quantitative Zn(II)-mediated conformational stability assay for 12 PMP22 variants, flow-cytometry-based cellular trafficking assay, correlation with patient NCV data\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biophysical assay + cell-based trafficking quantification + clinical correlation; multiple orthogonal methods\",\n      \"pmids\": [\"26102530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Inducible HSP70 (HSP70.1/3) is critical for preventing aggregation of misfolded PMP22 (especially Trembler-J PMP22) under proteotoxic stress; HSP70 aids processing of Tr-J PMP22 through the Golgi and delivery to lysosomes via Rab7-positive vesicles; HSP70 KO cells show increased PMP22 aggregation and proteasome dysfunction.\",\n      \"method\": \"HSP70.1/3 knockout mouse-derived cells, pharmacological induction of HSP70 (FDA-approved small molecule), immunofluorescence co-localization with Golgi/Rab7 markers, proteasome activity assay, Western blot\",\n      \"journal\": \"ASN neuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cell model with multiple readouts; single lab\",\n      \"pmids\": [\"25694550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Pmp22+/- (HNPP model) nerves, increased F-actin levels correlate with enhanced PAK1 activity; pharmacological PAK inhibition normalizes F-actin, prevents progression of myelin junction disruption, and prevents nerve conduction failure, positioning PAK1-mediated actin polymerization upstream of myelin junction disruption in HNPP.\",\n      \"method\": \"Immunofluorescence quantification of F-actin in nerve sections, PAK kinase activity assay, pharmacological PAK inhibitor treatment in Pmp22+/- mice, electrophysiology\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis in disease model with biochemical and functional readouts; single lab\",\n      \"pmids\": [\"27583434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A distal super-enhancer (~90-130 kb upstream of Pmp22 TSS) is required for full Pmp22 expression; CRISPR deletion of this super-enhancer significantly decreases Pmp22 transcript levels, with the Schwann cell-specific P1 promoter being disproportionately more sensitive than the P2 promoter.\",\n      \"method\": \"Genome editing (CRISPR) deletion of super-enhancer, allele-specific RT-qPCR, H3K27ac ChIP-seq chromatin mark identification\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — CRISPR deletion with allele-specific expression quantification; multiple methods in single study\",\n      \"pmids\": [\"29771329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PMP22 co-immunoprecipitates with ABCA1 from Schwann cell and nerve lysates, and both proteins co-localize at the Schwann cell plasma membrane; PMP22 absence reduces ABCA1 membrane localization and impairs ABCA1-mediated cholesterol efflux. Conversely, ABCA1 KO mice show elevated PMP22 expression with aberrant subcellular processing, establishing a reciprocal functional interaction between PMP22 and ABCA1 in cholesterol homeostasis.\",\n      \"method\": \"Co-immunoprecipitation from Schwann cell/nerve lysates, immunofluorescence co-localization, cholesterol efflux assay, whole-cell patch-clamp (membrane capacitance/resistance), Western blot in PMP22 KO and ABCA1 KO mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus KO functional assays in two genetic models plus electrophysiology; multiple orthogonal methods\",\n      \"pmids\": [\"31061090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"As the expression level of PMP22 (wild-type or disease variants) is increased in individual cells, the fraction of intracellularly retained (misfolded) PMP22 increases disproportionately relative to surface-trafficked protein, demonstrating that overexpression per se saturates ER quality control to produce mistrafficking.\",\n      \"method\": \"Single-cell flow-cytometry trafficking assay distinguishing surface vs. intracellular PMP22; stable and transient expression systems\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative single-cell trafficking assay with two expression systems; single lab\",\n      \"pmids\": [\"32647009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"N-glycosylation at Asn41 is a limiting factor for forward trafficking of PMP22: N41Q mutation increases wild-type trafficking efficiency ~3-fold and L16P ~10-fold in HEK293 and Schwann cells. WT PMP22 is glycosylated post-translationally by OST-B; L16P is co-translationally glycosylated by OST-A. CRISPR KO studies identify RER1 as limiting for all PMP22 forms, UGGT1 as limiting for WT and L16P but not N41Q, and calnexin as limiting for WT and N41Q but not L16P.\",\n      \"method\": \"N41Q mutagenesis, flow-cytometry trafficking assay, OST-A/B depletion, CRISPR KO of RER1/UGGT1/calnexin, quantitative proteomics interactome screens\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis, CRISPR KO of quality-control components, quantitative trafficking assay, proteomics interactome; multiple orthogonal methods in single study\",\n      \"pmids\": [\"33933451\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PMP22 is a tetraspan N-glycosylated integral membrane glycoprotein of Schwann cell compact myelin whose precise level is critical: it is transcriptionally induced in Schwann cells via Egr2/Sox10-bound intronic and distal super-enhancer elements and progesterone receptor signaling; only ~20% of newly synthesized PMP22 traffics efficiently to the cell surface, with N-glycosylation, calnexin, UGGT1, and RER1 limiting forward trafficking and the proteasome/HSP70/autophagy network degrading the misfolded majority; wild-type PMP22 at the plasma membrane regulates Schwann cell proliferation, apoptosis, actin-cytoskeleton linkage, lipid raft integrity, cholesterol homeostasis (through physical interaction with ABCA1), and myelin junction permeability (through interaction with JAM-C and MAG); disease-causing point mutations destabilize PMP22 fold proportionally to their clinical severity, causing ER retention (aided by glycan-independent calnexin binding) and aggresome formation, while PMP22 overexpression saturates ER quality control producing disproportionate mistrafficking and CMT1A-like demyelination, and haploinsufficiency disrupts myelin junctions and impairs PAK1/actin-regulated myelin permeability causing the HNPP phenotype.