Affinage

PLP1

Myelin proteolipid protein · UniProt P60201

Length
277 aa
Mass
30.1 kDa
Annotated
2026-06-10
100 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2003 High

    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

    PMID:12601703

    Open questions at the time
    • Molecular function of the PLP1-specific domain in Schwann cells not defined
    • No biochemical mechanism for how the domain supports peripheral nerve
  2. 2006 High

    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

    PMID:16287154 PMID:16288477

    Open questions at the time
    • Whether ASF/SF2 levels are the physiological developmental switch in vivo not shown
    • Other trans-factors acting on the ESE not identified
  3. 2006 High

    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

    PMID:16506223 PMID:16944321

    Open questions at the time
    • CHOP-dependence shown by correlation, not by genetic rescue
    • Mechanism linking misfolded PLP to selective proteasomal targeting unresolved
  4. 2008 High

    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

    PMID:18835559

    Open questions at the time
    • Molecular identity of factors binding the enhancer not defined here
    • How a modest ratio shift destabilizes myelin mechanistically unclear
  5. 2009 Medium

    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

    PMID:19376225

    Open questions at the time
    • Small sample size (n=3)
    • Fibroblast surrogate, not oligodendrocytes
  6. 2013 Medium

    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

    PMID:24019930

    Open questions at the time
    • Single mutation, single cell model
    • No in vivo or protein-level validation
  7. 2014 High

    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

    PMID:24890387

    Open questions at the time
    • Whether the structure is dynamically regulated during development not addressed
    • Protein factors stabilizing the structure unknown
  8. 2015 Medium

    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

    PMID:26125040

    Open questions at the time
    • Single lab
    • Mechanism connecting ratio reduction to the specific HEMS imaging phenotype not established
  9. 2017 High

    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

    PMID:28173160 PMID:28836307

    Open questions at the time
    • Identity of the inflammatory effector cells not resolved in these studies
    • How loss of myelin support triggers axonopathy at molecular level unclear
  10. 2018 High

    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

    PMID:29683207 PMID:34230963

    Open questions at the time
    • Full set of transcription factors at wmN1 not defined
    • How enhancer activity is coordinated with splicing regulation unknown
  11. 2018 High

    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

    PMID:30195779 PMID:30314286

    Open questions at the time
    • Functional/behavioral rescue of the morpholino not fully established
    • Cos-7 is a non-oligodendrocyte surrogate for the missense ER study
  12. 2019 Medium

    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

    PMID:31004103

    Open questions at the time
    • Single patient, single cell line
    • No in vivo demonstration
  13. 2021 Medium

    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

    PMID:34506833

    Open questions at the time
    • Fibroblast model, not oligodendrocytes
    • Causality between MAM changes and mitochondrial dysfunction correlative
  14. 2022 High

    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

    PMID:36354016

    Open questions at the time
    • Molecular mechanism by which PLP constrains axonal caliber unknown
    • Relationship to the inflammatory axonopathy not integrated
  15. 2023 High

    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

    PMID:37182098

    Open questions at the time
    • Identity of the targeted antigen/peptide not defined
    • How mutant oligodendrocytes present antigen unresolved
  16. 2024 Medium

    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

    PMID:39280331

    Open questions at the time
    • Single mutation in an immortalized cell line
    • No in vivo validation of the lysosomal rerouting

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
MYRFRAB7BSRSF1
Complex memberships
CNS myelin sheath

