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Investigating Splicing Efficiency in HRAS to Control Costello Syndrome Phenotype and Frequency in Cancer

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A detailed study of an HRAS mutational hotspot has revealed how oncogenic mutations can affect splicing efficiency and determine Costello syndrome phenotype and frequency in cancer (http://dx.doi.org/10.1371/journal.pgen.1006039).

The oncogene HRAS encodes a GTPase that mediates signal transduction for normal cell proliferation, growth and survival. Somatic mutations in HRAS are present in many cancers and p.G12V is the most severe; germline mutations in HRAS cause Costello syndrome which is characterised by growth retardation, developmental abnormalities and tumour predisposition. 

Research conducted between a number of Universities in Denmark and the United States investigated a patient with an attenuated phenotype of Costello syndrome. Hartung et al. demonstrated that the causative mutation, c.35_36GC>TG, which encodes the prototypical p.G12V oncogenic HRAS, causes exon 2 skipping and a reduced severity of the disorder due to limited production of the constitutively active oncogenic HRAS. Normally, individuals with Costello syndrome caused by p.G12V mutations have very severe clinical presentation with death typically within the first months of life.

Analysis of RNA from patient lymphocytes showed extensive exon 2 skipping and absence of the mutation in correctly spliced HRAS RNA. In silico analysis revealed that the HRAS gene has a weakly defined exon 2, and that the mutation c.35_36GC>TG simultaneously disrupts an exonic splicing enhancer (ESE) binding motif and creates a strong exonic splicing silencer (ESS) binding motif. 

Transfection of wildtype and mutant HRAS minigenes into cancer cell lines showed that different changes in codon 12 of exon 2 can regulate HRAS activity by affecting the efficiency of HRAS exon 2 inclusion into mRNA during splicing. Significantly, the group also found that introduction of a splice switch oligo (SSO) that blocks access to the critical ESE causes exon 2 skipping and halts proliferation of cancer cells in vitro.

Professor Brage Storstein Andresen from the University of Southern Denmark commented ‘HRAS was the first described human oncogene and the p.G12V mutation the first mutation. This is described in most text books today but the effect of this mutation is only focused at the protein level. Nobody considered the potential effects at the splicing level; our identification of a new characteristic/weakness regarding this gene and this mutation is particularly interesting. It reveals an additional layer of regulation through the different splicing efficiency of different mutations in the mutational hot spot in codons 12 and 13 of the HRAS oncogene, and emphasizes the importance of the so called "splicing code” when determining the effect of mutations. Importantly, our work also reveals that exon 2 in HRAS is vulnerable and can be targeted by SSOs, opening a new potential way to target cancer’.