Are splicing mutations the most frequent cause of hereditary disease?

López‐Bigas, Núria; Audit, Benjamin; Ouzounis, Christos A.; Parra, Genı́s; Guigó, Roderic

doi:10.1016/j.febslet.2005.02.047

Cited by 339 publications

(267 citation statements)

References 18 publications

(36 reference statements)

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“…Hence, it has been suggested that 15% may be a gross underestimation of the real number, and that the percentage of disease-causing mutations that cause splicing abnormalities, both in splice sites and in splicing-associated genes, is closer to 60%. 68,69 Studies on alternative splicing changes in the heart have revealed large differences between development or disease states. Intriguingly, much like reactivation of selected fetal genes, some fetal splice isoforms are also re-expressed in the stressed or diseased heart.…”

Section: Alternative Splicing In Diseasementioning

confidence: 99%

RNA Splicing

Hoogenhof

Pinto

Creemers

2016

Circulation Research

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RNA splicing, a post-transcriptional process necessary to form a mature mRNA, was discovered in the late 1970s. 1 Two different modes of splicing have been defined, that is, constitutive splicing and alternative splicing. Constitutive splicing is the process of removing introns from the premRNA, and joining the exons together to form a mature mRNA. Alternative splicing, on the other hand, is the process where exons can be included or excluded in different combinations to create a diverse array of mRNA transcripts from a single pre-mRNA and therefore serves as a process to increase the diversity of the transcriptome. The estimated number of alternative splicing events in the human transcriptome has risen sharply over the past decades. In the 1980s, it was thought that about 5% of human genes were subjected to alternative splicing.2 In 2002, this number had risen to 60%, 3 and now, after implementation of next-generation-sequencing technologies, we know that the vast majority, >95% of mRNAs, are subjected to alternative splicing. 4 Nevertheless, the function of a large fraction of these splice isoforms remains to be elucidated. Furthermore, it is anticipated that in different tissues, or in tissues with different disease states, new isoforms still remain to be identified. 5The process of splicing is highly conserved during evolution. Splicing is more prevalent in multicellular than in unicellular eukaryotes because of the lower number of introncontaining genes in the latter. 6 Later in evolution, alternative splicing becomes more prevalent in vertebrates than in invertebrates. Interestingly, just a single exon-skipping event in the RNA-binding protein (RBP), polypyrimidine tract binding protein 1 has been shown to direct numerous alternative splicing changes between species, indicating that a single splicing event can amplify transcriptome diversity between species. 7The recent observation that the total number of protein-coding genes does not differ much between species, fueled the hypothesis that alternative splicing largely contributes to organism diversity. And indeed, as we move up the phylogenetic tree, alternative splicing complexity increases, with the highest complexity in primates. 8,9The aim of this review is to give a comprehensive overview of all aspects of constitutive and alternative splicing and their regulators, as well as the importance of these different aspects in human disease, with a focus on the heart. In addition, we discuss possible therapeutic interventions and try to uncover potential future directions of research. Major and Minor SpliceosomeRNA splicing is performed by the spliceosome, a large and dynamic ribonucleoprotein complex composed of proteins and small nuclear RNAs (snRNAs), which assembles on the pre-mRNA (Figure 1). Ribonucleoproteins consist of 1 or 2 small nuclear RNAs (snRNAs; U1, U2, U4/U6, or U5), and a variable number of complex-specific proteins.

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Section: Alternative Splicing In Diseasementioning

confidence: 99%

RNA Splicing

Hoogenhof

Pinto

Creemers

2016

Circulation Research

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“…This information required to specify splicing presents a considerable mutational target-estimates of the fraction of disease mutations that affect splicing range from 15% (9) to 62% (10). Transcript analysis of genotyped cell lines has discovered numerous cases of allelic splicing demonstrating that polymorphisms also disrupt splicing (11,12).…”

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Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes

