Congenital End-Plate Acetylcholinesterase Deficiency Caused by a Nonsense Mutation and an A→G Splice-Donor–Site Mutation at Position +3 of the Collagenlike-Tail–Subunit Gene (COLQ): How Does G at Position +3 Result in Aberrant Splicing?

Ohno, Kinji; Brengman, Joan M.; Felice, Kevin J.; Cornblath, David R.; Engel, Andrew G.

doi:10.1086/302551

Cited by 74 publications

(53 citation statements)

References 51 publications

(47 reference statements)

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“…5 and 6 bp with 8 and 9). This dependency was described in previous studies (Burge and Karlin 1997;Ohno et al 1999;Thanaraj and Robinson 2000). Third, G at position −1 was selected before G at position +5 (Fig.…”

Section: Analysis Of the 5ss According To The Potential Number Of Basmentioning

confidence: 97%

“…This also suggests that the different positions of the 5Јss might have a mutual relationship: A mispair between U1 snRNA and one position of the 5Јss is compensated by a base pair of U1 snRNA to another position(s), thus maintaining the base pairs' number above the minimum. Indeed, evidence for such a mutual relationship among the 5Јss positions were found: The existence of G at position +3 depends on the concordance that the residues at positions +4 to +6 have with U1 snRNA (Ohno et al 1999); base-pairing of U1 snRNA with positions +3 and +4 compensates for a mispair of U1 snRNA with position +5 (Nelson and Green 1990); and the dependence of positions +5 with position +3 (Burge and Karlin 1997;Clark and Thanaraj 2002) and with positions +3 and +4 was demonstrated (Lund and Kjems 2002). Additionally, a linkage between the exonic and intronic portions of the 5Јss was indicated in a few studies (Burge and Karlin 1997;Rogozin and Milanesi 1997;Thanaraj and Robinson 2000).…”

Section: Introductionmentioning

confidence: 99%

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Comparative analysis detects dependencies among the 5′ splice-site positions

Carmel¹,

Tal²,

Vig³

et al. 2004

RNA

198

197

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Human-mouse comparative genomics is an informative tool to assess sequence functionality as inferred from its conservation level. We used this approach to examine dependency among different positions of the 5 splice site. We compiled a data set of 50,493 homologous human-mouse internal exons and analyzed the frequency of changes among different positions of homologous human-mouse 5 splice-site pairs. We found mutual relationships between positions +4 and +5, +5 and +6, −2 and +5, and −1 and +5. We also demonstrated the association between the exonic and the intronic positions of the 5 splice site, in which a stronger interaction of U1 snRNA and the intronic portion of the 5 splice site compensates for weak interaction of U1 snRNA and the exonic portion of the 5 splice site, and vice versa. By using an ex vivo system that mimics the effect of mutation in the 5 splice site leading to familial dysautonomia, we demonstrated that U1 snRNA base-pairing with positions +6 and −1 is the only functional requirement for mRNA splicing of this 5 splice site. Our findings indicate the importance of U1 snRNA base-pairing to the exonic portion of the 5 splice site.

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Section: Analysis Of the 5ss According To The Potential Number Of Basmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Comparative analysis detects dependencies among the 5′ splice-site positions

Carmel¹,

Tal²,

Vig³

et al. 2004

RNA

198

197

View full text Add to dashboard Cite

show abstract

“…It has been shown that 5Јss with disease-causing +3 A-to-G mutations exhibit two distinct features: (1) They are intrinsically weak (Madsen et al 2006); and (2) they frequently have nonconsensus nucleotides at positions +4 and +5 (for confirmation, see Fig. 4; Ohno et al 1999;Madsen et al 2006). Figure 4 also shows that 5Јss with G at position +3 and SNPs with A/G alleles at position +3 prefer consensus nucleotides at +4 and +5, in agreement with the second observation.…”

Section: Disease-causing Mutations At 5јssmentioning

confidence: 98%

Features of 5′-splice-site efficiency derived from disease-causing mutations and comparative genomics

Roca¹,

Olson²,

Rao³

et al. 2007

Genome Res.

