Biomedical impact of splicing mutations revealed through exome sequencing (original) (raw)

Splicing in action: assessing disease causing sequence changes

Journal of Medical Genetics, 2005

Variations in new splicing regulatory elements are difficult to identify exclusively by sequence inspection and may result in deleterious effects on precursor (pre) mRNA splicing. These mutations can result in either complete skipping of the exon, retention of the intron, or the introduction of a new splice site within an exon or intron. Sometimes mutations that do not disrupt or create a splice site activate pre-existing pseudo splice sites, consistent with the proposal that introns contain splicing inhibitory sequences. These variants can also affect the fine balance of isoforms produced by alternatively spliced exons and in consequence cause disease. Available genomic pathology data reveal that we are still partly ignorant of the basic mechanisms that underlie the pre-mRNA splicing process. The fact that human pathology can provide pointers to new modulatory elements of splicing should be exploited.

Cryptic splicing sites are differentially utilized in vivo

FEBS Journal, 2008

During pre-mRNA splicing, intron sequences are removed from the original transcript. The exon-intron boundaries, namely the 5¢ and the 3¢ splice sites (ss), are defined by relatively conserved sequences that are critical for the splicing reaction [1]. The natural 5¢ ss match the consensus (5¢-CAG ⁄ GUAAGU-3¢) to various extents, with the vast majority of them deviating at two or three positions. The most invariant positions are the almost universal GU dinucleotide at the cleavage site and the G at position +5, which is present in 85% of the sequences analyzed . The 5¢ ss consensus is complementary to the first nine nucleotides of the 5¢ end of U1 small nuclear RNA (snRNA) and recognition of the 5¢ ss involves base pairing of these two RNA molecules . However, controversy remains as to whether extended base pairing between a pre-mRNA and the U1 snRNA improves efficiency and increases 5¢ ss recognition [8], or rather stabilizes U1 snRNA binding to the 5¢ ss, which inhibits the assembly of the full spliceosome, particularly U6 recruitment .

Alternative splicing and disease

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2009

Almost all protein-coding genes are spliced and their majority is alternatively spliced. Alternative splicing is a key element in eukaryotic gene expression that increases the coding capacity of the human genome and an increasing number of examples illustrates that the selection of wrong splice sites causes human disease. A fine-tuned balance of factors regulates splice site selection. Here, we discuss well-studied examples that show how a disturbance of this balance can cause human disease. The rapidly emerging knowledge of splicing regulation now allows the development of treatment options.

Defective splicing, disease and therapy: searching for master checkpoints in exon definition

Nucleic Acids Research, 2006

The number of aberrant splicing processes causing human disease is growing exponentially and many recent studies have uncovered some aspects of the unexpectedly complex network of interactions involved in these dysfunctions. As a consequence, our knowledge of the various cis-and trans-acting factors playing a role on both normal and aberrant splicing pathways has been enhanced greatly. However, the resulting information explosion has also uncovered the fact that many splicing systems are not easy to model. In fact we are still unable, with certainty, to predict the outcome of a given genomic variation. Nonetheless, in the midst of all this complexity some hard won lessons have been learned and in this survey we will focus on the importance of the wide sequence context when trying to understand why apparently similar mutations can give rise to different effects. The examples discussed in this summary will highlight the fine 'balance of power' that is often present between all the various regulatory elements that define exon boundaries. In the final part, we shall then discuss possible therapeutic targets and strategies to rescue genetic defects of complex splicing systems.

Alternative splicing isoforms in health and disease

Pflugers Archiv : European journal of physiology, 2018

Alternative splicing (AS) of protein-coding messenger RNAs is an essential regulatory mechanism in eukaryotic gene expression that controls the proper function of proteins. It is also implicated in the physiological regulation of mitochondria and various ion channels. Considering that mis-splicing can result in various human diseases by modifying or abrogating important physiological protein functions, a fine-tuned balance of AS is essential for human health. Accumulated data highlight the importance of alternatively spliced isoforms in various diseases, including neurodegenerative disorders, cancer, immune and infectious diseases, cardiovascular diseases, and metabolic conditions. However, basic understanding of disease mechanisms and development of clinical applications still require the integration and interpretation of physiological roles of AS. This review discusses the roles of AS in health and various diseases, while highlighting potential AS-targeting therapeutic applications.

In Brief: (mis)splicing in disease

The Journal of pathology, 2014

Splicing of pre-mRNAs is a crucial step in the gene expression pathway. Disruption of splicing has been linked to the pathogenesis of several human diseases and is particularly widespread in cancer. Recently, a number of mutations affecting genes of the core spliceosome machinery have been identified in haematological malignancies, yet the effect of such mutations on RNA splicing is unclear. A better understanding of how mis-splicing contributes to malignancies may provide diagnostic or prognostic information and new drug targets for therapeutic approaches.