ArticleAnnals of clinical and translational neurology2015
Altered PLP1 splicing causes hypomyelination of early myelinating structures.
Article in Annals of clinical and translational neurology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 42 citations in OpenAlex.
- Review
- Long-read transcriptomics of purified human cortical cell types exposes glial isoform complexity and disease-relevant transcript architecture.bioRxiv : the preprint server for biology · 2026Article
- A scoping review of stem cell models of leukodystrophies: advances in understanding pathophysiological mechanisms.NPJ genomic medicine · 2025Article
- A copy number variant overlapping the 3'UTR of PLP1 causes spastic paraplegia.Journal of human genetics · 2025Article
- SRSF10 regulates oligodendrocyte differentiation during mouse central nervous system development by modulating pre-mRNA splicing.Nucleic acids research · 2025Article
- Neurodevelopmental Implications Underpinning Hereditary Spastic Paraplegia.CNS neuroscience & therapeutics · 2025Review
- Oligodendroglia and Myelin: Supporting the Connectome.Advances in neurobiology · 2025Review
- Diagnostic MR imaging features of hypomyelination of early myelinating structures: A case report.The neuroradiology journal · 2024Article
- Microdeletion in distal PLP1 enhancers causes hereditary spastic paraplegia 2.Annals of clinical and translational neurology · 2023Article
- PLP1 gene mutations cause spastic paraplegia type 2 in three families.Annals of clinical and translational neurology · 2023Article
- Mutation of Proteolipid Protein 1 Gene: From Severe Hypomyelinating Leukodystrophy to Inherited Spastic Paraplegia.Biomedicines · 2022Review
- Emerging cellular themes in leukodystrophies.Frontiers in cell and developmental biology · 2022Review
- Hypomyelinating leukodystrophies - unravelling myelin biology.Nature reviews. Neurology · 2021Review
- Expanding the Clinical and Mutational Spectrum of theBrain sciences · 2021Article
- Morpholino Antisense Oligomers as a Potential Therapeutic Option for the Correction of Alternative Splicing in PMD, SPG2, and HEMS.Molecular therapy. Nucleic acids · 2018Article
- Article
- The role of the clinician in the multi-omics era: are you ready?Journal of inherited metabolic disease · 2018Article
- Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms.Acta neuropathologica · 2017Review
- DNA methylation in oligodendroglial cells during developmental myelination and in disease.Neurogenesis (Austin, Tex.) · 2017Article
- Cellular Pathology of Pelizaeus-Merzbacher Disease Involving Chaperones Associated with Endoplasmic Reticulum Stress.Frontiers in molecular biosciences · 2017Review
Corrections and comments
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Authors and funding
26 authors at 16 institutions in 6 countries.
Funding
Abstract
objectiveThe objective of this study was to investigate the genetic etiology of the X-linked disorder "Hypomyelination of Early Myelinating Structures" (HEMS).
methodsWe included 16 patients from 10 families diagnosed with HEMS by brain MRI criteria. Exome sequencing was used to search for causal mutations. In silico analysis of effects of the mutations on splicing and RNA folding was performed. In vitro gene splicing was examined in RNA from patients' fibroblasts and an immortalized immature oligodendrocyte cell line after transfection with mutant minigene splicing constructs.
resultsAll patients had unusual hemizygous mutations of PLP1 located in exon 3B (one deletion, one missense and two silent), which is spliced out in isoform DM20, or in intron 3 (five mutations). The deletion led to truncation of PLP1, but not DM20. Four mutations were predicted to affect PLP1/DM20 alternative splicing by creating exonic splicing silencer motifs or new splice donor sites or by affecting the local RNA structure of the PLP1 splice donor site. Four deep intronic mutations were predicted to destabilize a long-distance interaction structure in the secondary PLP1 RNA fragment involved in regulating PLP1/DM20 alternative splicing. Splicing studies in fibroblasts and transfected cells confirmed a decreased PLP1/DM20 ratio.
interpretationBrain structures that normally myelinate early are poorly myelinated in HEMS, while they are the best myelinated structures in Pelizaeus-Merzbacher disease, also caused by PLP1 alterations. Our data extend the phenotypic spectrum of PLP1-related disorders indicating that normal PLP1/DM20 alternative splicing is essential for early myelination and support the need to include intron 3 in diagnostic sequencing.
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Registered trials
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