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. Clinical cohort analysis of PMD patients with defined PLP1 mutations; electrodiagnostic studies; genotype-phenotype correlation of PLP1 vs DM20 isoform-affecting mutations Annals of neurology High 12601703
2006 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. UV crosslinking and immunoprecipitation with ASF/SF2 antibody; overexpression of ASF/SF2 in differentiating oligodendrocytes; mutagenesis of ESE motifs; minigene splicing assays Journal of cellular biochemistry High 16288477
2006 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. Information theory-based splice site analysis; mRNA expression analysis in patient-derived cells for multiple PLP1 splice-site mutations Human mutation Medium 16287154
2008 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. 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 Experimental neurology High 18835559
2014 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. Minigene splicing constructs transfected into Oli-neu oligodendrocyte cell line; compensatory mutagenesis; patient mutation analysis in three families Human molecular genetics High 24890387
2014 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. iPSC generation from PMD patients; differentiation into oligodendrocytes; immunofluorescence for ER localization; ER stress assays; electron microscopy of myelin formation Stem cell reports High 24936452
2006 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. Pulse-chase analysis; proteasome inhibitor treatment; measurement of PLP synthesis and degradation rates in mouse model; myelin incorporation assays Glia High 16506223
2006 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. Western blot and RT-PCR for UPR markers (CHOP, BiP, Xbp1) in two genetic backgrounds of rumpshaker mice Neurochemical research Medium 16944321
2009 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. Real-time PCR with isoform-specific amplicons in fibroblasts from PMD patients with PLP1 duplication vs. controls Biochimica et biophysica acta Medium 19376225
2017 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. Conditional knockout mice with floxed Plp1 allele; Cre-mediated recombination in neurons vs. oligodendrocytes; histological and behavioral analysis Glia High 28836307
2015 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. Exome sequencing; minigene splicing constructs transfected into immature oligodendrocyte cell line; in silico splice prediction; RNA from patient fibroblasts Annals of clinical and translational neurology Medium 26125040
2013 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. Antisense oligonucleotide treatment of oligodendrocyte precursor cells; RT-PCR analysis of PLP1/DM20 splicing in treated cells PloS one Medium 24019930
2018 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. Morpholino oligomer treatment of oligodendrocyte cell line; intracerebroventricular injection in neonatal mice; RT-PCR and Western blot for PLP1/DM20 ratio; immunohistochemistry for inflammation Molecular therapy. Nucleic acids High 30195779
2018 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. Transfection of mCherry-tagged wild-type and mutant PLP1 constructs into Cos-7 cells; fluorescence microscopy for ER localization; UPR marker assays Journal of clinical medicine Medium 30314286
2021 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. CRISPRi epigenome editing; ATAC-seq; ChIP-seq; Hi-C chromatin interaction mapping in oligodendrocytes Human molecular genetics High 34230963
2018 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. Transgenic mice carrying human PLP1-lacZ with loxP-flanked wmN1 region; Cre-mediated deletion; X-gal staining and β-galactosidase activity measurement in brain Glia High 29683207
2022 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. Focused ion beam-scanning electron microscopy (FIB-SEM); 3D reconstruction and morphometric analysis in Plp-null and Mag-null mutant mice Glia High 36354016
2017 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. PLP1 point-mutation mouse models; RAG1 inactivation (immune-incompetent crosses); programmed cell death-1 gene inactivation; histology and brain imaging Human molecular genetics High 28173160
2023 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. 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 iScience High 37182098
2021 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. Super-resolution microscopy (SD-SIM) for ER-mitochondrion interface measurement; Seahorse XF extracellular flux analysis of mitochondrial respiration in patient and control fibroblasts Neuroscience Medium 34506833
2024 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. CRISPR/CasRx-mediated knockdown of Rab7B in oligodendroglial cell line expressing PLP1 p.Ala243Val; immunofluorescence for LAMP1 co-localization; cell morphology quantification Neuroscience insights Medium 39280331
2019 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. RNA sequencing confirming mono-allelic mutant PLP1 expression; drug treatment with VX680 and 5-azadC; allele-specific expression analysis post-treatment Journal of human genetics Medium 31004103
2023 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. 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 Frontiers in cellular neuroscience Medium 37293625