Lim

Ferraris

Filloux

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

243

214

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We present an intuitive strategy for predicting the effect of sequence variation on splicing. In contrast to transcriptional elements, splicing elements appear to be strongly position dependent. We demonstrated that exonic binding of the normally intronic splicing factor, U2AF65, inhibits splicing. Reasoning that the positional distribution of a splicing element is a signature of its function, we developed a method for organizing all possible sequence motifs into clusters based on the genomic profile of their positional distribution around splice sites. Binding sites for serine/arginine rich (SR) proteins tended to be exonic whereas heterogeneous ribonucleoprotein (hnRNP) recognition elements were mostly intronic. In addition to the known elements, novel motifs were returned and validated. This method was also predictive of splicing mutations. A mutation in a motif creates a new motif that sometimes has a similar distribution shape to the original motif and sometimes has a different distribution. We created an intraallelic distance measure to capture this property and found that mutations that created large intraallelic distances disrupted splicing in vivo whereas mutations with small distances did not alter splicing. Analyzing the dataset of human disease alleles revealed known splicing mutants to have high intraallelic distances and suggested that 22% of disease alleles that were originally classified as missense mutations may also affect splicing. This category together with mutations in the canonical splicing signals suggest that approximately one third of all disease-causing mutations alter pre-mRNA splicing. S plicing is catalyzed by the spliceosome, a riboprotein complex that rivals the ribosome in size and complexity. The ribosome has a large and small subunit whose assembly on the mRNA substrate corresponds to a functional switch from initiation to elongation. The spliceosome is composed of five subunits that appear to exist in at least four different stable configurations and, like the ribosomal subunits, transition between different assembled states corresponding to different stages of function (1-3). Mass spectroscopy has identified at least 300 RNA and protein components in this catalytic complex and studies have demonstrated heterogeneity in spliceosomal complexes isolated from different splicing substrates (4-6). The spliceosomal components that recognize the basic cis-elements of the splicing process are known. How the spliceosome assembles and reorganizes on these elements is also fairly well understood. However, several computational analyses estimate that these basic splicing elements contain at most half the information necessary for splice site recognition (7,8). The remaining information lies outside these splice sites presumably as enhancers or silencers.This information required to specify splicing presents a considerable mutational target-estimates of the fraction of disease mutations that affect splicing range from 15% (9) to 62% (10). Transcript analysis of genotyped cell lines has dis...

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“…Mutations that impair the recognition of the splice sites are responsible for a significant fraction of genetic diseases (1). Splice sites are defined by sequence elements in the pre-mRNA that are recognized by many splicing factors (2).…”

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confidence: 99%

Exon sequences at the splice junctions affect splicing fidelity and alternative splicing

Crotti

Horowitz²

2009

Proc. Natl. Acad. Sci. U.S.A.

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Identification of splice sites is essential for the expression of most eukaryotic genes, allowing accurate splicing of pre-mRNAs. The splice sites are recognized by the splicing machinery based on sequences within the pre-mRNA. Here, we show that the exon sequences at the splice junctions play a significant, previously unrecognized role in the selection of 3 splice sites during the second step of splicing. The influence of the exon sequences was enhanced by the Prp18 mutant Prp18⌬CR, and the strength of an exon sequence in Prp18⌬CR splicing predicted its effect in wild-type splicing. Analysis of the kinetics of splicing in vitro demonstrated that 3 splice sites were chosen competitively during the second step, likely at the same time as exon ligation. In wild-type yeast, splice site selection for two genes studied was altered by point mutations in their exon bases, affecting splicing fidelity and alternative splicing. Finally, we note that the degeneracy of the genetic code allows competing 3 splice sites to be eliminated from coding regions, and we suggest that the evolution of the splicing signals and the genetic code are connected.pre-mRNA splicing ͉ Prp18 ͉ splice site selection I dentification of splice sites is necessary both for ensuring the fidelity of pre-mRNA splicing and for the regulation of alternative splicing. Mutations that impair the recognition of the splice sites are responsible for a significant fraction of genetic diseases (1). Splice sites are defined by sequence elements in the pre-mRNA that are recognized by many splicing factors (2). The 3Ј splice site is usually the first AG downstream of the branchpoint and is immediately preceded by a pyrimidine or an A (3, 4). A polypyrimidine tract is often present upstream of the splice site. The influence of each element varies and not all are required (5). Recognition of elements in the 3Ј splice site region is required early in splicing in metazoans but not in yeast (6).Identification of the 3Ј splice site for exon ligation appears to occur in the second step, and these events are well studied in yeast. After the first transesterification, the RNA helicase Prp16 rearranges the spliceosome (7). Prp18, Slu7, and Prp22 join the spliceosome, which then rapidly ligates the exons (8-10). The U2, U5, and U6 snRNAs and the Prp8 protein, which are required for the first step of splicing, also participate directly in the second step (11,12).The 3Ј splice site is identified by various mechanisms. The distance between the branch point and the 3Ј splice site is important, with distant sites dependent on their polypyrimidine tracts (13,14). The G's at the 5Ј and 3Ј ends of the intron interact (13, 15), and base Ϫ3 at the 3Ј site interacts with base ϩ3 at the 5Ј site and the U6 snRNA (16). Prp8 is involved in recognition of both the polypyrimidine tract and the AG dinucleotide at the 3Ј splice site (12, 17). Mutation of Slu7 impairs the use of distant sites (18,19). Analyses of in vivo splicing suggest that the 3Ј splice site recognition events occur during th...

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Are splicing mutations the most frequent cause of hereditary disease?

Cited by 339 publications

References 18 publications

RNA Splicing

RNA Splicing

Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes

Exon sequences at the splice junctions affect splicing fidelity and alternative splicing

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