ArticlePLoS genetics2016
The Splicing Efficiency of Activating HRAS Mutations Can Determine Costello Syndrome Phenotype and Frequency in Cancer.
Article in PLoS genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 24 citations in OpenAlex.
- U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations.Nature genetics · 2026Article
- U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations.bioRxiv : the preprint server for biology · 2025Article
- Biomarker Landscape in RASopathies.International journal of molecular sciences · 2024Review
- All exons are not created equal-exon vulnerability determines the effect of exonic mutations on splicing.Nucleic acids research · 2024Article
- The role of alternative pre-mRNA splicing in cancer progression.Cancer cell international · 2023Review
- RAS pathway: The new frontier of brain mosaicism in epilepsy.Neurobiology of disease · 2023Review
- New prospectives on treatment opportunities in RASopathies.American journal of medical genetics. Part C, Seminars in medical genetics · 2022Review
- The RASopathies: from pathogenetics to therapeutics.Disease models & mechanisms · 2022Review
- Untangling the KRAS mutated lung cancer subsets and its therapeutic implications.Molecular biomedicine · 2021Review
- Germline and sporadic cancers driven by the RAS pathway: parallels and contrasts.Annals of oncology : official journal of the European Society for Medical Oncology · 2020Review
- Costello syndrome: Clinical phenotype, genotype, and management guidelines.American journal of medical genetics. Part A · 2019Article
- Genomic landscape analyses of reprogrammed cells using integrative and non-integrative methods reveal variable cancer-associated alterations.Oncotarget · 2019Article
- Progressive myoclonus epilepsy in Gaucher Disease due to a new Gly-Gly mutation causing loss of an Exonic Splicing Enhancer.Journal of neurology · 2019Article
- RAS GTPase-dependent pathways in developmental diseases: old guys, new lads, and current challenges.Current opinion in cell biology · 2018Review
- Blocking of an intronic splicing silencer completely rescues IKBKAP exon 20 splicing in familial dysautonomia patient cells.Nucleic acids research · 2018Article
- Dysregulation of mRNA splicing in urothelial carcinoma: Clinical, diagnostic and therapeutic implications.Bladder cancer (Amsterdam, Netherlands)Review
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Authors and funding
18 authors at 7 institutions in 2 countries.
Funding
Abstract
Costello syndrome (CS) may be caused by activating mutations in codon 12/13 of the HRAS proto-oncogene. HRAS p.Gly12Val mutations have the highest transforming activity, are very frequent in cancers, but very rare in CS, where they are reported to cause a severe, early lethal, phenotype. We identified an unusual, new germline p.Gly12Val mutation, c.35_36GC>TG, in a 12-year-old boy with attenuated CS. Analysis of his HRAS cDNA showed high levels of exon 2 skipping. Using wild type and mutant HRAS minigenes, we confirmed that c.35_36GC>TG results in exon 2 skipping by simultaneously disrupting the function of a critical Exonic Splicing Enhancer (ESE) and creation of an Exonic Splicing Silencer (ESS). We show that this vulnerability of HRAS exon 2 is caused by a weak 3' splice site, which makes exon 2 inclusion dependent on binding of splicing stimulatory proteins, like SRSF2, to the critical ESE. Because the majority of cancer- and CS- causing mutations are located here, they affect splicing differently. Therefore, our results also demonstrate that the phenotype in CS and somatic cancers is not only determined by the different transforming potentials of mutant HRAS proteins, but also by the efficiency of exon 2 inclusion resulting from the different HRAS mutations. Finally, we show that a splice switching oligonucleotide (SSO) that blocks access to the critical ESE causes exon 2 skipping and halts proliferation of cancer cells. This unravels a potential for development of new anti-cancer therapies based on SSO-mediated HRAS exon 2 skipping.
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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.