ArticleAmerican journal of human genetics2017
Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes.
Article in American journal of human genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 67 citations in OpenAlex.
- Developmental trajectory of individuals with Pelizaeus-Merzbacher Disease (PMD).Molecular genetics and metabolism · 2026Article
- A canineProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Integrated stress response inhibition prolongs the lifespan of a Pelizaeus-Merzbacher disease mouse model by increasing oligodendrocyte survival.Nature communications · 2025Article
- A scoping review of stem cell models of leukodystrophies: advances in understanding pathophysiological mechanisms.NPJ genomic medicine · 2025Article
- The Effect of Tumor Necrosis Factor-α and Interleu-Kin-1β on the Restorative Properties of Human Oligodendrocyte Precursor Cells In Vitro.Bioengineering (Basel, Switzerland) · 2025Article
- Article
- The Polygenic Nature of Multiple Sclerosis: Genetic Variants, Immunological Modulation, and Environmental Connections.Endocrine, metabolic & immune disorders drug targets · 2025Review
- Pelizaeus-Merzbacher disease: on the cusp of myelin medicine.Trends in molecular medicine · 2024Review
- Developing a human iPSC-derived three-dimensional myelin spheroid platform for modeling myelin diseases.iScience · 2023Article
- Generation of Induced Pluripotent Stem Cells from Lymphoblastoid Cell Lines by Electroporation of Episomal Vectors.International journal of stem cells · 2023Article
- Utilizing hiPSC-derived oligodendrocytes to study myelin pathophysiology in neuropsychiatric and neurodegenerative disorders.Frontiers in cellular neuroscience · 2023Review
- Genotype-phenotype correlations of marfan syndrome and related fibrillinopathies: Phenomenon and molecular relevance.Frontiers in genetics · 2022Review
- One-step Reprogramming of Human Fibroblasts into Oligodendrocyte-like Cells by SOX10, OLIG2, and NKX6.2.Stem cell reports · 2021Article
- A robust culture system to generate neural progenitors with gliogenic competence from clinically relevant induced pluripotent stem cells for treatment of spinal cord injury.Stem cells translational medicine · 2021Article
- Patient-derived iPSC modeling of rare neurodevelopmental disorders: Molecular pathophysiology and prospective therapies.Neuroscience and biobehavioral reviews · 2021Review
- Novel Tools and Investigative Approaches for the Study of Oligodendrocyte Precursor Cells (NG2-Glia) in CNS Development and Disease.Frontiers in cellular neuroscience · 2021Article
- Rapid and Efficient Generation of Myelinating Human Oligodendrocytes in Organoids.Frontiers in cellular neuroscience · 2021Article
- Growing Glia: Cultivating Human Stem Cell Models of Gliogenesis in Health and Disease.Frontiers in cell and developmental biology · 2021Review
- RNA Polymerase III Subunit Mutations in Genetic Diseases.Frontiers in molecular biosciences · 2021Review
- NovelFrontiers in cellular neuroscience · 2021Review
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
Abstract
Pelizaeus-Merzbacher disease (PMD) is a pediatric disease of myelin in the central nervous system and manifests with a wide spectrum of clinical severities. Although PMD is a rare monogenic disease, hundreds of mutations in the X-linked myelin gene proteolipid protein 1 (PLP1) have been identified in humans. Attempts to identify a common pathogenic process underlying PMD have been complicated by an incomplete understanding of PLP1 dysfunction and limited access to primary human oligodendrocytes. To address this, we generated panels of human induced pluripotent stem cells (hiPSCs) and hiPSC-derived oligodendrocytes from 12 individuals with mutations spanning the genetic and clinical diversity of PMD-including point mutations and duplication, triplication, and deletion of PLP1-and developed an in vitro platform for molecular and cellular characterization of all 12 mutations simultaneously. We identified individual and shared defects in PLP1 mRNA expression and splicing, oligodendrocyte progenitor development, and oligodendrocyte morphology and capacity for myelination. These observations enabled classification of PMD subgroups by cell-intrinsic phenotypes and identified a subset of mutations for targeted testing of small-molecule modulators of the endoplasmic reticulum stress response, which improved both morphologic and myelination defects. Collectively, these data provide insights into the pathogeneses of a variety of PLP1 mutations and suggest that disparate etiologies of PMD could require specific treatment approaches for subsets of individuals. More broadly, this study demonstrates the versatility of a hiPSC-based panel spanning the mutational heterogeneity within a single disease and establishes a widely applicable platform for genotype-phenotype correlation and drug screening in any human myelin disorder.
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