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics 233 15627202
2002 Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females. American journal of human genetics 132 12297985
2014 Involvement of ER stress in dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 missense mutations shown by iPSC-derived oligodendrocytes. Stem cell reports 100 24936452
2017 Colitis promotes neuronal differentiation of Sox2+ and PLP1+ enteric cells. Scientific reports 91 28566702
2005 Three or more copies of the proteolipid protein gene PLP1 cause severe Pelizaeus-Merzbacher disease. Brain : a journal of neurology 91 15689360
2006 Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Annals of neurology 70 16374829
2006 Role of genomic architecture in PLP1 duplication causing Pelizaeus-Merzbacher disease. Human molecular genetics 67 16774974
2015 Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication. PLoS genetics 56 25749076
1989 Structural organization of pLP1, a cryptic plasmid from Lactobacillus plantarum CCM 1904. Plasmid 55 2517345
2003 Schwann cell expression of PLP1 but not DM20 is necessary to prevent neuropathy. Annals of neurology 51 12601703
2000 Functional analysis of Plp1 and Plp2, two homologues of phosducin in yeast. The Journal of biological chemistry 50 10749875
2002 Brain N-acetylaspartate is elevated in Pelizaeus-Merzbacher disease with PLP1 duplication. Neurology 49 11805250
2005 Primary progressive multiple sclerosis as a phenotype of a PLP1 gene mutation. Annals of neurology 43 16130097
2015 Altered PLP1 splicing causes hypomyelination of early myelinating structures. Annals of clinical and translational neurology 41 26125040
2017 Genetic dissection of oligodendroglial and neuronal Plp1 function in a novel mouse model of spastic paraplegia type 2. Glia 39 28836307
2011 Molecular genetic analysis of the PLP1 gene in 38 families with PLP1-related disorders: identification and functional characterization of 11 novel PLP1 mutations. Orphanet journal of rare diseases 38 21679407
2004 A family-based association study of PLP1 and schizophrenia. Neuroscience letters 33 15694262
1989 Characterization, cloning, curing, and distribution in lactic acid bacteria of pLP1, a plasmid from Lactobacillus plantarum CCM 1904 and its use in shuttle vector construction. Plasmid 33 2699038
1993 X linked spastic paraplegia (SPG2): clinical heterogeneity at a single gene locus. Journal of medical genetics 32 8320699
2019 Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants. Genome medicine 31 31818324
2014 PMD patient mutations reveal a long-distance intronic interaction that regulates PLP1/DM20 alternative splicing. Human molecular genetics 31 24890387
2005 Seventeen novel PLP1 mutations in patients with Pelizaeus-Merzbacher disease. Human mutation 31 15712223
2016 Pathogenic inflammation in the CNS of mice carrying human PLP1 mutations. Human molecular genetics 30 28173160
2012 Pelizaeus-Merzbacher disease caused by a duplication-inverted triplication-duplication in chromosomal segments including the PLP1 region. European journal of medical genetics 30 22490426
2018 Targeting microglia attenuates neuroinflammation-related neural damage in mice carrying human PLP1 mutations. Glia 29 30565754
2021 Identifying oligodendrocyte enhancers governing Plp1 expression. Human molecular genetics 28 34230963
2017 The balance between cathepsin C and cystatin F controls remyelination in the brain of Plp1-overexpressing mouse, a chronic demyelinating disease model. Glia 28 28251676
2009 Comprehensive genetic analyses of PLP1 in patients with Pelizaeus-Merzbacher disease applied by array-CGH and fiber-FISH analyses identified new mutations and variable sizes of duplications. Brain & development 28 19328639
2008 Deletion of a splicing enhancer disrupts PLP1/DM20 ratio and myelin stability. Experimental neurology 26 18835559
2006 Splice-site contribution in alternative splicing of PLP1 and DM20: molecular studies in oligodendrocytes. Human mutation 26 16287154
1999 Different mutations in the same codon of the proteolipid protein gene, PLP, may help in correlating genotype with phenotype in Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2). American journal of medical genetics 25 9934976
2018 PLP1 Mutations in Patients with Multiple Sclerosis: Identification of a New Mutation and Potential Pathogenicity of the Mutations. Journal of clinical medicine 24 30314286
2009 PLP1 gene duplication causes overexpression and alteration of the PLP/DM20 splicing balance in fibroblasts from Pelizaeus-Merzbacher disease patients. Biochimica et biophysica acta 24 19376225
2001 Prenatal interphase FISH diagnosis of PLP1 duplication associated with Pelizaeus-Merzbacher disease. Prenatal diagnosis 23 11787038
2008 PLP1 splicing abnormalities identified in Pelizaeus-Merzbacher disease and SPG2 fibroblasts are associated with different types of mutations. Human mutation 22 18470932
2018 Teriflunomide attenuates neuroinflammation-related neural damage in mice carrying human PLP1 mutations. Journal of neuroinflammation 21 29970109