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Many human diseases, including Fanconi anemia, hemophilia B, neurofibromatosis, and phenylketonuria, can be caused by 5Ј-splice-site (5Јss) mutations that are not predicted to disrupt splicing, according to position weight matrices. By using comparative genomics, we identify pairwise dependencies between 5Јss nucleotides as a conserved feature of the entire set of 5Јss. These dependencies are also conserved in human-mouse pairs of orthologous 5Јss. Many disease-associated 5Јss mutations disrupt these dependencies, as can some human SNPs that appear to alter splicing. The consistency of the evidence signifies the relevance of this approach and suggests that 5Јss SNPs play a role in complex diseases.[Supplemental material is available online at www.genome.org.]The sequenced genomes of a wide range of organisms allow global, comparative analyses of regulatory sequences. The genomic set of splice-site sequences corresponds to a large-scale splicing experiment performed by nature under evolutionary constraints. Here we focus on 5Ј-splice-site (5Јss) sequences of the U2-type GT-AG class, which comprise over 98% of all splice sites, and use disease-causing mutations, human single nucleotide polymorphisms (SNPs), and variations in natural splice sites in the genome (within and between species) to infer properties inherent to 5Јss, with important implications for human genetics.Splice sites are conserved sequences at both ends of an intron that are recognized during the initial steps of splicing (Hastings and Krainer 2001;Brow 2002;Jurica and Moore 2003). Both the 5Јss and the 3Ј splice site (3Јss) conform to degenerate motifs that are recognized by specific splicing factors. The U2-type GT-AG 5Јss, spanning 3 nucleotides (nt) at the 3Ј end of the exon and 6 nt at the 5Ј end of the intron, is initially recognized via base pairing to the 5Ј end of the U1 snRNA (Fig.

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“…The effects of certain mutations are more complex, as is the case of +3A-to-G transitions causing genetic diseases, even though both A and G occur with almost equal frequency at this position in bona fide 59ss. Such transitions are deleterious when the affected 59ss has nonconsensus nucleotides at the adjacent positions +4 and +5, as proven by pairwise associations in genomic data sets and experimental analyses (Ohno et al 1999;Madsen et al 2006;Roca et al 2008). In certain cases, the 59ss scores do not reflect the effect of the mutation on 59ss strength.…”

Section: Implications For Genetic Diseasesmentioning

confidence: 99%

Pick one, but be quick: 5′ splice sites and the problems of too many choices

2013

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Splice site selection is fundamental to pre-mRNA splicing and the expansion of genomic coding potential. 59 Splice sites (59ss) are the critical elements at the 59 end of introns and are extremely diverse, as thousands of different sequences act as bona fide 59ss in the human transcriptome. Most 59ss are recognized by base-pairing with the 59 end of the U1 small nuclear RNA (snRNA). Here we review the history of research on 59ss selection, highlighting the difficulties of establishing how basepairing strength determines splicing outcomes. We also discuss recent work demonstrating that U1 snRNA:59ss helices can accommodate noncanonical registers such as bulged duplexes. In addition, we describe the mechanisms by which other snRNAs, regulatory proteins, splicing enhancers, and the relative positions of alternative 59ss contribute to selection. Moreover, we discuss mechanisms by which the recognition of numerous candidate 59ss might lead to selection of a single 59ss and propose that protein complexes propagate along the exon, thereby changing its physical behavior so as to affect 59ss selection.Questions about the mechanisms by which 59 splice sites (59ss) are selected are deeply rooted in the history of research on pre-mRNA splicing. Identification of the sequences associated with 59ss triggered the first key insights into splicing mechanisms, efforts that are reflected now in the widespread use of genomic methods to quantify the contributions of other sequences and their cognate factors. The first factors shown to modulate alternative splicing affected 59ss selection, and the difficulties of working out the molecular mechanisms involved provided a foretaste of the complexities awaiting investigations into other regulatory proteins. Despite the many insights resulting from such studies over the years, it is clear that our conceptual frameworks are not yet adequate. New ideas and models are needed for studies on splice site selection. One purpose of this review is to emphasize that developing new ideas may involve first the challenge of uprooting commonsense but unsubstantiated preconceptions hidden in established models.The 59ss is involved in both steps of splicing. In the first step, the 29-hydroxyl group of the branchpoint adenosine attacks the phosphodiester bond at the 59ss and displaces the 59 exon; in the second step, the 39-hydroxyl group of the 59 exon attacks the phosphodiester bond at the 39 splice site (39ss) and displaces the lariat intron. Splicing was discovered just before new, gel-based DNA-sequencing methods transformed molecular biology. Thus, although the original discoveries were made without the benefit of sequence information (Berget et al. 1977;Chow et al. 1977), sequences emerged rapidly thereafter and revealed clear similarities among 59ss. Moreover, the ''consensus'' sequence (comprising, at each position, the nucleotide most commonly found there) was complementary to the sequence at the 59 end of U1 small nuclear RNA (snRNA), which immediately suggested a mechanism for recognition of t...

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Congenital End-Plate Acetylcholinesterase Deficiency Caused by a Nonsense Mutation and an A→G Splice-Donor–Site Mutation at Position +3 of the Collagenlike-Tail–Subunit Gene (COLQ): How Does G at Position +3 Result in Aberrant Splicing?

Cited by 74 publications

References 51 publications

Comparative analysis detects dependencies among the 5′ splice-site positions

Comparative analysis detects dependencies among the 5′ splice-site positions

Features of 5′-splice-site efficiency derived from disease-causing mutations and comparative genomics

Pick one, but be quick: 5′ splice sites and the problems of too many choices

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