Splice Enhancer

2011 ◽  
Keyword(s):  
Splice Enhancer

scholarly journals Exon Splice Enhancer Mutation (GH-E32A) Causes Autosomal Dominant Growth Hormone Deficiency

2007 ◽  
Vol 92 (11) ◽  
pp. 4427-4435 ◽  
Author(s):  
Vibor Petkovic ◽  
Didier Lochmatter ◽  
James Turton ◽  
Peter E. Clayton ◽  
Peter J. Trainer ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Autosomal Dominant ◽  
Secretory Granules ◽  
Cellular Level ◽  
Hormone Deficiency ◽  
Mutant Form ◽  
Splice Enhancer ◽  
Exon Splice ◽  
Microscopy Analysis ◽  
Derived Data

Abstract Context and Objective: Alteration of exon splice enhancers (ESE) may cause autosomal dominant GH deficiency (IGHD II). Disruption analysis of a (GAA) (n) ESE motif within exon 3 by introducing single-base mutations has shown that single nucleotide mutations within ESE1 affect pre-mRNA splicing. Design, Setting, and Patients: Confirming the laboratory-derived data, a heterozygous splice enhancer mutation in exon 3 (exon 3 + 2 A→C) coding for GH-E32A mutation of the GH-1 gene was found in two independent pedigrees, causing familial IGHD II. Because different ESE mutations have a variable impact on splicing of exon 3 of GH and therefore on the expression of the 17.5-kDa GH mutant form, the GH-E32A was studied at the cellular level. Interventions and Results: The splicing of GH-E32A, assessed at the protein level, produced significantly increased amounts of 17.5-kDa GH isoform (55% of total GH protein) when compared with the wt-GH. AtT-20 cells coexpressing both wt-GH and GH-E32A presented a significant reduction in cell proliferation as well as GH production after forskolin stimulation when compared with the cells expressing wt-GH. These results were complemented with confocal microscopy analysis, which revealed a significant reduction of the GH-E32A-derived isoform colocalized with secretory granules, compared with wt-GH. Conclusion: GH-E32A mutation found within ESE1 weakens recognition of exon 3 directly, and therefore, an increased production of the exon 3-skipped 17.5-kDa GH isoform in relation to the 22-kDa, wt-GH isoform was found. The GH-E32A mutant altered stimulated GH production as well as cell proliferation, causing IGHD II.

KLHDC8B Is a Novel, Mitotically-Regulated Classical Hodgkin’s Lymphoma Candidate Susceptibility Gene.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 473-473
Author(s):  
Mathew E. Mealiffe ◽  
Tomas Kirchhoff ◽  
Peter H. Wiernik ◽  
Henry T. Lynch ◽  
Masanori Daibata ◽  
...  
Keyword(s):  
B Cell ◽  
Gene Product ◽  
Hodgkin’S Lymphoma ◽  
Susceptibility Gene ◽  
Hodgkin's Lymphoma ◽  
Genetic Linkage Analysis ◽  
Coding Region ◽  
Splice Enhancer ◽  
Exonic Splice ◽  
Translocation Breakpoints

