{"gene":"PLP1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2003,"finding":"PLP1 (but not its alternatively spliced isoform DM20) expression in Schwann cells is necessary to prevent peripheral neuropathy. Mutations that truncate PLP1 within the 35-amino-acid PLP1-specific domain (absent in DM20) or null mutations cause peripheral neuropathy, whereas mutations that preserve an intact PLP1-specific domain or PLP1 duplications do not. This demonstrates that the PLP1-specific domain plays a critical role in normal peripheral nerve function.","method":"Clinical cohort analysis of PMD patients with defined PLP1 mutations; electrodiagnostic studies; genotype-phenotype correlation of PLP1 vs DM20 isoform-affecting mutations","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — large patient cohort with multiple mutation types, clear genotype-phenotype dissection between PLP1-specific domain and DM20, independently consistent across 61+ patients with duplications and multiple point mutation carriers","pmids":["12601703"],"is_preprint":false},{"year":2006,"finding":"Alternative splicing of PLP1 pre-mRNA is regulated by an exonic splicing enhancer (ESE) in exon 3B. The ASF/SF2 splicing factor specifically binds to nucleotides 406–412 of exon 3B, and this binding positively regulates selection of the PLP1 5' splice donor site in a concentration-dependent manner. Single nucleotide mutations in the ESE that reduced PLP1 splice site selection also diminished ASF/SF2 binding.","method":"UV crosslinking and immunoprecipitation with ASF/SF2 antibody; overexpression of ASF/SF2 in differentiating oligodendrocytes; mutagenesis of ESE motifs; minigene splicing assays","journal":"Journal of cellular biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding assay (UV-crosslink IP), mutagenesis of binding site, functional splicing assay with overexpression, multiple orthogonal methods in one study","pmids":["16288477"],"is_preprint":false},{"year":2006,"finding":"The relative strengths of the PLP1 and DM20 5' splice donor sites play an important role in determining the PLP1/DM20 alternative splicing ratio. Information theory-based analysis of splice site strength correlated well with observed PLP1 and DM20 mRNA expression patterns from patient mutations affecting splice sites in intron 3.","method":"Information theory-based splice site analysis; mRNA expression analysis in patient-derived cells for multiple PLP1 splice-site mutations","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mRNA expression in patient cells plus computational analysis; single lab but multiple mutations tested with consistent results","pmids":["16287154"],"is_preprint":false},{"year":2008,"finding":"A splicing enhancer in PLP1 intron 3 is required for the developmental increase in the PLP1/DM20 transcript and protein ratio during myelination. Deletion of this intronic splicing enhancer in a knockin mouse impairs the postnatal increase in PLP1/DM20 ratio and results in abnormal myelin wraps with fragmented whorls (progressive with age) and a motor coordination defect, establishing that full PLP1 dosage relative to DM20 is necessary for myelin stability.","method":"Knockin mouse with deletion of intronic splicing enhancer; Real-Time RT-PCR and Western blot for PLP1/DM20 ratio; electron microscopy of myelin; motor testing","journal":"Experimental neurology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vivo genetic knockin model with multiple orthogonal readouts (molecular, ultrastructural, behavioral), single lab but rigorous","pmids":["18835559"],"is_preprint":false},{"year":2014,"finding":"Alternative splicing of PLP1 is regulated by a long-distance RNA secondary structure formed by base-pairing between two conserved elements separated by 581 bases within intron 3. Mutations of either element that destabilize the secondary structure decreased the PLP1/DM20 ratio, while compensatory swap mutations that restored the structure brought the ratio to near-normal levels. Patient mutations in these elements that destabilize the structure also reduce the PLP1/DM20 ratio and segregate with PMD disease.","method":"Minigene splicing constructs transfected into Oli-neu oligodendrocyte cell line; compensatory mutagenesis; patient mutation analysis in three families","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — functional minigene assay with compensatory mutagenesis (structure-function validation), patient mutations confirm mechanism, multiple orthogonal approaches in one study","pmids":["24890387"],"is_preprint":false},{"year":2014,"finding":"Missense mutations in PLP1 cause accumulation of mutant PLP1 protein in the rough endoplasmic reticulum (ER) in PMD patient iPSC-derived oligodendrocytes. This ER mislocalization is associated with increased susceptibility to ER stress, increased oligodendrocyte apoptosis, and drastically reduced myelin formation with abnormal ER morphology by electron microscopy.","method":"iPSC generation from PMD patients; differentiation into oligodendrocytes; immunofluorescence for ER localization; ER stress assays; electron microscopy of myelin formation","journal":"Stem cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — patient-derived iPSC-to-oligodendrocyte model with multiple orthogonal methods (localization, stress markers, ultrastructure), single lab but rigorous","pmids":["24936452"],"is_preprint":false},{"year":2006,"finding":"The rumpshaker PLP1 mutation causes low steady-state PLP levels due to accelerated proteasomal degradation (T½ of 11 h for rumpshaker vs 23 h for wild type), not decreased synthesis. A minority of newly synthesized rumpshaker PLP is incorporated into myelin. However, inhibition of proteasomal degradation does not increase myelin incorporation of PLP, suggesting that dysmyelination is not simply caused by reduced PLP levels.","method":"Pulse-chase analysis; proteasome inhibitor treatment; measurement of PLP synthesis and degradation rates in mouse model; myelin incorporation assays","journal":"Glia","confidence":"High","confidence_rationale":"Tier 1 / Moderate — pulse-chase kinetics with pharmacological inhibition, multiple quantitative assays, mechanistically informative negative result also established","pmids":["16506223"],"is_preprint":false},{"year":2006,"finding":"The unfolded protein response (UPR) is activated in rumpshaker PLP1 mutant oligodendrocytes. CHOP activation correlates with phenotypic severity across genetic backgrounds, whereas BiP and Xbp1 responses do not differ between mild (C3H) and severe (C57BL/6) backgrounds, indicating that differential CHOP-dependent UPR contributes to phenotypic variation.","method":"Western blot and RT-PCR for UPR markers (CHOP, BiP, Xbp1) in two genetic backgrounds of rumpshaker mice","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, two genetic backgrounds, molecular markers only; no functional rescue experiment","pmids":["16944321"],"is_preprint":false},{"year":2009,"finding":"PLP1 gene duplication results in a 4–5 fold increase in PLP1 gene expression in fibroblasts and also shifts the PLP1/DM20 alternative splicing balance toward the PLP isoform (decreased DM20/(DM20+PLP) ratio), demonstrating that gene dosage affects both total expression and splicing equilibrium.","method":"Real-time PCR with isoform-specific amplicons in fibroblasts from PMD patients with PLP1 duplication vs. controls","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — patient fibroblast gene expression assay, single lab, limited sample size (n=3 patients, n=3 controls)","pmids":["19376225"],"is_preprint":false},{"year":2017,"finding":"Oligodendroglial loss of Plp1 (not neuronal loss) is the primary cause of axonal degeneration and the full neurodegenerative spectrum of SPG2. Cre-mediated deletion of Plp1 selectively in excitatory projection neurons does not cause neuropathology, whereas oligodendroglial-targeted Plp1 deletion recapitulates axonopathy and secondary neuroinflammation.","method":"Conditional knockout mice with floxed Plp1 allele; Cre-mediated recombination in neurons vs. oligodendrocytes; histological and behavioral analysis","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional KO with direct comparison between neuronal and oligodendroglial deletion, clear phenotypic readout, rigorous genetic epistasis","pmids":["28836307"],"is_preprint":false},{"year":2015,"finding":"Mutations in PLP1 exon 3B or deep within intron 3 that decrease the PLP1/DM20 splicing ratio cause Hypomyelination of Early