ArticleHuman molecular genetics2014
PMD patient mutations reveal a long-distance intronic interaction that regulates PLP1/DM20 alternative splicing.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
23 citing papers in PubMed, 35 citations in OpenAlex.
- A copy number variant overlapping the 3'UTR of PLP1 causes spastic paraplegia.Journal of human genetics · 2025Article
- RNA structure in alternative splicing regulation: from mechanism to therapy.Acta biochimica et biophysica Sinica · 2024Review
- How does precursor RNA structure influence RNA processing and gene expression?Bioscience reports · 2023Review
- PLP1 gene mutations cause spastic paraplegia type 2 in three families.Annals of clinical and translational neurology · 2023Article
- Combining genetic constraint with predictions of alternative splicing to prioritize deleterious splicing in rare disease studies.BMC bioinformatics · 2022Article
- Mutation of Proteolipid Protein 1 Gene: From Severe Hypomyelinating Leukodystrophy to Inherited Spastic Paraplegia.Biomedicines · 2022Review
- Structural Context of a Critical Exon of Spinal Muscular Atrophy Gene.Frontiers in molecular biosciences · 2022Review
- Emerging cellular themes in leukodystrophies.Frontiers in cell and developmental biology · 2022Review
- Impact of Genetic Testing on Human Health:: The Current Landscape and Future for Personalized Medicine.Delaware journal of public health · 2021Article
- Conserved long-range base pairings are associated with pre-mRNA processing of human genes.Nature communications · 2021Article
- Hypomyelinating leukodystrophies - unravelling myelin biology.Nature reviews. Neurology · 2021Review
- Morpholino Antisense Oligomers as a Potential Therapeutic Option for the Correction of Alternative Splicing in PMD, SPG2, and HEMS.Molecular therapy. Nucleic acids · 2018Article
- Review
- Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes.Advances in neurobiology · 2018Review
- Neurogenetics of Pelizaeus-Merzbacher disease.Handbook of clinical neurology · 2018Review
- The determinants of alternative RNA splicing in human cells.Molecular genetics and genomics : MGG · 2017Review
- Gender-Specific Amelioration of SMA Phenotype upon Disruption of a Deep Intronic Structure by an Oligonucleotide.Molecular therapy : the journal of the American Society of Gene Therapy · 2017Article
- Leukodystrophies: Five new things.Neurology. Clinical practice · 2016Article
- Altered PLP1 splicing causes hypomyelination of early myelinating structures.Annals of clinical and translational neurology · 2015Article
- Splicing regulation in spinal muscular atrophy by an RNA structure formed by long-distance interactions.Annals of the New York Academy of Sciences · 2015Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Alternative splicing of the proteolipid protein 1 gene (PLP1) produces two forms, PLP1 and DM20, due to alternative use of 5' splice sites with the same acceptor site in intron 3. The PLP1 form predominates in central nervous system RNA. Mutations that reduce the ratio of PLP1 to DM20, whether mutant or normal protein is formed, result in the X-linked leukodystrophy Pelizaeus-Merzbacher disease (PMD). We investigated the ability of sequences throughout PLP1 intron 3 to regulate alternative splicing using a splicing minigene construct transfected into the oligodendrocyte cell line, Oli-neu. Our data reveal that the alternative splice of PLP1 is regulated by a long-distance interaction between two highly conserved elements that are separated by 581 bases within the 1071-base intron 3. Further, our data suggest that a base-pairing secondary structure forms between these two elements, and we demonstrate that mutations of either element designed to destabilize the secondary structure decreased the PLP1/DM20 ratio, while swap mutations designed to restore the structure brought the PLP1/DM20 ratio to near normal levels. Sequence analysis of intron 3 in families with clinical symptoms of PMD who did not have coding-region mutations revealed mutations that segregated with disease in three families. We showed that these patient mutations, which potentially destabilize the secondary structure, also reduced the PLP1/DM20 ratio. This is the first report of patient mutations causing disease by disruption of a long-distance intronic interaction controlling alternative splicing. This finding has important implications for molecular diagnostics of PMD.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.