Pseudoexons as disease cause and modifiers of gene expression

Project: Research

Project Details


Using our own software, we have found that introns in all human genes harbor pseudoexons (PEs). PEs are nonfunctional
exons that disrupt the normal mRNA if they are included during splicing. Therefore PEs represents a
vulnerable part of our genome. Typically inclusion of PEs lead to NMD degradation of the mRNA and this is
therefore not recognized or simply observed as decreased expression of the affected gene.
Intronic SNPs/mutations can affect splicing regulatory elements and activate PE inclusion to cause disease. We
believe that this is a severely underreported disease mechanism. Moreover, we have observed that also some
wild-type PEs are included at high levels in the mRNA of their host gene and thus decrease normal gene
expression. This implies that gene expression can be significantly increased if PE inclusion is blocked.
We will use RNA-seq and our own data-analysis pipelines for global identification of human PEs from cells where
NMD has been blocked and/or splicing regulatory factors have been down-regulated. We will use a new high
throughput system for functional validation and characterization of identified wild-type and mutant PEs. We will
employ splice switching oligonucleotides (SSOs) to block inclusion of PEs, which have been activated by
SNPs/mutations. We will also explore the potential of identified human wild-type PEs to serve as regulatory
switches to increase or decrease gene expression when targeted by SSOs. This may be a new way to specifically
regulate expression of individual genes important in human disease and could potentially be used therapeutically.
Finally, we will establish a searchable PE database and software tools allowing clinicians and researchers to
evaluate the pathogenicity of intronic sequence variants.
This project will dramatically increase the number of known PEs in the human genome and provide important
knowledge about their regulation, involvement in disease and potential to serve as regulatory switches for gene
Effective start/end date01/01/201831/12/2019


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