Myelinating Structures (HEMS). Four deep intronic mutations destabilize a long-distance RNA interaction structure regulating PLP1/DM20 alternative splicing. In vitro splicing studies in patient fibroblasts and transfected cells confirmed a decreased PLP1/DM20 ratio from these mutations.","method":"Exome sequencing; minigene splicing constructs transfected into immature oligodendrocyte cell line; in silico splice prediction; RNA from patient fibroblasts","journal":"Annals of clinical and translational neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional splicing assays in cells, patient fibroblast RNA, multiple mutations tested; single lab","pmids":["26125040"],"is_preprint":false},{"year":2013,"finding":"An antisense oligonucleotide directed against an exonic splicing regulatory motif introduced by the PLP1 c.436C>G missense mutation can restore normal PLP1 splicing (rescue of major PLP transcript production) in oligodendrocyte precursor cells, demonstrating that this mutation acts by creating aberrant splicing regulatory motifs rather than solely through amino acid substitution.","method":"Antisense oligonucleotide treatment of oligodendrocyte precursor cells; RT-PCR analysis of PLP1/DM20 splicing in treated cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue by antisense oligonucleotide in cell model; single lab, single mutation","pmids":["24019930"],"is_preprint":false},{"year":2018,"finding":"Morpholino antisense oligomers blocking the DM20 5' splice donor site shift PLP1/DM20 alternative splicing toward the PLP1 form in oligodendrocyte cell lines and in neonatal mouse brain after intracerebroventricular injection. In a knockin mouse with an intronic splicing enhancer deletion, a single injection corrected PLP1/DM20 splicing at RNA and protein levels for at least 90 days post-injection, with sustained reduction of inflammatory markers.","method":"Morpholino oligomer treatment of oligodendrocyte cell line; intracerebroventricular injection in neonatal mice; RT-PCR and Western blot for PLP1/DM20 ratio; immunohistochemistry for inflammation","journal":"Molecular therapy. Nucleic acids","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo correction in disease mouse model with protein-level validation and functional inflammatory readout, multiple orthogonal methods","pmids":["30195779"],"is_preprint":false},{"year":2018,"finding":"PLP1 missense mutations (including Leu30Val) cause significant accumulation of PLP in the endoplasmic reticulum and induction of the unfolded protein response (UPR) in transfected Cos-7 cells, as shown by comparison with wild-type PLP1 and known PMD/SPG2-causing mutations.","method":"Transfection of mCherry-tagged wild-type and mutant PLP1 constructs into Cos-7 cells; fluorescence microscopy for ER localization; UPR marker assays","journal":"Journal of clinical medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — cell transfection with tagged protein, single lab, non-oligodendrocyte cell system","pmids":["30314286"],"is_preprint":false},{"year":2021,"finding":"Two oligodendrocyte-specific enhancers (Plp1-E1 and Plp1-E2) located distal to the Plp1 promoter regulate Plp1 expression with exquisite specificity. CRISPRi epigenome editing showed these enhancers do not regulate two neighboring genes. Hi-C data revealed strong, OL-specific physical interactions between these enhancers and the PLP1 promoter. Myrf, a master regulator of oligodendrocyte development, acts on Plp1-E1 and Plp1-E2 to promote Plp1 expression.","method":"CRISPRi epigenome editing; ATAC-seq; ChIP-seq; Hi-C chromatin interaction mapping in oligodendrocytes","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — CRISPRi functional validation, chromatin interaction data (Hi-C), and ChIP-seq in the same study with multiple orthogonal methods","pmids":["34230963"],"is_preprint":false},{"year":2018,"finding":"A wmN1 enhancer region within human PLP1 intron 1 is required for high levels of PLP1 gene expression in oligodendrocytes. Removal of the wmN1 region from a human PLP1-lacZ transgene using Cre recombinase caused a dramatic reduction in transgene activity in mouse brain, demonstrating this intronic element is necessary for robust PLP1 expression.","method":"Transgenic mice carrying human PLP1-lacZ with loxP-flanked wmN1 region; Cre-mediated deletion; X-gal staining and β-galactosidase activity measurement in brain","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic deletion of regulatory element with reporter readout, multiple transgenic lines, consistent result","pmids":["29683207"],"is_preprint":false},{"year":2022,"finding":"PLP-deficient (Plp-null) mice develop pathological myelin outfoldings extending up to 10 μm longitudinally along myelinated axons, associated with complex axonal pathology including axonal sprouting and anastomosing underneath outfoldings. Normal-appearing axon/myelin units showed significantly increased axonal diameters in Plp-null mice, indicating PLP is required to maintain normal axonal diameter and shape.","method":"Focused ion beam-scanning electron microscopy (FIB-SEM); 3D reconstruction and morphometric analysis in Plp-null and Mag-null mutant mice","journal":"Glia","confidence":"High","confidence_rationale":"Tier 1 / Moderate — 3D ultrastructural reconstruction with quantitative morphometry in genetic null model, rigorous methodology","pmids":["36354016"],"is_preprint":false},{"year":2017,"finding":"PLP1 loss-of-function mutations in oligodendrocytes cause neuroinflammation (comprising adaptive immune reactions) that promotes disease progression including axonopathy and neurodegeneration. Inactivation of RAG1 (abolishing adaptive immunity) in PLP1 mutant mice demonstrated that neuroinflammation drives clinically relevant axonal degeneration, neuronal loss, and brain atrophy.","method":"PLP1 point-mutation mouse models; RAG1 inactivation (immune-incompetent crosses); programmed cell death-1 gene inactivation; histology and brain imaging","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (RAG1 knockout rescues neurodegeneration in PLP1 mutant background), two independent PLP1 mutant models, multiple readouts","pmids":["28173160"],"is_preprint":false},{"year":2023,"finding":"Cytotoxic CD8+ T cells drive axonal damage in PLP1 mutant mice by targeting mutant oligodendrocytes in an antigen-specific manner. Bone marrow chimerism experiments and random X chromosome inactivation models demonstrated that CD8+ T cells from PLP1-mutant mice specifically target oligodendrocytes expressing mutant PLP1.","method":"Single-cell transcriptomics of CNS-associated T cells; bone marrow chimerism; X chromosome inactivation mosaic model; sphingosine-1-phosphate receptor modulation; histological readouts of axonal damage","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple genetic approaches (bone marrow chimerism, X-inactivation mosaicism) with single-cell transcriptomics and functional rescue experiments","pmids":["37182098"],"is_preprint":false},{"year":2021,"finding":"PLP1 duplication mutations cause closer ER-mitochondrion interfaces (mediated through structural changes in both ER and mitochondria-associated membranes, MAMs) compared to controls, and this is associated with mitochondrial dysfunction as measured by extracellular flux analysis. This identifies MAM structural changes as a bridge between PLP1 ER accumulation and mitochondrial pathology.","method":"Super-resolution microscopy (SD-SIM) for ER-mitochondrion interface measurement; Seahorse XF extracellular flux analysis of mitochondrial respiration in patient and control fibroblasts","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — two orthogonal methods (super-resolution microscopy, metabolic flux) in patient fibroblasts; single lab, limited sample size","pmids":["34506833"],"is_preprint":false},{"year":2024,"finding":"Knockdown of Rab7B (a small GTPase involved in lysosomal vesicle trafficking) using CRISPR/CasRx rescues the incomplete cell morphology induced by the PLP1 p.Ala243Val mutation in oligodendroglial FBD-102b cells, and promotes trafficking of mutant PLP1 to LAMP1-positive lysosomal organelles, suggesting Rab7B modulates the intracellular fate of misfolded PLP1.","method":"CRISPR/CasRx-mediated knockdown of Rab7B in oligodendroglial cell line expressing PLP1 p.Ala243Val; immunofluorescence for LAMP1 co-localization; cell morphology quantification","journal":"Neuroscience insights","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — CRISPR knockdown with