Decoding Abnormal Splicing Code in Human Diseases

Abstract

RNA splicing is an intricate process in humans and higher metazoans. Splicing is regulated through multifaceted coordinated factors, such as cis-acting splicing code and RNA-binding splicing trans-factors that associate or compete with ribonucleoproteins (RNPs). Individual cis-acting splicing code and their functional coordination with cognate splicing trans-factors still remain elusive in most genes, because these code are comprised of highly degenerative short sequence motifs and multiple splicing trans-factors can recognize an identical motif. In addition, a specific splicing motif functions differentially in different genes, which is determined by additional factors such as neighboring sequence context, cell types and association/competition with other splicing trans-factors. Genetic and cellular alterations compromising the fidelity of splicing processes provoke many human diseases. Analyses of abnormal splicing code in human diseases not only uncover the underlying maladies of splicing regulations in pathological conditions, but also allow us to gain insight into splicing mechanisms in physiological conditions. This review introduces accumulating knowledge of numerous modes of splicing aberrations and provides critical information to understand the underlying pathomechanisms of human diseases, which hopefully leads to development of rational therapies.