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PMP22 is an N-glycosylated tetraspan integral membrane glycoprotein of Schwann cells whose dosage and folding fidelity are critical determinants of peripheral nerve myelination, with point mutations causing dominant CMT1A and gene-dosage imbalance underlying CMT1A and HNPP [#0, #5]. The protein is synthesized as an 18-kDa precursor and matured to ~22 kDa by N-linked glycosylation, and its expression is restricted to myelinating Schwann cells where it is induced by cAMP signaling [#1, #2], by Egr2/Sox10 acting through a conserved intronic enhancer and a distal super-enhancer that drives the Schwann cell-specific promoter [#16, #22], and by progesterone receptor signaling [#12]. Functionally, surface-resident wild-type PMP22 restrains Schwann cell proliferation and regulates apoptosis and cell spreading through RhoA, and controls myelin thickness and stability rather than myelin initiation [#3, #5, #6, #7, #10]. At the plasma membrane PMP22 resides in cholesterol-enriched lipid rafts and links the actin cytoskeleton to the membrane, physically partnering with ABCA1 to govern cholesterol efflux and homeostasis, and with JAM-C and MAG to maintain myelin junction integrity and permeability [#17, #18, #23]. PMP22 trafficking is intrinsically inefficient: conformational stability is rate-limiting for forward trafficking, with N-glycosylation at Asn41 and the ER quality-control factors calnexin, UGGT1, and RER1 acting as restraints, such that destabilizing point mutations are retained in the ER in proportion to their clinical severity, while overexpression disproportionately saturates this quality control to produce mistrafficking [#13, #19, #24, #25]. Misfolded PMP22 is cleared by the proteasome, HSP70 chaperones, and autophagy, and its failure produces ubiquitinated perinuclear aggresomes [#8, #15, #20]. In HNPP, PMP22 haploinsufficiency disrupts myelin junctions via PAK1-driven F-actin dysregulation, impairing action potential propagation [#17, #21].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that PMP22 is a peripheral myelin gene whose mutation causes inherited neuropathy, defining the gene's clinical and tissue relevance.\",\n      \"evidence\": \"Point-mutation identification and co-segregation in CMT1A families; biochemical characterization of the glycoprotein in cultured Schwann cells\",\n      \"pmids\": [\"8510709\", \"8486695\", \"7691737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the cellular function of PMP22\", \"Mechanism linking mutation to demyelination unknown\", \"Trafficking and folding behavior uncharacterized\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Showed that PMP22 dosage actively regulates Schwann cell proliferation, apoptosis, and myelin thickness/stability, moving it from a structural marker to a functional regulator.\",\n      \"evidence\": \"Retroviral gain/loss-of-function with BrdU and cell-cycle analysis; NIH-3T3 apoptosis assay with dominant/recessive mutant alleles; Pmp22 knockout mouse histopathology\",\n      \"pmids\": [\"7720703\", \"7649472\", \"7581450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners mediating proliferation/apoptosis effects not identified\", \"Whether effects require surface localization unresolved at this stage\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Refined PMP22's role to control of myelin thickness and stability rather than myelin initiation or compaction.\",\n      \"evidence\": \"Retroviral over/under-expression in Schwann cell-DRG co-culture with EM ultrastructure\",\n      \"pmids\": [\"9086179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of thickness control not defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Linked PMP22's effects on cell shape to RhoA signaling and Arf6-dependent membrane recycling, indicating cytoskeletal and trafficking-pathway engagement.\",\n      \"evidence\": \"Rho construct epistasis and C3 exoenzyme treatment; dominant-negative Arf6 and live-cell trafficking imaging\",\n      \"pmids\": [\"10397775\", \"12584243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical interaction with Rho/Arf6 not shown\", \"Relevance to in vivo myelination not established\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated that disease-causing missense mutants are retained in the ER and that cell-surface exposure is required for PMP22 function, establishing mislocalization as the pathogenic mechanism.\",\n      \"evidence\": \"Adenoviral expression in live rat sciatic nerve with ER marker colocalization; surface staining, ER-retrieval and N-glycosylation site mutagenesis with functional assays\",\n      \"pmids\": [\"11114256\", \"10982389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chaperones mediating retention not yet identified\", \"Quantitative relationship between retention and severity not defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed that PMP22 dosage and point mutations affect Schwann cell proliferation and survival specifically in later postnatal development, timing the cellular phenotype.\",\n      \"evidence\": \"BrdU, TUNEL, and density quantification across Pmp22 null, heterozygous, and overexpressing mouse nerves\",\n      \"pmids\": [\"11673320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular trigger of late-developmental effect unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified progesterone receptor signaling as a transcriptional regulator of Pmp22, providing a pharmacologically tractable node modulating disease severity.