![]() In the same time, the SF1 protein binds to the branch point. The U1 snRNP recognizes and binds to the complementary AG-GU sequence at the donor splice site (5′ end of the intron). During the splicing process, four complexes between the pre-mRNA and spliceosome are formed. The first step is the recognition of the splicing sites at intron/exon junctions, and the second one is the intron removal and exon ends joining. The splicing process is performed in two steps. The presence of small nuclear RNAs (snRNAs) in snRNPs allows to form complementary RNA-RNA complexes and thus identify the specific sequences of the splicing sites by the spliceosome (Fig. In brief, the splicing process is catalyzed by the spliceosome, a protein-RNA complex containing five small nuclear ribonucleoproteins (snRNPs, U1, U2, U4–U6) and over 300 different proteins. Spliceosome proteins together with splicing repressors and activators recognize cis splicing elements and are called trans-acting elements The branch site and the polypyrimidine tract sequences are highly degenerated and together with donor and acceptor sites are recognized by the elements of the splicing complex called spliceosome. Donor and acceptor sites are evolutionary conserved and are usually defined by GT and AG nucleotides at the 5′ and 3′ ends of the intron, respectively. The cis elements are the DNA sequences that include donor (5′) and acceptor (3′) splice sites, branch point and polypyrimidine tract sequences, and splicing silencers and enhancers. The schematic localization of the cis and trans splicing elements. This article summarizes the current knowledge about the “splicing mutations” and methods that help to identify such changes in clinical diagnosis. However, it should be underlined that the results of such tests are only predictive, and the exact effect of the specific mutation should be verified in functional studies. ![]() The bioinformatic algorithms can be applied as a tool to assess the possible effect of the identified changes. The application of modern techniques allowed to identify synonymous and nonsynonymous variants as well as deep intronic mutations that affected pre-mRNA splicing. Recent research has underlined the abundance and importance of splicing mutations in the etiology of inherited diseases. Usually such mutations result in errors during the splicing process and may lead to improper intron removal and thus cause alterations of the open reading frame. The splicing mutation may occur in both introns and exons and disrupt existing splice sites or splicing regulatory sequences (intronic and exonic splicing silencers and enhancers), create new ones, or activate the cryptic ones. Point mutations at these consensus sequences can cause improper exon and intron recognition and may result in the formation of an aberrant transcript of the mutated gene. Precise pre-mRNA splicing, essential for appropriate protein translation, depends on the presence of consensus “cis” sequences that define exon-intron boundaries and regulatory sequences recognized by splicing machinery.
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