immunofluorescence in cell line, single lab, single mutation model","pmids":["39280331"],"is_preprint":false},{"year":2019,"finding":"Treatment with VX680 or 5-azadC in a lymphoblastoid cell line from a female PLP1 mutation carrier with skewed X-inactivation (silencing the wild-type allele) restored expression of the wild-type PLP1 allele, demonstrating that pharmacological reversal of skewed X-inactivation can rescue PLP1 expression.","method":"RNA sequencing confirming mono-allelic mutant PLP1 expression; drug treatment with VX680 and 5-azadC; allele-specific expression analysis post-treatment","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional rescue experiment in patient-derived cell line; single lab, single patient","pmids":["31004103"],"is_preprint":false},{"year":2023,"finding":"Plp1 expression in enteric nervous system glia preferentially occurs during early postnatal development primarily as the DM20 isoform. An intronic enhancer element (wmN1) within Plp1 intron 1 is required for Plp1 expression in intestinal enteric glia; removal of wmN1 from a human PLP1-lacZ transgene dramatically reduced transgene mRNA and reporter activity throughout intestinal development.","method":"Western blot and transgenic reporter (lacZ) mice at multiple postnatal ages; Cre-mediated removal of wmN1 enhancer from transgene; β-galactosidase activity measurement along intestinal segments","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo transgenic reporter with genetic element deletion, single lab, uses reporter rather than endogenous gene for enhancer test","pmids":["37293625"],"is_preprint":false}],"current_model":"PLP1 encodes the major CNS myelin transmembrane protein (and its alternatively spliced DM20 isoform); its expression in oligodendrocytes is governed by intronic enhancers (wmN1, Plp1-E1/E2) and regulated by the transcription factor Myrf, while the PLP1/DM20 splicing ratio is controlled by a long-distance RNA secondary structure in intron 3 and an exonic splicing enhancer bound by ASF/SF2; missense mutations cause ER retention and UPR-mediated oligodendrocyte apoptosis, null mutations and rumpshaker mutations lead to accelerated proteasomal degradation of PLP, and oligodendroglial PLP1 deficiency (not neuronal) causes progressive axonal degeneration via loss of myelin support and secondary antigen-specific CD8+ T cell-driven neuroinflammation, while PLP itself is required to maintain normal axonal diameter and shape."},"narrative":{"mechanistic_narrative":"PLP1 encodes the major transmembrane protein of CNS myelin and, through alternative splicing of exon 3, its shorter DM20 isoform; the PLP1/DM20 ratio is a developmentally regulated quantity whose disruption causes hypomyelinating disease [PMID:18835559, PMID:24890387]. The splicing decision is controlled by the relative strength of the PLP1 and DM20 5' splice donor sites [PMID:16287154], by an exonic splicing enhancer in exon 3B bound by the splicing factor ASF/SF2 [PMID:16288477], and by a long-distance RNA secondary structure formed within intron 3 whose disruption lowers the PLP1/DM20 ratio and segregates with disease [PMID:24890387, PMID:26125040]. Oligodendrocyte-restricted PLP1 expression is driven by distal enhancers (Plp1-E1/E2) acted on by the master oligodendrocyte regulator Myrf, which physically loop to the promoter, and by an intron-1 enhancer (wmN1) required for high expression in both CNS oligodendrocytes and enteric glia [PMID:34230963, PMID:29683207, PMID:37293625]. PLP1 supports myelin and axonal integrity: oligodendroglial — not neuronal — loss of Plp1 drives axonal degeneration, and PLP is required to maintain normal axonal diameter and myelin shape [PMID:28836307, PMID:36354016]. Disease arises through two genetic logics: missense mutations cause mutant protein to accumulate in the ER, triggering the unfolded protein response and oligodendrocyte apoptosis [PMID:24936452, PMID:30314286, PMID:16944321], while loss-of-function leads to axonopathy compounded by antigen-specific CD8+ T-cell-driven neuroinflammation that promotes neurodegeneration [PMID:28173160, PMID:37182098]. Truncating mutations within the 35-residue PLP1-specific domain absent from DM20 additionally cause peripheral neuropathy, establishing an isoform-specific role for PLP1 in peripheral nerve [PMID:12601703]. These mechanisms have motivated splice-correcting antisense and morpholino strategies that restore the PLP1/DM20 ratio and reduce inflammation in disease models [PMID:24019930, PMID:30195779].","teleology":[{"year":2003,"claim":"Established that the PLP1-specific 35-amino-acid domain (absent in DM20) has a distinct functional requirement, resolving why some mutations produce peripheral neuropathy while others do not.","evidence":"Clinical cohort genotype-phenotype correlation of PMD patients with PLP1-specific vs DM20-affecting mutations and electrodiagnostics","pmids":["12601703"],"confidence":"High","gaps":["Molecular function of the PLP1-specific domain in Schwann cells not defined","No biochemical mechanism for how the domain supports peripheral nerve"]},{"year":2006,"claim":"Defined the cis and trans determinants of PLP1/DM20 alternative splicing, showing splice-site strength and an exon 3B enhancer bound by ASF/SF2 jointly tune isoform choice.","evidence":"UV-crosslink IP, ESE mutagenesis, minigene assays and ASF/SF2 overexpression; information-theory splice-site analysis with patient mRNA","pmids":["16288477","16287154"],"confidence":"High","gaps":["Whether ASF/SF2 levels are the physiological developmental switch in vivo not shown","Other trans-factors acting on the ESE not identified"]},{"year":2006,"claim":"Identified the rumpshaker mutation as acting through accelerated proteasomal degradation of PLP and UPR activation, and showed that restoring PLP levels alone does not rescue myelination, decoupling protein abundance from dysmyelination.","evidence":"Pulse-chase kinetics with proteasome inhibition and myelin incorporation assays; UPR marker analysis across two genetic backgrounds","pmids":["16506223","16944321"],"confidence":"High","gaps":["CHOP-dependence shown by correlation, not by genetic rescue","Mechanism linking misfolded PLP to selective proteasomal targeting unresolved"]},{"year":2008,"claim":"Demonstrated in vivo that an intron-3 splicing enhancer drives the developmental rise in PLP1/DM20 ratio and that full PLP1 dosage is required for myelin stability.","evidence":"Knockin mouse with intronic enhancer deletion; RT-PCR, Western blot, EM of myelin, motor testing","pmids":["18835559"],"confidence":"High","gaps":["Molecular identity of factors binding the enhancer not defined here","How a modest ratio shift destabilizes myelin mechanistically unclear"]},{"year":2009,"claim":"Showed that PLP1 duplication raises both total expression and shifts the splicing balance toward PLP1, linking gene dosage to two distinct consequences.","evidence":"Isoform-specific real-time PCR in patient vs control fibroblasts","pmids":["19376225"],"confidence":"Medium","gaps":["Small sample size (n=3)","Fibroblast surrogate, not oligodendrocytes"]},{"year":2013,"claim":"Revealed that a coding missense mutation (c.436C>G) acts partly by creating an aberrant splicing motif, and that antisense oligonucleotides can restore normal PLP1 splicing.","evidence":"Antisense oligonucleotide treatment of oligodendrocyte precursor cells with RT-PCR readout","pmids":["24019930"],"confidence":"Medium","gaps":["Single mutation, single cell model","No in vivo or protein-level validation"]},{"year":2014,"claim":"Established the structural basis of splicing regulation: a long-distance intron-3 RNA secondary structure whose integrity, validated by compensatory mutagenesis, sets the PLP1/DM20 ratio and links patient mutations to disease.","evidence":"Minigene assays in Oli-neu cells with compensatory swap mutations and patient mutation analysis","pmids":["24890387"],"confidence":"High","gaps":["Whether the structure is dynamically regulated during development not addressed","Protein factors stabilizing the structure unknown"]},{"year":2015,"claim":"Extended the splicing-ratio model to a distinct disease (HEMS), showing deep intronic mutations that destabilize the RNA structure and lower PLP1/DM20 produce a specific hypomyelination phenotype.","evidence":"Exome sequencing, minigene splicing assays, and patient fibroblast RNA analysis","pmids":["26125040"],"confidence":"Medium","gaps":["Single lab","Mechanism connecting ratio reduction to the specific