2012 Clinical and genetic characterization of a 2-year-old boy with complete PLP1 deletion. Brain & development 20 22401669
2006 PLP1 and GPM6B intragenic copy number analysis by MAPH in 262 patients with hypomyelinating leukodystrophies: Identification of one partial triplication and two partial deletions of PLP1. Neurogenetics 20 16416265
2006 Genetic background influences UPR but not PLP processing in the rumpshaker model of PMD/SPG2. Neurochemical research 20 16944321
2007 Genotype-phenotype correlation in five Pelizaeus-Merzbacher disease patients with PLP1 gene duplications. Clinical genetics 19 18190592
2006 PLP1 alternative splicing in differentiating oligodendrocytes: characterization of an exonic splicing enhancer. Journal of cellular biochemistry 19 16288477
2015 Curcumin therapy in a Plp1 transgenic mouse model of Pelizaeus-Merzbacher disease. Annals of clinical and translational neurology 18 26339673
2012 Reduced PLP1 expression in induced pluripotent stem cells derived from a Pelizaeus-Merzbacher disease patient with a partial PLP1 duplication. Journal of human genetics 18 22695888
2021 ASD-like behaviors, a dysregulated inflammatory response and decreased expression of PLP1 characterize mice deficient for sialyltransferase ST3GAL5. Brain, behavior, & immunity - health 17 34589798
2006 Processing of PLP in a model of Pelizaeus-Merzbacher disease/SPG2 due to the rumpshaker mutation. Glia 17 16506223
2018 Immuno-efficacy of DNA vaccines encoding PLP1 and ROP18 against experimental Toxoplasma gondii infection in mice. Experimental parasitology 16 29626423
2022 Focused ion beam-scanning electron microscopy links pathological myelin outfoldings to axonal changes in mice lacking Plp1 or Mag. Glia 15 36354016
2018 Morpholino Antisense Oligomers as a Potential Therapeutic Option for the Correction of Alternative Splicing in PMD, SPG2, and HEMS. Molecular therapy. Nucleic acids 15 30195779
2017 SPG2 mimicking multiple sclerosis in a family identified using next generation sequencing. Journal of the neurological sciences 15 28320130
2013 Partial PLP1 deletion causing X-linked dominant spastic paraplegia type 2. Pediatric neurology 15 24095575
2019 Elucidation of the pathogenic mechanism and potential treatment strategy for a female patient with spastic paraplegia derived from a single-nucleotide deletion in PLP1. Journal of human genetics 14 31004103
2018 Myelin Water Fraction Imaging Reveals Hemispheric Asymmetries in Human White Matter That Are Associated with Genetic Variation in PLP1. Molecular neurobiology 13 30242727
2017 Integrative proteomics, genomics, and translational immunology approaches reveal mutated forms of Proteolipid Protein 1 (PLP1) and mutant-specific immune response in multiple sclerosis. Proteomics 13 28191734
2005 Prenatal diagnosis of PLP1 copy number by array comparative genomic hybridization. Prenatal diagnosis 13 16353282
2021 The key to egress? Babesia bovis perforin-like protein 1 (PLP1) with hemolytic capacity is required for blood stage replication and is involved in the exit of the parasite from the host cell. International journal for parasitology 12 33753093
2013 Three new PLP1 splicing mutations demonstrate pathogenic and phenotypic diversity of Pelizaeus-Merzbacher disease. Journal of child neurology 12 23771846
2009 Mild phenotype in Pelizaeus-Merzbacher disease caused by a PLP1-specific mutation. Brain & development 12 20022439
2013 Restoration of the normal splicing pattern of the PLP1 gene by means of an antisense oligonucleotide directed against an exonic mutation. PloS one 11 24019930
2009 Hereditary spastic paraplegia caused by the PLP1 'rumpshaker mutation'. Journal of neurology, neurosurgery, and psychiatry 11 19955111
2013 PLP1 gene analysis in 88 patients with leukodystrophy. Clinical genetics 10 23347225
2006 Quantitative multiplex real-time PCR for detection of PLP1 gene duplications in Pelizaeus-Merzbacher patients. Genetic testing 10 17020474
2005 Mild Pelizaeus-Merzbacher disease caused by a point mutation affecting correct splicing of PLP1 mRNA. Neuroscience 10 15837131
2018 PLP1 and CNTN1 gene variation modulates the microstructure of human white matter in the corpus callosum. Brain structure & function 9 30094605
2016 Myelin Genes and the Corpus Callosum: Proteolipid Protein 1 (PLP1) and Contactin 1 (CNTN1) Gene Variation Modulates Interhemispheric Integration. Molecular neurobiology 9 27864734
2015 Perinatal methylmercury exposure perturbs the expression of Plp1 and Cnp splice variants in cerebellum of rat pups. Neurotoxicology 9 25936639
2012 PLP1 duplication at the breakpoint regions of an apparently balanced t(X;22) translocation causes Pelizaeus-Merzbacher disease in a girl. Clinical genetics 9 22320281
2013 A novel mutation in PLP1 causes severe hereditary spastic paraplegia type 2. Gene 8 24103481
2013 The spectrum of PLP1 gene mutations in patients with the classical form of the Pelizaeus-Merzbacher disease. Medycyna wieku rozwojowego 8 24519770