\",\n      \"evidence\": \"Progesterone and onapristone treatment of CMT1A transgenic rats with qRT-PCR, electrophysiology, and phenotype scoring\",\n      \"pmids\": [\"14608378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PR binding to Pmp22 regulatory elements not mapped\", \"Interaction with other transcriptional inputs unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined calnexin as a glycan-independent chaperone retaining misfolded PMP22 transmembrane domains in the ER, providing a molecular mechanism for mutant retention.\",\n      \"evidence\": \"Co-IP of calnexin with TMD-GFP fusions and live-cell FRAP\",\n      \"pmids\": [\"15537650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Other quality-control factors not yet defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed both proteasomal and autophagic degradation pathways are engaged and dysregulated in PMP22 aggregate pathology, expanding the disposal network for misfolded protein.\",\n      \"evidence\": \"Pulse-chase, proteasome activity assay, detergent fractionation, and autophagosome/lysosome immunofluorescence in CMT1A mice; earlier proteasome/aggresome study\",\n      \"pmids\": [\"16326107\", \"10527811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Causal contribution of each pathway to disease not separated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapped the transcriptional control of Pmp22 to an Egr2/Krox20-bound intronic enhancer requiring Sox10, defining the core Schwann cell-specific regulatory logic.\",\n      \"evidence\": \"ChIP, luciferase reporters, Sox10 manipulation, and mouse transgenic validation\",\n      \"pmids\": [\"21411665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distal regulatory elements not yet identified\", \"Contribution to gene-dosage disease unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established PMP22 as a component of myelin junction complexes and lipid-raft membrane organization, identifying JAM-C, MAG, and ABCA1-relevant cholesterol pathways as effectors.\",\n      \"evidence\": \"Reciprocal Co-IP with JAM-C and MAG plus Jam-c/Mag knockout epistasis; lipid raft fractionation, F-actin staining, and cholesterol rescue in PMP22 KO Schwann cells\",\n      \"pmids\": [\"24339129\", \"25429154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and architecture of the junction complex unresolved\", \"Direct binding interfaces not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Quantitatively linked PMP22 conformational stability to trafficking efficiency and clinical severity, and identified HSP70 as a key chaperone preventing mutant aggregation.\",\n      \"evidence\": \"Zn(II)-mediated stability assay across 12 variants with trafficking and patient NCV correlation; HSP70 KO cells with Golgi/Rab7 colocalization and proteasome assays\",\n      \"pmids\": [\"26102530\", \"25694550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of destabilization not defined\", \"HSP70 study single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Positioned PAK1-mediated actin polymerization upstream of myelin junction disruption in HNPP, defining a targetable effector of PMP22 haploinsufficiency.\",\n      \"evidence\": \"F-actin and PAK activity quantification with pharmacological PAK inhibition and electrophysiology in Pmp22+/- mice\",\n      \"pmids\": [\"27583434\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"How PMP22 loss activates PAK1 not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a distal super-enhancer required for full Pmp22 expression with promoter-specific sensitivity, refining the dosage-sensitive transcriptional architecture relevant to CMT1A/HNPP.\",\n      \"evidence\": \"CRISPR deletion of super-enhancer with allele-specific RT-qPCR and H3K27ac ChIP-seq\",\n      \"pmids\": [\"29771329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factors binding the super-enhancer not fully defined\", \"Interaction with intronic enhancer unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a reciprocal physical and functional partnership between PMP22 and ABCA1 governing Schwann cell cholesterol efflux and homeostasis.\",\n      \"evidence\": \"Reciprocal Co-IP, colocalization, cholesterol efflux and patch-clamp assays in PMP22 KO and ABCA1 KO mice\",\n      \"pmids\": [\"31061090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface unmapped\", \"Whether the interaction is altered by disease mutants untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Dissected the ER quality-control machinery restraining PMP22 trafficking and showed overexpression saturates this control, unifying point-mutation and gene-dosage mechanisms.\",\n      \"evidence\": \"Single-cell flow trafficking assays, N41Q mutagenesis, OST-A/B depletion, CRISPR KO of RER1/UGGT1/calnexin, and interactome proteomics\",\n      \"pmids\": [\"32647009\", \"33933451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of glycosylation-limited trafficking not tested\", \"Structural reason for inherent inefficiency unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct PMP22 partner complexes (ABCA1, JAM-C/MAG, lipid rafts) are coordinated at the Schwann cell membrane and whether modulating trafficking efficiency can therapeutically rescue myelination remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model of PMP22 membrane complexes\", \"Whether enhancing forward trafficking corrects disease phenotypes in vivo untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [18, 21]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [5, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10, 18, 23]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [9, 10, 13]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [15, 19, 25]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [16, 22, 12]}\n    ],\n    \"complexes\": [\"myelin junction complex\"],\n    \"partners\": [\"ABCA1\", \"JAM-C\", \"MAG\", \"calnexin\", \"UGGT1\", \"RER1\", \"HSP70\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}