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RNA-Binding Proteins: Splicing Factors and Disease.

Fredericks AM, Cygan KJ, Brown BA, Fairbrother WG - Biomolecules (2015)

Bottom Line: Splicing is a major regulatory component in higher eukaryotes.Disruptions in splicing are a major contributor to human disease.One of the challenges of medical genetics is identifying causal variants from the thousands of possibilities discovered in a clinical sequencing experiment.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, 70 Ship Street, Providence, RI 02903, USA. alger_fredericks@brown.edu.

ABSTRACT
Pre-mRNA splicing is mediated by interactions of the Core Spliceosome and an array of accessory RNA binding proteins with cis-sequence elements. Splicing is a major regulatory component in higher eukaryotes. Disruptions in splicing are a major contributor to human disease. One in three hereditary disease alleles are believed to cause aberrant splicing. Hereditary disease alleles can alter splicing by disrupting a splicing element, creating a toxic RNA, or affecting splicing factors. One of the challenges of medical genetics is identifying causal variants from the thousands of possibilities discovered in a clinical sequencing experiment. Here we review the basic biochemistry of splicing, the mechanisms of splicing mutations, the methods for identifying splicing mutants, and the potential of therapeutic interventions.

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Related in: MedlinePlus

Three mechanisms of RBP-caused splicing dysregulation. (A) Disruption and/or creation of cis-elements by disease variants. (B) The RNA becomes toxic as a result of repeat expansion. Misregulation of splicing by the toxic RNA occurs through sponge-like titration of a splicing factor. (C) Mutation in splicing factor (e.g., U2AF) prevents it from binding to the pre-mRNA and stabilizing U2 snRNP. This results in unsuccessful transcript recognition.
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biomolecules-05-00893-f002: Three mechanisms of RBP-caused splicing dysregulation. (A) Disruption and/or creation of cis-elements by disease variants. (B) The RNA becomes toxic as a result of repeat expansion. Misregulation of splicing by the toxic RNA occurs through sponge-like titration of a splicing factor. (C) Mutation in splicing factor (e.g., U2AF) prevents it from binding to the pre-mRNA and stabilizing U2 snRNP. This results in unsuccessful transcript recognition.

Mentions: Disease mutations can also alter splicing by the disruption of cis-elements that modulate the recognition of splice sites. These auxiliary elements are often ligands for RBPs. The principle splicing factors that bind these auxiliary enhancers and silencers are the SR and hnRNP protein families. Both protein families are generalized to function in a position specific manner. In other words, SR proteins bound in the exon are generally regarded as activating splicing whereas the same protein relocated to the intron can act as a repressor. Conversely, hnRNPs are regarded as repressors when bound to exonic locations and activators when bound to the intron. The binding specificities of many RBPs have been modeled in vitro and can be used to evaluate the potential of a variant to disrupt a binding site [59]. This position dependence seems to be a general property of splicing elements. Exonic splicing enhancer (ESEs) motifs functionally repress splicing when found in the intron, becoming intronic splicing silencers (ISSs) [60]. Likewise exonic splicing silencer (ESSs) motifs have been shown to function as intronic splicing enhancers (ISEs) (Figure 2A) [61]. Positional distribution analysis uses this property to predict loss of binding without knowledge of the trans-acting factor ([7], see also Spliceman below). Non-coding, and functionally conservative or silent mutations that have little to no effect on the translated protein have been demonstrated to cause disease by disrupting splicing [62]. In a recent mutational survey of HGMD, it was estimated that 25% of reported missense and nonsense mutations disrupt splicing by creating or destroying auxiliary exonic signals [63]. It is worth noting that causal alleles with mutations in auxiliary cis-sequence that disrupt splicing have also been identified in each disease previously described.


RNA-Binding Proteins: Splicing Factors and Disease.

Fredericks AM, Cygan KJ, Brown BA, Fairbrother WG - Biomolecules (2015)

Three mechanisms of RBP-caused splicing dysregulation. (A) Disruption and/or creation of cis-elements by disease variants. (B) The RNA becomes toxic as a result of repeat expansion. Misregulation of splicing by the toxic RNA occurs through sponge-like titration of a splicing factor. (C) Mutation in splicing factor (e.g., U2AF) prevents it from binding to the pre-mRNA and stabilizing U2 snRNP. This results in unsuccessful transcript recognition.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496701&req=5

biomolecules-05-00893-f002: Three mechanisms of RBP-caused splicing dysregulation. (A) Disruption and/or creation of cis-elements by disease variants. (B) The RNA becomes toxic as a result of repeat expansion. Misregulation of splicing by the toxic RNA occurs through sponge-like titration of a splicing factor. (C) Mutation in splicing factor (e.g., U2AF) prevents it from binding to the pre-mRNA and stabilizing U2 snRNP. This results in unsuccessful transcript recognition.
Mentions: Disease mutations can also alter splicing by the disruption of cis-elements that modulate the recognition of splice sites. These auxiliary elements are often ligands for RBPs. The principle splicing factors that bind these auxiliary enhancers and silencers are the SR and hnRNP protein families. Both protein families are generalized to function in a position specific manner. In other words, SR proteins bound in the exon are generally regarded as activating splicing whereas the same protein relocated to the intron can act as a repressor. Conversely, hnRNPs are regarded as repressors when bound to exonic locations and activators when bound to the intron. The binding specificities of many RBPs have been modeled in vitro and can be used to evaluate the potential of a variant to disrupt a binding site [59]. This position dependence seems to be a general property of splicing elements. Exonic splicing enhancer (ESEs) motifs functionally repress splicing when found in the intron, becoming intronic splicing silencers (ISSs) [60]. Likewise exonic splicing silencer (ESSs) motifs have been shown to function as intronic splicing enhancers (ISEs) (Figure 2A) [61]. Positional distribution analysis uses this property to predict loss of binding without knowledge of the trans-acting factor ([7], see also Spliceman below). Non-coding, and functionally conservative or silent mutations that have little to no effect on the translated protein have been demonstrated to cause disease by disrupting splicing [62]. In a recent mutational survey of HGMD, it was estimated that 25% of reported missense and nonsense mutations disrupt splicing by creating or destroying auxiliary exonic signals [63]. It is worth noting that causal alleles with mutations in auxiliary cis-sequence that disrupt splicing have also been identified in each disease previously described.

Bottom Line: Splicing is a major regulatory component in higher eukaryotes.Disruptions in splicing are a major contributor to human disease.One of the challenges of medical genetics is identifying causal variants from the thousands of possibilities discovered in a clinical sequencing experiment.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, 70 Ship Street, Providence, RI 02903, USA. alger_fredericks@brown.edu.

ABSTRACT
Pre-mRNA splicing is mediated by interactions of the Core Spliceosome and an array of accessory RNA binding proteins with cis-sequence elements. Splicing is a major regulatory component in higher eukaryotes. Disruptions in splicing are a major contributor to human disease. One in three hereditary disease alleles are believed to cause aberrant splicing. Hereditary disease alleles can alter splicing by disrupting a splicing element, creating a toxic RNA, or affecting splicing factors. One of the challenges of medical genetics is identifying causal variants from the thousands of possibilities discovered in a clinical sequencing experiment. Here we review the basic biochemistry of splicing, the mechanisms of splicing mutations, the methods for identifying splicing mutants, and the potential of therapeutic interventions.

Show MeSH
Related in: MedlinePlus