Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA270218 | ENA |
REPOSITORIES: ENA
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Project description:Detection of copy number variation in patients with Pelizaeus-Merzbacher disease (PMD) - NimbleGen
| PRJNA269588 | ENA
Project description:We investigated the features of the genomic rearrangements in a cohort of 50 male individuals with proteolipid protein 1 (PLP1) copy number gain events who were ascertained with Pelizaeus-Merzbacher disease (PMD; MIM: 312080). Genomic rearrangements in PMD individuals with PLP1 copy number gain events were investigated by high-density customized array and breakpoint junction sequence analysis. Analysis of these data enabled the spectrum and relative distribution of the underlying genomic mutational signatures to be delineated. Genomic rearrangements in PMD individuals with PLP1 copy number gain events were investigated by high-density customized array and breakpoint junction sequence analysis.
2019-10-09 | GSE138542 | GEO
Project description:Inverted repeats (IRs) can facilitate structural variation as crucibles of genomic rearrangement. Complex DUP-TRP/INV-DUP rearrangements that contain breakpoint junctions within IRs have been recently associated with both MECP2 duplication syndrome (MIM#300260) and Pelizaeus-Merzbacher disease (PMD, MIM#312080). We investigated 17 unrelated PMD subjects with copy number gains at the PLP1 locus including triplication and quadruplication of specific genomic intervals M-bM-^@M-^S 16/17 were found to have a DUP-TRP/INV-DUP rearrangement product. An IR distal to PLP1 facilitates DUP-TRP/INV-DUP formation as well as an inversion structural variation found frequently amongst normal individuals. We show that a homologyM-bM-^@M-^Tor homeologyM-bM-^@M-^Tdriven replicative mechanism of DNA repair can apparently mediate template switches within stretches of microhomology. Moreover, we provide evidence that quadruplication, and potentially higher order amplification of a genomic interval, can occur in a manner consistent with rolling circle amplification as predicted by the microhomology mediated break induced replication (MMBIR) model. To determine size, genomic extent and gene content for each rearrangement, we used a customized tiling-path oligonucleotide microarray spanning the Xq22 chromosomal region to query the genomic DNA of 7 males with Pelizaeus-Merzbacher disease, and 5 unaffected or carrier/unaffected family members. A 4x44k Agilent Technologies (Santa Clara, CA) microarray was designed using the Agilent e-array website targeting the region of the genome encompassing the dosage-sensitive PLP1 gene.
2014-11-25 | E-GEOD-63594 | biostudies-arrayexpress
Project description:Inverted repeats (IRs) can facilitate structural variation as crucibles of genomic rearrangement. Complex DUP-TRP/INV-DUP rearrangements that contain breakpoint junctions within IRs have been recently associated with both MECP2 duplication syndrome (MIM#300260) and Pelizaeus-Merzbacher disease (PMD, MIM#312080). We investigated 17 unrelated PMD subjects with copy number gains at the PLP1 locus including triplication and quadruplication of specific genomic intervals – 16/17 were found to have a DUP-TRP/INV-DUP rearrangement product. An IR distal to PLP1 facilitates DUP-TRP/INV-DUP formation as well as an inversion structural variation found frequently amongst normal individuals. We show that a homology—or homeology—driven replicative mechanism of DNA repair can apparently mediate template switches within stretches of microhomology. Moreover, we provide evidence that quadruplication, and potentially higher order amplification of a genomic interval, can occur in a manner consistent with rolling circle amplification as predicted by the microhomology mediated break induced replication (MMBIR) model.
2014-11-25 | GSE63594 | GEO
Project description:Pelizaeus-Merzbacher disease (PMD) is a severe hypomyelinating disease, characterized by ataxia, intellectual disability, epilepsy and premature death. In the majority of cases, PMD is caused by duplication of PLP1 that is expressed in myelinating oligodendrocytes. Despite detailed knowledge of PLP1, there is presently no curative therapy for PMD. We used a Plp1 transgenic PMD mouse model to test the therapeutic effect of Lonaprisan, an antagonist of the nuclear progesterone receptor, in lowering Plp1 mRNA overexpression. We applied placebo-controlled Lonaprisan therapy to PMD mice for 10 weeks and performed the grid slip analysis to assess the clinical phenotype. Additionally, mRNA expression and protein accumulation as well as histological analysis of the central nervous system were performed. While Plp1 mRNA levels are increased about 1.8-fold in PMD mice compared to wildtype controls, daily Lonaprisan treatment reduced overexpression at the RNA level up to 1.5-fold, which was sufficient to significantly improve a poor motor phenotype. Electron microscopy confirmed a 25% increase in the number of myelinated axons in the corticospinal tract when compared to untreated PMD mice. Microarray analysis revealed the upregulation of pro-apoptotic genes in PMD mice that could be partially rescued by Lonaprisan treatment, which also reduced microgliosis, astrogliosis, and lymphocyte infiltration. We treated mice with Lonaprisan or vehicle for 10 weeks. Brains from 13 week old mice were collected and subsequently lysed for total RNA extraction. We took three biological replicates for each Treatment and Placebo.