HEMS imaging phenotype not established"]},{"year":2017,"claim":"Used cell-type-specific knockouts to prove oligodendroglial, not neuronal, PLP1 loss causes axonal degeneration, and genetic ablation of adaptive immunity to show neuroinflammation drives the neurodegenerative spectrum.","evidence":"Conditional Plp1 deletion in neurons vs oligodendrocytes; RAG1 and PD-1 inactivation in PLP1 mutant mice with histology and imaging","pmids":["28836307","28173160"],"confidence":"High","gaps":["Identity of the inflammatory effector cells not resolved in these studies","How loss of myelin support triggers axonopathy at molecular level unclear"]},{"year":2018,"claim":"Mapped the oligodendrocyte-specific transcriptional control of PLP1 to distal Myrf-bound enhancers and an intron-1 wmN1 enhancer required for robust expression.","evidence":"CRISPRi, ATAC-seq, ChIP-seq, Hi-C in oligodendrocytes; transgenic PLP1-lacZ with Cre-mediated wmN1 deletion","pmids":["34230963","29683207"],"confidence":"High","gaps":["Full set of transcription factors at wmN1 not defined","How enhancer activity is coordinated with splicing regulation unknown"]},{"year":2018,"claim":"Provided in vivo proof-of-concept that morpholino-based splice correction restores the PLP1/DM20 ratio at RNA and protein levels and reduces inflammation durably, and reproduced ER accumulation/UPR for additional missense mutations.","evidence":"Morpholino injection in neonatal mice and oligodendrocyte cells with RT-PCR/Western/IHC; mCherry-PLP1 mutant transfection in Cos-7 with ER localization and UPR assays","pmids":["30195779","30314286"],"confidence":"High","gaps":["Functional/behavioral rescue of the morpholino not fully established","Cos-7 is a non-oligodendrocyte surrogate for the missense ER study"]},{"year":2019,"claim":"Demonstrated that pharmacological reversal of skewed X-inactivation can re-express the wild-type PLP1 allele in carrier-derived cells.","evidence":"RNA-seq and allele-specific expression after VX680 / 5-azadC treatment of a patient lymphoblastoid line","pmids":["31004103"],"confidence":"Medium","gaps":["Single patient, single cell line","No in vivo demonstration"]},{"year":2021,"claim":"Linked PLP1 duplication-driven ER accumulation to mitochondrial pathology via altered ER-mitochondrion (MAM) contacts.","evidence":"Super-resolution microscopy of ER-mitochondrion interfaces and Seahorse flux analysis in patient fibroblasts","pmids":["34506833"],"confidence":"Medium","gaps":["Fibroblast model, not oligodendrocytes","Causality between MAM changes and mitochondrial dysfunction correlative"]},{"year":2022,"claim":"Used 3D ultrastructure to show PLP is required to maintain axonal diameter and myelin shape, with null mice developing myelin outfoldings and axonal pathology.","evidence":"FIB-SEM 3D reconstruction and morphometry in Plp-null and Mag-null mice","pmids":["36354016"],"confidence":"High","gaps":["Molecular mechanism by which PLP constrains axonal caliber unknown","Relationship to the inflammatory axonopathy not integrated"]},{"year":2023,"claim":"Identified the inflammatory effector as antigen-specific cytotoxic CD8+ T cells that target mutant-PLP1-expressing oligodendrocytes, refining the mechanism of immune-driven axonal damage.","evidence":"Single-cell transcriptomics, bone marrow chimerism, X-inactivation mosaicism, and S1P receptor modulation in PLP1 mutant mice","pmids":["37182098"],"confidence":"High","gaps":["Identity of the targeted antigen/peptide not defined","How mutant oligodendrocytes present antigen unresolved"]},{"year":2024,"claim":"Showed that the small GTPase Rab7B modulates the fate of misfolded PLP1, with its knockdown rerouting mutant PLP1 to lysosomes and rescuing oligodendroglial morphology.","evidence":"CRISPR/CasRx knockdown of Rab7B in FBD-102b cells expressing PLP1 p.Ala243Val with LAMP1 co-localization","pmids":["39280331"],"confidence":"Medium","gaps":["Single mutation in an immortalized cell line","No in vivo validation of the lysosomal rerouting"]},{"year":null,"claim":"How the structural/transcriptional regulation of PLP1 dosage mechanistically converges with ER-stress, mitochondrial, and immune pathways to determine the divergent disease phenotypes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking splicing-ratio defects, ER accumulation, and CD8+ T-cell autoimmunity","Molecular function of PLP/DM20 within the myelin membrane not biochemically defined in the corpus","Antigen recognized by autoreactive CD8+ T cells unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,16]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[5,13,19]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,16]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[14,9]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[5,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17,18]}],"complexes":["CNS myelin sheath"],"partners":["SRSF1","MYRF","RAB7B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P60201","full_name":"Myelin proteolipid protein","aliases":["Lipophilin"],"length_aa":277,"mass_kda":30.1,"function":"This is the major myelin protein from the central nervous system. 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PLP1.","date":"2018","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/29683207","citation_count":6,"is_preprint":false},{"pmid":"21082496","id":"PMC_21082496","title":"PLP1 gene duplication as a cause of the classic form of Pelizaeus-Merzbacher disease - case report.","date":"2010","source":"Neurologia i neurochirurgia polska","url":"https://pubmed.ncbi.nlm.nih.gov/21082496","citation_count":6,"is_preprint":false},{"pmid":"25694552","id":"PMC_25694552","title":"Control of human PLP1 expression through transcriptional regulatory elements and alternatively spliced exons in intron 1.","date":"2015","source":"ASN neuro","url":"https://pubmed.ncbi.nlm.nih.gov/25694552","citation_count":5,"is_preprint":false},{"pmid":"23711321","id":"PMC_23711321","title":"Further genotype-phenotype correlation emerging from two families with PLP1 exon 4 skipping.","date":"2013","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23711321","citation_count":5,"is_preprint":false},{"pmid":"30261498","id":"PMC_30261498","title":"Brain Diffusion Imaging and Tractography to Distinguish Clinical Severity of Human PLP1-Related Disorders.","date":"2018","source":"Developmental neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30261498","citation_count":5,"is_preprint":false},{"pmid":"25491635","id":"PMC_25491635","title":"Identification and functional study of novel PLP1 mutations in Chinese patients with Pelizaeus-Merzbacher disease.","date":"2014","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/25491635","citation_count":5,"is_preprint":false},{"pmid":"16267406","id":"PMC_16267406","title":"PLP-1 binds nematode double-stranded telomeric DNA.","date":"2005","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/16267406","citation_count":5,"is_preprint":false},{"pmid":"36622199","id":"PMC_36622199","title":"PLP1 gene mutations cause spastic paraplegia type 2 in three families.","date":"2023","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36622199","citation_count":4,"is_preprint":false},{"pmid":"22343157","id":"PMC_22343157","title":"A novel PLP1 mutation further expands the clinical heterogeneity at the locus.","date":"2012","source":"The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques","url":"https://pubmed.ncbi.nlm.nih.gov/22343157","citation_count":4,"is_preprint":false},{"pmid":"33051256","id":"PMC_33051256","title":"PLP-1 is essential for germ cell development and germline gene silencing in Caenorhabditiselegans.","date":"2020","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/33051256","citation_count":4,"is_preprint":false},{"pmid":"39280331","id":"PMC_39280331","title":"CRISPR/CasRx-Mediated Knockdown of Rab7B Restores Incomplete Cell Shape Induced by Pelizaeus-Merzbacher Disease-Associated PLP1 p.Ala243Val.","date":"2024","source":"Neuroscience insights","url":"https://pubmed.ncbi.nlm.nih.gov/39280331","citation_count":4,"is_preprint":false},{"pmid":"34506833","id":"PMC_34506833","title":"Novel Insight into the Potential Pathogenicity of Mitochondrial Dysfunction Resulting from PLP1 Duplication Mutations in Patients with Pelizaeus-Merzbacher Disease.","date":"2021","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34506833","citation_count":4,"is_preprint":false},{"pmid":"28101371","id":"PMC_28101371","title":"A novel PLP1 mutation F240L identified in a patient with connatal type Pelizaeus-Merzbacher disease.","date":"2017","source":"Human genome variation","url":"https://pubmed.ncbi.nlm.nih.gov/28101371","citation_count":4,"is_preprint":false},{"pmid":"24685771","id":"PMC_24685771","title":"Brain magnetic resonance imaging findings and auditory brainstem response in a child with spastic paraplegia 2 due to a PLP1 splice site mutation.","date":"2014","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/24685771","citation_count":4,"is_preprint":false},{"pmid":"38743566","id":"PMC_38743566","title":"Plp1-expresssing perineuronal DRG cells facilitate colonic and somatic chronic mechanical pain involving Piezo2 upregulation in DRG neurons.