ArticlePLoS genetics2018
Intronic PAH gene mutations cause a splicing defect by a novel mechanism involving U1snRNP binding downstream of the 5' splice site.
Article in PLoS genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 26 citations in OpenAlex.
- RNA dysfunction in age-related macular degeneration: the role of U1 snRNP complex and neurodegenerative diseases.International journal of retina and vitreous · 2025Review
- [Genetic profiling and intervention strategies for phenylketonuria in Gansu, China: an analysis of 1 159 cases].Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2025Article
- PAH deficient pathology in humanized c.1066-11G>A phenylketonuria mice.Human molecular genetics · 2024Article
- Compound heterozygous variants of THG1L result in autosomal recessive cerebellar ataxia.Journal of human genetics · 2023Article
- Development of Engineered-U1 snRNA Therapies: Current Status.International journal of molecular sciences · 2023Review
- The spectrum of phenylalanine hydroxylase variants and genotype-phenotype correlation in phenylketonuria patients in Gansu, China.Human genomics · 2023Article
- Antisense Oligonucleotide Rescue of Deep-Intronic Variants Activating Pseudoexons in the 6-Pyruvoyl-Tetrahydropterin Synthase Gene.Nucleic acid therapeutics · 2022Article
- Identification of phenylketonuria patient genotypes using single-gene full-length sequencing.Human genomics · 2022Article
- Modeling Splicing Variants Amenable to Antisense Therapy by Use of CRISPR-Cas9-Based Gene Editing in HepG2 Cells.Methods in molecular biology (Clifton, N.J.) · 2022Article
- OTC intron 4 variations mediate pathogenic splicing patterns caused by the c.386G>A mutation in humans and spfMolecular medicine (Cambridge, Mass.) · 2021Article
- Autosomal dominant optic atrophy: A novel treatment forMolecular therapy. Nucleic acids · 2021Article
- Analysis of Pathogenic Pseudoexons Reveals Novel Mechanisms Driving Cryptic Splicing.Frontiers in genetics · 2021Article
- Next Generation Sequencing in Newborn Screening in the United Kingdom National Health Service.International journal of neonatal screening · 2019Article
- Molecular Mechanisms and Determinants of Innovative Correction Approaches in Coagulation Factor Deficiencies.International journal of molecular sciences · 2019Review
- A novel role of U1 snRNP: Splice site selection from a distance.Biochimica et biophysica acta. Gene regulatory mechanisms · 2019Review
- An Altered Splicing Registry Explains the Differential ExSpeU1-Mediated Rescue of Splicing Mutations Causing Haemophilia A.Frontiers in genetics · 2019Article
- Identification of the association betweenArchives animal breeding · 2019Article
- Ranking noncanonical 5' splice site usage by genome-wide RNA-seq analysis and splicing reporter assays.Genome research · 2018Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Phenylketonuria (PKU), one of the most common inherited diseases of amino acid metabolism, is caused by mutations in the phenylalanine hydroxylase (PAH) gene. Recently, PAH exon 11 was identified as a vulnerable exon due to a weak 3' splice site, with different exonic mutations affecting exon 11 splicing through disruption of exonic splicing regulatory elements. In this study, we report a novel intron 11 regulatory element, which is involved in exon 11 splicing, as revealed by the investigated pathogenic effect of variants c.1199+17G>A and c.1199+20G>C, identified in PKU patients. Both mutations cause exon 11 skipping in a minigene system. RNA binding assays indicate that binding of U1snRNP70 to this intronic region is disrupted, concomitant with a slightly increased binding of inhibitors hnRNPA1/2. We have investigated the effect of deletions and point mutations, as well as overexpression of adapted U1snRNA to show that this splicing regulatory motif is important for regulation of correct splicing at the natural 5' splice site. The results indicate that U1snRNP binding downstream of the natural 5' splice site determines efficient exon 11 splicing, thus providing a basis for development of therapeutic strategies to correct PAH exon 11 splicing mutations. In this work, we expand the functional effects of non-canonical intronic U1 snRNP binding by showing that it may enhance exon definition and that, consequently, intronic mutations may cause exon skipping by a novel mechanism, where they disrupt stimulatory U1 snRNP binding close to the 5' splice site. Notably, our results provide further understanding of the reported therapeutic effect of exon specific U1 snRNA for splicing mutations in disease.
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