ArticleNucleic acids research2018
Blocking of an intronic splicing silencer completely rescues IKBKAP exon 20 splicing in familial dysautonomia patient cells.
Article in Nucleic acids research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 20 citations in OpenAlex.
- Peripheral neuron phenotypes of familial dysautonomia are rescued by AAV-mediated gene therapy.Clinical autonomic research : official journal of the Clinical Autonomic Research Society · 2026Article
- Prime editing of the common Familial Dysautonomia-causing c.2204 + 6T > C splicing mutation.Orphanet journal of rare diseases · 2026Article
- Peripheral neuron phenotypes of familial dysautonomia are rescued by AAV-mediated gene therapy.Research square · 2025Article
- Antisense oligonucleotide therapy for patients with Friedreich's ataxia carrying the c.165+5G>C splicing mutation.Molecular therapy. Nucleic acids · 2025Article
- Genipin rescues developmental and degenerative defects in familial dysautonomia models and accelerates axon regeneration.Science translational medicine · 2024Article
- CRISPR activation to characterize splice-altering variants in easily accessible cells.American journal of human genetics · 2024Article
- Age-dependent regulation of ELP1 exon 20 splicing in Familial Dysautonomia by RNA Polymerase II kinetics and chromatin structure.PloS one · 2024Article
- Regulation of pre-mRNA splicing: roles in physiology and disease, and therapeutic prospects.Nature reviews. Genetics · 2023Review
- Rescue of mis-splicing of a commonMolecular therapy. Nucleic acids · 2022Article
- hnRNP A1 in RNA metabolism regulation and as a potential therapeutic target.Frontiers in pharmacology · 2022Review
- RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays.Molecules (Basel, Switzerland) · 2021Review
- RNA-binding proteins in human genetic disease.Nature reviews. Genetics · 2021Review
- DeepCLIP: predicting the effect of mutations on protein-RNA binding with deep learning.Nucleic acids research · 2020Article
- Disruption of splicing-regulatory elements using CRISPR/Cas9 to rescue spinal muscular atrophy in human iPSCs and mice.National science review · 2020Article
- Combinatorial treatment increases IKAP levels in human cells generated from Familial Dysautonomia patients.PloS one · 2019Article
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Familial dysautonomia (FD) is a severe genetic disorder causing sensory and autonomic dysfunction. It is predominantly caused by a c.2204+6T>C mutation in the IKBKAP gene. This mutation decreases the 5' splice site strength of IKBKAP exon 20 leading to exon 20 skipping and decreased amounts of full-length IKAP protein. We identified a binding site for the splicing regulatory protein hnRNP A1 downstream of the IKBKAP exon 20 5'-splice site. We show that hnRNP A1 binds to this splicing regulatory element (SRE) and that two previously described inhibitory SREs inside IKBKAP exon 20 are also bound by hnRNP A1. Knockdown of hnRNP A1 in FD patient fibroblasts increases IKBKAP exon 20 inclusion demonstrating that hnRNP A1 is a negative regulator of IKBKAP exon 20 splicing. Furthermore, by mutating the SREs in an IKBKAP minigene we show that all three SREs cause hnRNP A1-mediated exon repression. We designed splice switching oligonucleotides (SSO) that blocks the intronic hnRNP A1 binding site, and demonstrate that this completely rescues splicing of IKBKAP exon 20 in FD patient fibroblasts and increases the amounts of IKAP protein. We propose that this may be developed into a potential new specific treatment of FD.
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