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38743566","citation_count":3,"is_preprint":false},{"pmid":"32353175","id":"PMC_32353175","title":"Identity and lineage fate of proteolipid protein 1 gene (Plp1)-expressing cells in the embryonic murine spinal cord.","date":"2020","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/32353175","citation_count":3,"is_preprint":false},{"pmid":"18368307","id":"PMC_18368307","title":"Cloning and identification of a novel RNF6 transcriptional splice variant Spg2 in human development.","date":"2008","source":"Science in China. Series C, Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18368307","citation_count":3,"is_preprint":false},{"pmid":"31110947","id":"PMC_31110947","title":"Drug screening for Pelizaeus-Merzbacher disease by quantifying the total levels and membrane localization of PLP1.","date":"2019","source":"Molecular genetics and metabolism reports","url":"https://pubmed.ncbi.nlm.nih.gov/31110947","citation_count":3,"is_preprint":false},{"pmid":"18604471","id":"PMC_18604471","title":"No association between the oligodendrocyte-related gene PLP1 and schizophrenia in the Japanese population.","date":"2008","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18604471","citation_count":3,"is_preprint":false},{"pmid":"36672024","id":"PMC_36672024","title":"In Silico Structural Analysis Predicting the Pathogenicity of PLP1 Mutations in Multiple Sclerosis.","date":"2022","source":"Brain sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36672024","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47053,"output_tokens":6209,"usd":0.117147,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15109,"output_tokens":4967,"usd":0.09986,"stage2_stop_reason":"end_turn"},"total_usd":0.217007,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"PLP1 (but not its alternatively spliced isoform DM20) expression in Schwann cells is necessary to prevent peripheral neuropathy. Mutations that truncate PLP1 within the 35-amino-acid PLP1-specific domain (absent in DM20) or null mutations cause peripheral neuropathy, whereas mutations that preserve an intact PLP1-specific domain or PLP1 duplications do not. This demonstrates that the PLP1-specific domain plays a critical role in normal peripheral nerve function.\",\n      \"method\": \"Clinical cohort analysis of PMD patients with defined PLP1 mutations; electrodiagnostic studies; genotype-phenotype correlation of PLP1 vs DM20 isoform-affecting mutations\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — large patient cohort with multiple mutation types, clear genotype-phenotype dissection between PLP1-specific domain and DM20, independently consistent across 61+ patients with duplications and multiple point mutation carriers\",\n      \"pmids\": [\"12601703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Alternative splicing of PLP1 pre-mRNA is regulated by an exonic splicing enhancer (ESE) in exon 3B. The ASF/SF2 splicing factor specifically binds to nucleotides 406–412 of exon 3B, and this binding positively regulates selection of the PLP1 5' splice donor site in a concentration-dependent manner. Single nucleotide mutations in the ESE that reduced PLP1 splice site selection also diminished ASF/SF2 binding.\",\n      \"method\": \"UV crosslinking and immunoprecipitation with ASF/SF2 antibody; overexpression of ASF/SF2 in differentiating oligodendrocytes; mutagenesis of ESE motifs; minigene splicing assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assay (UV-crosslink IP), mutagenesis of binding site, functional splicing assay with overexpression, multiple orthogonal methods in one study\",\n      \"pmids\": [\"16288477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The relative strengths of the PLP1 and DM20 5' splice donor sites play an important role in determining the PLP1/DM20 alternative splicing ratio. Information theory-based analysis of splice site strength correlated well with observed PLP1 and DM20 mRNA expression patterns from patient mutations affecting splice sites in intron 3.\",\n      \"method\": \"Information theory-based splice site analysis; mRNA expression analysis in patient-derived cells for multiple PLP1 splice-site mutations\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mRNA expression in patient cells plus computational analysis; single lab but multiple mutations tested with consistent results\",\n      \"pmids\": [\"16287154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A splicing enhancer in PLP1 intron 3 is required for the developmental increase in the PLP1/DM20 transcript and protein ratio during myelination. Deletion of this intronic splicing enhancer in a knockin mouse impairs the postnatal increase in PLP1/DM20 ratio and results in abnormal myelin wraps with fragmented whorls (progressive with age) and a motor coordination defect, establishing that full PLP1 dosage relative to DM20 is necessary for myelin stability.\",\n      \"method\": \"Knockin mouse with deletion of intronic splicing enhancer; Real-Time RT-PCR and Western blot for PLP1/DM20 ratio; electron microscopy of myelin; motor testing\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vivo genetic knockin model with multiple orthogonal readouts (molecular, ultrastructural, behavioral), single lab but rigorous\",\n      \"pmids\": [\"18835559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Alternative splicing of PLP1 is regulated by a long-distance RNA secondary structure formed by base-pairing between two conserved elements separated by 581 bases within intron 3. Mutations of either element that destabilize the secondary structure decreased the PLP1/DM20 ratio, while compensatory swap mutations that restored the structure brought the ratio to near-normal levels. Patient mutations in these elements that destabilize the structure also reduce the PLP1/DM20 ratio and segregate with PMD disease.\",\n      \"method\": \"Minigene splicing constructs transfected into Oli-neu oligodendrocyte cell line; compensatory mutagenesis; patient mutation analysis in three families\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional minigene assay with compensatory mutagenesis (structure-function validation), patient mutations confirm mechanism, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"24890387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Missense mutations in PLP1 cause accumulation of mutant PLP1 protein in the rough endoplasmic reticulum (ER) in PMD patient iPSC-derived oligodendrocytes. This ER mislocalization is associated with increased susceptibility to ER stress, increased oligodendrocyte apoptosis, and drastically reduced myelin formation with abnormal ER morphology by electron microscopy.\",\n      \"method\": \"iPSC generation from PMD patients; differentiation into oligodendrocytes; immunofluorescence for ER localization; ER stress assays; electron microscopy of myelin formation\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived iPSC-to-oligodendrocyte model with multiple orthogonal methods (localization, stress markers, ultrastructure), single lab but rigorous\",\n      \"pmids\": [\"24936452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The rumpshaker PLP1 mutation causes low steady-state PLP levels due to accelerated proteasomal degradation (T½ of 11 h for rumpshaker vs 23 h for wild type), not decreased synthesis. A minority of newly synthesized rumpshaker PLP is incorporated into myelin. However, inhibition of proteasomal degradation does not increase myelin incorporation of PLP, suggesting that dysmyelination is not simply caused by reduced PLP levels.