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 RNAbinding 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 mostgenes, 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 patho mechanisms of human diseases, which hopefully leads to development of rational therapies.Keywords: alternative splicing, cis-acting splicing code, splicing trans-factor, spliceosome, mutation, aberrant splicing, neurodegenerative diseases, cancers Journal of Investigative Genomics Review Article Open AccessDecoding abnormal splicing code in human diseases site sequences are highly degenerative, which partly compromises appropriate recognition and binding of essential trans-acting factors. As a consequence, multiple auxiliary trans-acting factors need to co-operate to form spliceosome and to favor folding of nuclear premRNA to commit splicing. The assembly of spliceosome is further regulated by auxiliary splicing cis-elements either in a positive or negative manner (Figure 1b). Positively modulating cis-elements are termed as intronic/exonic splicing enhancers (ISEs/ESEs), whereas negatively modulating cis-elements are termed as intronic/exonic splicing silencers (ISSs/ESSs). Most of these auxiliary cis-elements function by binding to cognate trans-factors (Table 1), whereas some cis-elements function by forming secondary structures. The majority of splicing trans-factors for ESE are serine/arginine-rich (SR) proteins, which function as either an essential or regulatory factor. 3,4SR proteins can modulate several steps of spliceosome assembly through protein-protein and protein-RNA interaction.5,6 They possess one or two RNA-recognition motif (RRM) at the N-terminal end and arginine and serine residues (RS domains) at the C-terminal end. The majority of splicing trans-factors for splicing silencer elements (ISSs/ ESSs) are heterogeneous nuclear ribonucleoproteins (hnRNPs). 7Members of this family usually contain an RRM-type and KHtype RNA-bind...

Evaluation of Suspected Autosomal Alport Syndrome Synonymous Variants

“…Mature mRNA comprises only the coding sequence because introns are removed from the transcript during the splicing process (25). In most situations, adjacent pre-mRNA regulatory sequences, called ESEs or ESSs, influence splice site recognition and selection, which can have positive or negative effects on splice site utilization.…”

Novel splicing (c.6529-1G>T) and missense (c.1667G>A) mutations causing factor V deficiency

“…As can be expected, this process is regulated and involves donor and acceptor splice sites, branch point and polypyrimidine tract sequences, splicing silencers/enhancers and other regulatory elements. Donor and acceptor sites are highly conserved and contain GT and AG motifs at intronic ends [21,22]. Any errors during splicing will lead to improper intron removal and can alter the reading frame or activate cryptic splice sites.…”