2009 Variable expression of a novel PLP1 mutation in members of a family with Pelizaeus-Merzbacher disease. Journal of child neurology 8 19151366
2022 PLP1 may serve as a potential diagnostic biomarker of uterine fibroids. Frontiers in genetics 7 36386836
2021 Expanding the Clinical and Mutational Spectrum of the PLP1-Related Hypomyelination of Early Myelinated Structures (HEMS). Brain sciences 7 33450882
2017 Effects of Intron 1 Sequences on Human PLP1 Expression: Implications for PLP1-Related Disorders. ASN neuro 7 28735559
2015 Insertion of an extra copy of Xq22.2 into 1p36 results in functional duplication of the PLP1 gene in a girl with classical Pelizaeus-Merzbacher disease. BMC medical genetics 7 26329556
2023 Cytotoxic CNS-associated T cells drive axon degeneration by targeting perturbed oligodendrocytes in PLP1 mutant mice. iScience 6 37182098
2023 Plp1 in the enteric nervous system is preferentially expressed during early postnatal development in mouse as DM20, whose expression appears reliant on an intronic enhancer. Frontiers in cellular neuroscience 6 37293625
2019 Advantages of ddPCR in detection of PLP1 duplications. Intractable & rare diseases research 6 31523598
2018 PLP1 Gene Variation Modulates Leftward and Rightward Functional Hemispheric Asymmetries. Molecular neurobiology 6 29435918
2018 The wmN1 enhancer region in intron 1 is required for expression of human PLP1. Glia 6 29683207
2014 A novel PLP1 frameshift mutation causing a milder form of Pelizaeus-Merzbacher disease. Brain & development 6 25043250
2012 Targeted deletion of the antisilencer/enhancer (ASE) element from intron 1 of the myelin proteolipid protein gene (Plp1) in mouse reveals that the element is dispensable for Plp1 expression in brain during development and remyelination. Journal of neurochemistry 6 23157328
2010 PLP1 gene duplication as a cause of the classic form of Pelizaeus-Merzbacher disease - case report. Neurologia i neurochirurgia polska 6 21082496
2005 Rabbit paralytic tremor phenotype--a plp1 gene mutation as a model of human Pelizaeus-Merzbacher disease. Acta neurobiologiae experimentalis 6 15960310
2018 Brain Diffusion Imaging and Tractography to Distinguish Clinical Severity of Human PLP1-Related Disorders. Developmental neuroscience 5 30261498
2015 Control of human PLP1 expression through transcriptional regulatory elements and alternatively spliced exons in intron 1. ASN neuro 5 25694552
2014 Identification and functional study of novel PLP1 mutations in Chinese patients with Pelizaeus-Merzbacher disease. Brain & development 5 25491635
2013 Further genotype-phenotype correlation emerging from two families with PLP1 exon 4 skipping. Clinical genetics 5 23711321
2005 PLP-1 binds nematode double-stranded telomeric DNA. Molecules and cells 5 16267406
2024 CRISPR/CasRx-Mediated Knockdown of Rab7B Restores Incomplete Cell Shape Induced by Pelizaeus-Merzbacher Disease-Associated PLP1 p.Ala243Val. Neuroscience insights 4 39280331
2023 PLP1 gene mutations cause spastic paraplegia type 2 in three families. Annals of clinical and translational neurology 4 36622199
2021 Novel Insight into the Potential Pathogenicity of Mitochondrial Dysfunction Resulting from PLP1 Duplication Mutations in Patients with Pelizaeus-Merzbacher Disease. Neuroscience 4 34506833
2020 PLP-1 is essential for germ cell development and germline gene silencing in Caenorhabditiselegans. Development (Cambridge, England) 4 33051256
2017 A novel PLP1 mutation F240L identified in a patient with connatal type Pelizaeus-Merzbacher disease. Human genome variation 4 28101371
2014 Brain magnetic resonance imaging findings and auditory brainstem response in a child with spastic paraplegia 2 due to a PLP1 splice site mutation. Brain & development 4 24685771
2012 A novel PLP1 mutation further expands the clinical heterogeneity at the locus. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 4 22343157
2024 Plp1-expresssing perineuronal DRG cells facilitate colonic and somatic chronic mechanical pain involving Piezo2 upregulation in DRG neurons. Cell reports 3 38743566
2020 Identity and lineage fate of proteolipid protein 1 gene (Plp1)-expressing cells in the embryonic murine spinal cord. Developmental dynamics : an official publication of the American Association of Anatomists 3 32353175
2019 Drug screening for Pelizaeus-Merzbacher disease by quantifying the total levels and membrane localization of PLP1. Molecular genetics and metabolism reports 3 31110947
2008 Cloning and identification of a novel RNF6 transcriptional splice variant Spg2 in human development. Science in China. Series C, Life sciences 3 18368307
2008 No association between the oligodendrocyte-related gene PLP1 and schizophrenia in the Japanese population. Journal of human genetics 3 18604471
2022 In Silico Structural Analysis Predicting the Pathogenicity of PLP1 Mutations in Multiple Sclerosis. Brain sciences 2 36672024

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