\",\n      \"method\": \"Pulse-chase analysis; proteasome inhibitor treatment; measurement of PLP synthesis and degradation rates in mouse model; myelin incorporation assays\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — pulse-chase kinetics with pharmacological inhibition, multiple quantitative assays, mechanistically informative negative result also established\",\n      \"pmids\": [\"16506223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The unfolded protein response (UPR) is activated in rumpshaker PLP1 mutant oligodendrocytes. CHOP activation correlates with phenotypic severity across genetic backgrounds, whereas BiP and Xbp1 responses do not differ between mild (C3H) and severe (C57BL/6) backgrounds, indicating that differential CHOP-dependent UPR contributes to phenotypic variation.\",\n      \"method\": \"Western blot and RT-PCR for UPR markers (CHOP, BiP, Xbp1) in two genetic backgrounds of rumpshaker mice\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, two genetic backgrounds, molecular markers only; no functional rescue experiment\",\n      \"pmids\": [\"16944321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PLP1 gene duplication results in a 4–5 fold increase in PLP1 gene expression in fibroblasts and also shifts the PLP1/DM20 alternative splicing balance toward the PLP isoform (decreased DM20/(DM20+PLP) ratio), demonstrating that gene dosage affects both total expression and splicing equilibrium.\",\n      \"method\": \"Real-time PCR with isoform-specific amplicons in fibroblasts from PMD patients with PLP1 duplication vs. controls\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — patient fibroblast gene expression assay, single lab, limited sample size (n=3 patients, n=3 controls)\",\n      \"pmids\": [\"19376225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Oligodendroglial loss of Plp1 (not neuronal loss) is the primary cause of axonal degeneration and the full neurodegenerative spectrum of SPG2. Cre-mediated deletion of Plp1 selectively in excitatory projection neurons does not cause neuropathology, whereas oligodendroglial-targeted Plp1 deletion recapitulates axonopathy and secondary neuroinflammation.\",\n      \"method\": \"Conditional knockout mice with floxed Plp1 allele; Cre-mediated recombination in neurons vs. oligodendrocytes; histological and behavioral analysis\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional KO with direct comparison between neuronal and oligodendroglial deletion, clear phenotypic readout, rigorous genetic epistasis\",\n      \"pmids\": [\"28836307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mutations in PLP1 exon 3B or deep within intron 3 that decrease the PLP1/DM20 splicing ratio cause Hypomyelination of Early Myelinating Structures (HEMS). Four deep intronic mutations destabilize a long-distance RNA interaction structure regulating PLP1/DM20 alternative splicing. In vitro splicing studies in patient fibroblasts and transfected cells confirmed a decreased PLP1/DM20 ratio from these mutations.\",\n      \"method\": \"Exome sequencing; minigene splicing constructs transfected into immature oligodendrocyte cell line; in silico splice prediction; RNA from patient fibroblasts\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional splicing assays in cells, patient fibroblast RNA, multiple mutations tested; single lab\",\n      \"pmids\": [\"26125040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"An antisense oligonucleotide directed against an exonic splicing regulatory motif introduced by the PLP1 c.436C>G missense mutation can restore normal PLP1 splicing (rescue of major PLP transcript production) in oligodendrocyte precursor cells, demonstrating that this mutation acts by creating aberrant splicing regulatory motifs rather than solely through amino acid substitution.\",\n      \"method\": \"Antisense oligonucleotide treatment of oligodendrocyte precursor cells; RT-PCR analysis of PLP1/DM20 splicing in treated cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue by antisense oligonucleotide in cell model; single lab, single mutation\",\n      \"pmids\": [\"24019930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Morpholino antisense oligomers blocking the DM20 5' splice donor site shift PLP1/DM20 alternative splicing toward the PLP1 form in oligodendrocyte cell lines and in neonatal mouse brain after intracerebroventricular injection. In a knockin mouse with an intronic splicing enhancer deletion, a single injection corrected PLP1/DM20 splicing at RNA and protein levels for at least 90 days post-injection, with sustained reduction of inflammatory markers.\",\n      \"method\": \"Morpholino oligomer treatment of oligodendrocyte cell line; intracerebroventricular injection in neonatal mice; RT-PCR and Western blot for PLP1/DM20 ratio; immunohistochemistry for inflammation\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo correction in disease mouse model with protein-level validation and functional inflammatory readout, multiple orthogonal methods\",\n      \"pmids\": [\"30195779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PLP1 missense mutations (including Leu30Val) cause significant accumulation of PLP in the endoplasmic reticulum and induction of the unfolded protein response (UPR) in transfected Cos-7 cells, as shown by comparison with wild-type PLP1 and known PMD/SPG2-causing mutations.\",\n      \"method\": \"Transfection of mCherry-tagged wild-type and mutant PLP1 constructs into Cos-7 cells; fluorescence microscopy for ER localization; UPR marker assays\",\n      \"journal\": \"Journal of clinical medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — cell transfection with tagged protein, single lab, non-oligodendrocyte cell system\",\n      \"pmids\": [\"30314286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Two oligodendrocyte-specific enhancers (Plp1-E1 and Plp1-E2) located distal to the Plp1 promoter regulate Plp1 expression with exquisite specificity. CRISPRi epigenome editing showed these enhancers do not regulate two neighboring genes. Hi-C data revealed strong, OL-specific physical interactions between these enhancers and the PLP1 promoter. Myrf, a master regulator of oligodendrocyte development, acts on Plp1-E1 and Plp1-E2 to promote Plp1 expression.\",\n      \"method\": \"CRISPRi epigenome editing; ATAC-seq; ChIP-seq; Hi-C chromatin interaction mapping in oligodendrocytes\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — CRISPRi functional validation, chromatin interaction data (Hi-C), and ChIP-seq in the same study with multiple orthogonal methods\",\n      \"pmids\": [\"34230963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A wmN1 enhancer region within human PLP1 intron 1 is required for high levels of PLP1 gene expression in oligodendrocytes. Removal of the wmN1 region from a human PLP1-lacZ transgene using Cre recombinase caused a dramatic reduction in transgene activity in mouse brain, demonstrating this intronic element is necessary for robust PLP1 expression.\",\n      \"method\": \"Transgenic mice carrying human PLP1-lacZ with loxP-flanked wmN1 region; Cre-mediated deletion; X-gal staining and β-galactosidase activity measurement in brain\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic deletion of regulatory element with reporter readout, multiple transgenic lines, consistent result\",\n      \"pmids\": [\"29683207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PLP-deficient (Plp-null) mice develop pathological myelin outfoldings extending up to 10 μm longitudinally along myelinated axons, associated with complex axonal pathology including axonal sprouting and anastomosing underneath outfoldings. Normal-appearing axon/myelin units showed significantly increased axonal diameters in Plp-null mice, indicating PLP is required to maintain normal axonal diameter and shape.\",\n      \"method\": \"Focused ion beam-scanning electron microscopy (FIB-SEM); 3D reconstruction and morphometric analysis in Plp-null and Mag-null mutant mice\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — 3D ultrastructural reconstruction with quantitative morphometry in genetic null model, rigorous methodology\",\n      \"pmids\": [\"36354016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PLP1 loss-of-function mutations in oligodendrocytes cause neuroinflammation (comprising adaptive immune reactions) that promotes disease progression including axonopathy and neurodegeneration. Inactivation of RAG1 (abolishing adaptive immunity) in PLP1 mutant mice demonstrated that neuroinflammation drives clinically relevant axonal degeneration, neuronal loss, and brain atrophy.