2014-02-26 | E-GEOD-55315 | biostudies-arrayexpress
Project description:Pelizaeus-Merzbacher disease (PMD) is a severe hypomyelinating disease, characterized by ataxia, intellectual disability, epilepsy and premature death. In the majority of cases, PMD is caused by duplication of PLP1 that is expressed in myelinating oligodendrocytes. Despite detailed knowledge of PLP1, there is presently no curative therapy for PMD. We used a Plp1 transgenic PMD mouse model to test the therapeutic effect of Lonaprisan, an antagonist of the nuclear progesterone receptor, in lowering Plp1 mRNA overexpression. We applied placebo-controlled Lonaprisan therapy to PMD mice for 10 weeks and performed the grid slip analysis to assess the clinical phenotype. Additionally, mRNA expression and protein accumulation as well as histological analysis of the central nervous system were performed. While Plp1 mRNA levels are increased about 1.8-fold in PMD mice compared to wildtype controls, daily Lonaprisan treatment reduced overexpression at the RNA level up to 1.5-fold, which was sufficient to significantly improve a poor motor phenotype. Electron microscopy confirmed a 25% increase in the number of myelinated axons in the corticospinal tract when compared to untreated PMD mice. Microarray analysis revealed the upregulation of pro-apoptotic genes in PMD mice that could be partially rescued by Lonaprisan treatment, which also reduced microgliosis, astrogliosis, and lymphocyte infiltration.
2014-02-26 | GSE55315 | GEO
Project description:Pelizaeus-Merzbacher disease (PMD) is a fatal X-linked disorder caused by loss of myelinating oligodendrocytes and consequent hypomyelination. The underlying cellular and molecular dysfunctions are not fully defined, but therapeutic enhancement of oligodendrocyte survival could restore functional myelination in patients. Here we generated pure, scalable quantities of iPSC-derived oligodendrocyte progenitor cells (OPCs) from a severe mouse model of PMD, Plp1jimpy. Temporal phenotypic and transcriptomic studies defined an early pathological window characterized by endoplasmic-reticulum (ER) stress and cell death as OPCs exit their progenitor state. High-throughput phenotypic screening identified a compound, Ro 25-6981, which modulates the ER stress response and rescues mutant oligodendrocyte survival in jimpy, in vitro and in vivo, and in human PMD oligocortical spheroids. Surprisingly, increasing oligodendrocyte survival did not restore subsequent myelination, revealing a second pathological phase. Collectively, our work shows that PMD oligodendrocyte loss can be rescued pharmacologically and defines a need for multifactorial intervention to restore myelination.
2018-08-22 | GSE111595 | GEO
Project description:The leukodystrophy Pelizaeus-Merzbacher disease (PMD) is caused by myelin protein proteolipid protein (PLP) gene mutations. PMD is characterized by oligodendrocyte death and CNS hypomyelination; thus, increasing oligodendrocyte survival and enhancing myelination could provide therapeutic benefit. We used the PMD mouse model Jimpy to explore the impact of the integrated stress response (ISR) on the oligodendrocyte response to mutant PLP expression. Jimpy animals in which the ISR-triggering eIF2 kinase PERK is inactivated have an extended lifespan that correlates with increased oligodendrocyte survival and enhanced CNS myelination. Inactivation of the downstream components of the ISR pathway CHOP and GADD34, in contrast, did not rescue oligodendrocytes or myelin. Phosphorylated eIF2 inhibits the exchange factor eIF2B, resulting in diminished protein synthesis. Treatment with small molecule eIF2B activators 2BAct and ISRIB dramatically increased oligodendrocyte survival, CNS myelination, and doubled the lifespan of Jimpy mice. These results suggest that ISR modulation could provide therapeutic benefit to PMD patients.
2025-11-07 | GSE277705 | GEO
Project description:Pelizaeus-Merzbacher disease (PMD) is a fatal X-linked disorder caused by loss of myelinating oligodendrocytes and consequent hypomyelination. The underlying cellular and molecular dysfunctions are not fully defined, but therapeutic enhancement of oligodendrocyte survival could restore functional myelination in patients. Here we generated pure, scalable quantities of iPSC-derived oligodendrocyte progenitor cells (OPCs) from a severe mouse model of PMD, Plp1jimpy. Temporal phenotypic and transcriptomic studies defined an early pathological window characterized by endoplasmic-reticulum (ER) stress and cell death as OPCs exit their progenitor state. High-throughput phenotypic screening identified a compound, Ro 25-6981, which modulates the ER stress response and rescues mutant oligodendrocyte survival in jimpy, in vitro and in vivo, and in human PMD oligocortical spheroids. Surprisingly, increasing oligodendrocyte survival did not restore subsequent myelination, revealing a second pathological phase. Collectively, our work shows that PMD oligodendrocyte loss can be rescued pharmacologically and defines a need for multifactorial intervention to restore myelination.
2018-08-22 | GSE111599 | GEO