\",\n      \"method\": \"PLP1 point-mutation mouse models; RAG1 inactivation (immune-incompetent crosses); programmed cell death-1 gene inactivation; histology and brain imaging\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (RAG1 knockout rescues neurodegeneration in PLP1 mutant background), two independent PLP1 mutant models, multiple readouts\",\n      \"pmids\": [\"28173160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cytotoxic CD8+ T cells drive axonal damage in PLP1 mutant mice by targeting mutant oligodendrocytes in an antigen-specific manner. Bone marrow chimerism experiments and random X chromosome inactivation models demonstrated that CD8+ T cells from PLP1-mutant mice specifically target oligodendrocytes expressing mutant PLP1.\",\n      \"method\": \"Single-cell transcriptomics of CNS-associated T cells; bone marrow chimerism; X chromosome inactivation mosaic model; sphingosine-1-phosphate receptor modulation; histological readouts of axonal damage\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic approaches (bone marrow chimerism, X-inactivation mosaicism) with single-cell transcriptomics and functional rescue experiments\",\n      \"pmids\": [\"37182098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PLP1 duplication mutations cause closer ER-mitochondrion interfaces (mediated through structural changes in both ER and mitochondria-associated membranes, MAMs) compared to controls, and this is associated with mitochondrial dysfunction as measured by extracellular flux analysis. This identifies MAM structural changes as a bridge between PLP1 ER accumulation and mitochondrial pathology.\",\n      \"method\": \"Super-resolution microscopy (SD-SIM) for ER-mitochondrion interface measurement; Seahorse XF extracellular flux analysis of mitochondrial respiration in patient and control fibroblasts\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — two orthogonal methods (super-resolution microscopy, metabolic flux) in patient fibroblasts; single lab, limited sample size\",\n      \"pmids\": [\"34506833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Knockdown of Rab7B (a small GTPase involved in lysosomal vesicle trafficking) using CRISPR/CasRx rescues the incomplete cell morphology induced by the PLP1 p.Ala243Val mutation in oligodendroglial FBD-102b cells, and promotes trafficking of mutant PLP1 to LAMP1-positive lysosomal organelles, suggesting Rab7B modulates the intracellular fate of misfolded PLP1.\",\n      \"method\": \"CRISPR/CasRx-mediated knockdown of Rab7B in oligodendroglial cell line expressing PLP1 p.Ala243Val; immunofluorescence for LAMP1 co-localization; cell morphology quantification\",\n      \"journal\": \"Neuroscience insights\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — CRISPR knockdown with immunofluorescence in cell line, single lab, single mutation model\",\n      \"pmids\": [\"39280331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Treatment with VX680 or 5-azadC in a lymphoblastoid cell line from a female PLP1 mutation carrier with skewed X-inactivation (silencing the wild-type allele) restored expression of the wild-type PLP1 allele, demonstrating that pharmacological reversal of skewed X-inactivation can rescue PLP1 expression.\",\n      \"method\": \"RNA sequencing confirming mono-allelic mutant PLP1 expression; drug treatment with VX680 and 5-azadC; allele-specific expression analysis post-treatment\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional rescue experiment in patient-derived cell line; single lab, single patient\",\n      \"pmids\": [\"31004103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Plp1 expression in enteric nervous system glia preferentially occurs during early postnatal development primarily as the DM20 isoform. An intronic enhancer element (wmN1) within Plp1 intron 1 is required for Plp1 expression in intestinal enteric glia; removal of wmN1 from a human PLP1-lacZ transgene dramatically reduced transgene mRNA and reporter activity throughout intestinal development.\",\n      \"method\": \"Western blot and transgenic reporter (lacZ) mice at multiple postnatal ages; Cre-mediated removal of wmN1 enhancer from transgene; β-galactosidase activity measurement along intestinal segments\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo transgenic reporter with genetic element deletion, single lab, uses reporter rather than endogenous gene for enhancer test\",\n      \"pmids\": [\"37293625\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLP1 encodes the major CNS myelin transmembrane protein (and its alternatively spliced DM20 isoform); its expression in oligodendrocytes is governed by intronic enhancers (wmN1, Plp1-E1/E2) and regulated by the transcription factor Myrf, while the PLP1/DM20 splicing ratio is controlled by a long-distance RNA secondary structure in intron 3 and an exonic splicing enhancer bound by ASF/SF2; missense mutations cause ER retention and UPR-mediated oligodendrocyte apoptosis, null mutations and rumpshaker mutations lead to accelerated proteasomal degradation of PLP, and oligodendroglial PLP1 deficiency (not neuronal) causes progressive axonal degeneration via loss of myelin support and secondary antigen-specific CD8+ T cell-driven neuroinflammation, while PLP itself is required to maintain normal axonal diameter and shape.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLP1 encodes the major transmembrane protein of CNS myelin and, through alternative splicing of exon 3, its shorter DM20 isoform; the PLP1/DM20 ratio is a developmentally regulated quantity whose disruption causes hypomyelinating disease [#3, #4]. The splicing decision is controlled by the relative strength of the PLP1 and DM20 5' splice donor sites [#2], by an exonic splicing enhancer in exon 3B bound by the splicing factor ASF/SF2 [#1], and by a long-distance RNA secondary structure formed within intron 3 whose disruption lowers the PLP1/DM20 ratio and segregates with disease [#4, #10]. Oligodendrocyte-restricted PLP1 expression is driven by distal enhancers (Plp1-E1/E2) acted on by the master oligodendrocyte regulator Myrf, which physically loop to the promoter, and by an intron-1 enhancer (wmN1) required for high expression in both CNS oligodendrocytes and enteric glia [#14, #15, #22]. PLP1 supports myelin and axonal integrity: oligodendroglial — not neuronal — loss of Plp1 drives axonal degeneration, and PLP is required to maintain normal axonal diameter and myelin shape [#9, #16]. Disease arises through two genetic logics: missense mutations cause mutant protein to accumulate in the ER, triggering the unfolded protein response and oligodendrocyte apoptosis [#5, #13, #7], while loss-of-function leads to axonopathy compounded by antigen-specific CD8+ T-cell-driven neuroinflammation that promotes neurodegeneration [#17, #18]. Truncating mutations within the 35-residue PLP1-specific domain absent from DM20 additionally cause peripheral neuropathy, establishing an isoform-specific role for PLP1 in peripheral nerve [#0]. These mechanisms have motivated splice-correcting antisense and morpholino strategies that restore the PLP1/DM20 ratio and reduce inflammation in disease models [#11, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that the PLP1-specific 35-amino-acid domain (absent in DM20) has a distinct functional requirement, resolving why some mutations produce peripheral neuropathy while others do not.\",\n      \"evidence\": \"Clinical cohort genotype-phenotype correlation of PMD patients with PLP1-specific vs DM20-affecting mutations and electrodiagnostics\",\n      \"pmids\": [\"12601703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular function of the PLP1-specific domain in Schwann cells not defined\", \"No biochemical mechanism for how the domain supports peripheral nerve\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the cis and trans determinants of PLP1/DM20 alternative splicing, showing splice-site strength and an exon 3B enhancer bound by ASF/SF2 jointly tune isoform choice.\",\n      \"evidence\": \"UV-crosslink IP, ESE mutagenesis, minigene assays and ASF/SF2 overexpression; information-theory splice-site analysis with patient mRNA\",\n      \"pmids\": [\"16288477\", \"16287154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ASF/SF2 levels are the physiological developmental switch in vivo not shown\", \"Other trans-factors acting on the ESE not identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified the rumpshaker mutation as acting through accelerated proteasomal degradation of PLP and UPR activation, and showed that restoring PLP levels alone does not rescue myelination, decoupling protein abundance from dysmyelination.\",\n      \"evidence\": \"Pulse-chase kinetics with proteasome inhibition and myelin incorporation assays; UPR marker analysis across two genetic backgrounds\",\n      \"pmids\": [\"16506223\", \"16944321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CHOP-dependence shown by correlation, not by genetic rescue\", \"Mechanism linking misfolded PLP to selective proteasomal targeting unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated in vivo that an intron-3 splicing enhancer drives the developmental rise in PLP1/DM20 ratio and that full PLP1 dosage is required for myelin stability.\",\n      \"evidence\": \"Knockin mouse with intronic enhancer deletion; RT-PCR, Western blot, EM of myelin, motor testing\",\n      \"pmids\": [\"18835559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of factors binding the enhancer not defined here\", \"How a modest ratio shift destabilizes myelin mechanistically unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that PLP1 duplication raises both total expression and shifts the splicing balance toward PLP1, linking gene dosage to two distinct consequences.\",\n      \"evidence\": \"Isoform-specific real-time PCR in patient vs control fibroblasts\",\n      \"pmids\": [\"19376225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Small sample size (n=3)\", \"Fibroblast surrogate, not oligodendrocytes\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed that a coding missense mutation (c.436C>G) acts partly by creating an aberrant splicing motif, and that antisense oligonucleotides can restore normal PLP1 splicing.\",\n      \"evidence\": \"Antisense oligonucleotide treatment of oligodendrocyte precursor cells with RT-PCR readout\",\n      \"pmids\": [\"24019930\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single mutation, single cell model\", \"No in vivo or protein-level validation\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established the structural basis of splicing regulation: a long-distance intron-3 RNA secondary structure whose integrity, validated by compensatory mutagenesis, sets the PLP1/DM20 ratio and links patient mutations to disease.\",\n      \"evidence\": \"Minigene assays in Oli-neu cells with compensatory swap mutations and patient mutation analysis\",\n      \"pmids\": [\"24890387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the structure is dynamically regulated during development not addressed\", \"Protein factors stabilizing the structure unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended the splicing-ratio model to a distinct disease (HEMS), showing deep intronic mutations that destabilize the RNA structure and lower PLP1/DM20 produce a specific hypomyelination phenotype.\",\n      \"evidence\": \"Exome sequencing, minigene splicing assays, and patient fibroblast RNA analysis\",\n      \"pmids\": [\"26125040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism connecting ratio reduction to the specific HEMS imaging phenotype not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Used cell-type-specific knockouts to prove oligodendroglial, not neuronal, PLP1 loss causes axonal degeneration, and genetic ablation of adaptive immunity to show neuroinflammation drives the neurodegenerative spectrum.\",\n      \"evidence\": \"Conditional Plp1 deletion in neurons vs oligodendrocytes; RAG1 and PD-1 inactivation in PLP1 mutant mice with histology and imaging\",\n      \"pmids\": [\"28836307\", \"28173160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the inflammatory effector cells not resolved in these studies\", \"How loss of myelin support triggers axonopathy at molecular level unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped the oligodendrocyte-specific transcriptional control of PLP1 to distal Myrf-bound enhancers and an intron-1 wmN1 enhancer required for robust expression.\",\n      \"evidence\": \"CRISPRi, ATAC-seq, ChIP-seq, Hi-C in oligodendrocytes; transgenic PLP1-lacZ with Cre-mediated wmN1 deletion\",\n      \"pmids\": [\"34230963\", \"29683207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of transcription factors at wmN1 not defined\", \"How enhancer activity is coordinated with splicing regulation unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided in vivo proof-of-concept that morpholino-based splice correction restores the PLP1/DM20 ratio at RNA and protein levels and reduces inflammation durably, and reproduced ER accumulation/UPR for additional missense mutations.\",\n      \"evidence\": \"Morpholino injection in neonatal mice and oligodendrocyte cells with RT-PCR/Western/IHC; mCherry-PLP1 mutant transfection in Cos-7 with ER localization and UPR assays\",\n      \"pmids\": [\"30195779\", \"30314286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional/behavioral rescue of the morpholino not fully established\", \"Cos-7 is a non-oligodendrocyte surrogate for the missense ER study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that pharmacological reversal of skewed X-inactivation can re-express the wild-type PLP1 allele in carrier-derived cells.\",\n      \"evidence\": \"RNA-seq and allele-specific expression after VX680 / 5-azadC treatment of a patient lymphoblastoid line\",\n      \"pmids\": [\"31004103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient, single cell line\", \"No in vivo demonstration\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked PLP1 duplication-driven ER accumulation to mitochondrial pathology via altered ER-mitochondrion (MAM) contacts.\",\n      \"evidence\": \"Super-resolution microscopy of ER-mitochondrion interfaces and Seahorse flux analysis in patient fibroblasts\",\n      \"pmids\": [\"34506833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Fibroblast model, not oligodendrocytes\", \"Causality between MAM changes and mitochondrial dysfunction correlative\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Used 3D ultrastructure to show PLP is required to maintain axonal diameter and myelin shape, with null mice developing myelin outfoldings and axonal pathology.\",\n      \"evidence\": \"FIB-SEM 3D reconstruction and morphometry in Plp-null and Mag-null mice\",\n      \"pmids\": [\"36354016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which PLP constrains axonal caliber unknown\", \"Relationship to the inflammatory axonopathy not integrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified the inflammatory effector as antigen-specific cytotoxic CD8+ T cells that target mutant-PLP1-expressing oligodendrocytes, refining the mechanism of immune-driven axonal damage.\",\n      \"evidence\": \"Single-cell transcriptomics, bone marrow chimerism, X-inactivation mosaicism, and S1P receptor modulation in PLP1 mutant mice\",\n      \"pmids\": [\"37182098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the targeted antigen/peptide not defined\", \"How mutant oligodendrocytes present antigen unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed that the small GTPase Rab7B modulates the fate of misfolded PLP1, with its knockdown rerouting mutant PLP1 to lysosomes and rescuing oligodendroglial morphology.\",\n      \"evidence\": \"CRISPR/CasRx knockdown of Rab7B in FBD-102b cells expressing PLP1 p.Ala243Val with LAMP1 co-localization\",\n      \"pmids\": [\"39280331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single mutation in an immortalized cell line\", \"No in vivo validation of the lysosomal rerouting\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the structural/transcriptional regulation of PLP1 dosage mechanistically converges with ER-stress, mitochondrial, and immune pathways to determine the divergent disease phenotypes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking splicing-ratio defects, ER accumulation, and CD8+ T-cell autoimmunity\", \"Molecular function of PLP/DM20 within the myelin membrane not biochemically defined in the corpus\", \"Antigen recognized by autoreactive CD8+ T cells unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5, 13, 19]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [14, 9]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17, 18]}\n    ],\n    \"complexes\": [\"CNS myelin sheath\"],\n    \"partners\": [\"SRSF1\", \"MYRF\", \"RAB7B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}