Abstract Classical Hodgkin’s lymphoma (HL) is a B-cell malignancy associated with exposure to Epstein-Barr virus (EBV). Heritable factors also strongly contribute to its risk in the general population, but, except for rare immunodeficiency syndromes, susceptibility genes remain unidentified. We ascertained a family in which multiple individuals carrying a constitutional translocation between chromosomes 2 and 3 (t(2;3)(q11.2;p21.31)) have developed HL. The translocation is especially intriguing, because genetic linkage analysis had previously mapped a predisposition locus for another EBV-associated malignancy, nasopharyngeal carcinoma, to the vicinity of the breakpoint at 3p21.31, and this region is also frequently deleted or rearranged in sporadic B-cell lymphomas and other malignancies, suggesting that it may be the location of a tumor suppressor gene with broad cancer relevance. In order to identify the gene likely responsible for HL in this family, we molecularly cloned both translocation breakpoints. The chromosome 2 breakpoint is intergenic, but the chromosome 3 breakpoint disrupts the first intron of a previously uncharacterized gene, KLHDC8B (Kelch domain-containing 8B). The translocation separates the non-coding first exon from the remainder of the gene and appears to result in haploinsufficiency for the gene product, as demonstrated by the fact that lymphoblastoid cells from the translocation carriers have approximately half the level of KLHDC8B mRNA as found in controls (and there is no evidence supporting fusion transcript formation). In order to assess KLHDC8B’s broader significance in familial HL, we sequenced all six of its exons and flanking intronic sequence in affected probands from 52 families with two or more cases of HL. We detected no coding region variants. However, we did identify a 5′-UTR variant (+42CtoT) at a conserved position within a predicted exonic splice enhancer sequence that was present in 3 of 52 familial HL probands (5.8%) as compared to 4 of 307 controls (1.3%; Odds Ratio [95% C.I.] = 4.64 [1.01–21.4]) and that may be associated with decreased allele-specific expression. To investigate the functional role of KLHDC8B in the cell, we raised a polyclonal chicken IgY antibody against a KLHDC8B-derived peptide and have characterized the expression of KLHDC8B at the protein level in HeLa cells. The gene product locates to the cytoplasm. Interestingly, by both immunofluorescence and flow cytometry, KLHDC8B protein levels are significantly upregulated in cells undergoing mitosis. Given the dysregulation of normal mitotic processes that is well known to occur in Hodgkin and Reed-Sternberg cells, this protein may play an important role in HL pathogenesis. Although further studies will be necessary to replicate the genetic association, this study suggests that a SNP present in >1% of the Caucasian population may influence HL risk.

scholarly journals Characterization of an intron splice enhancer that regulates alternative splicing of human GH pre-mRNA

1998 ◽  
Vol 7 (9) ◽  
pp. 1491-1496 ◽  
Author(s):  
E. McCarthy
Keyword(s):  
Alternative Splicing ◽  
Splice Enhancer ◽  
Intron Splice

Binding of a candidate splice regulator to a calcitonin-specific splice enhancer regulates calcitonin/CGRP pre-mRNA splicing

2003 ◽  
Vol 1625 (2) ◽  
pp. 153-164 ◽  
Author(s):  
Timothy P. Coleman ◽  
Quincy Tran ◽  
James R. Roesser
Keyword(s):  
Mrna Splicing ◽  
Splice Enhancer ◽  
Splice Regulator

scholarly journals Cryptic Exon Activation by Disruption of Exon Splice Enhancer

2009 ◽  
Vol 284 (42) ◽  
pp. 28953-28957 ◽  
Author(s):  
Martin Stucki ◽  
Terttu Suormala ◽  
Brian Fowler ◽  
David Valle ◽  
Matthias R. Baumgartner
Keyword(s):  
Splice Enhancer ◽  
Cryptic Exon ◽  
Exon Splice

Human transformer 2β and SRp55 interact with a calcitonin-specific splice enhancer

2003 ◽  
Vol 1625 (2) ◽  
pp. 141-152 ◽  
Author(s):  
Quincy Tran ◽  
Timothy P Coleman ◽  
James R Roesser
Keyword(s):  
Splice Enhancer

scholarly journals Analysis of FUS, PFN2, TDP-43, and PLS3 as potential disease severity modifiers in spinal muscular atrophy

2020 ◽  
Vol 6 (1) ◽  
pp. e386 ◽  
Author(s):  
Renske I. Wadman ◽  
Marc D. Jansen ◽  
Chantall A.D. Curial ◽  
Ewout J.N. Groen ◽  
Marloes Stam ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Muscular Atrophy ◽  
Clinical Effects ◽  
Severe Phenotype ◽  
Splice Enhancer ◽  
Expression Levels ◽  
Exonic Splice Silencer ◽  
Exonic Splice ◽  
Intronic Variants

ObjectiveTo investigate mutations in genes that are potential modifiers of spinal muscular atrophy (SMA) severity.MethodsWe performed a hypothesis-based search into the presence of variants in fused in sarcoma (FUS), transactive response DNA-binding protein 43 (TDP-43), plastin 3 (PLS3), and profilin 2 (PFN2) in a cohort of 153 patients with SMA types 1–4, including 19 families. Variants were detected with targeted next-generation sequencing and confirmed with Sanger sequencing. Functional effects of the identified variants were analyzed in silico and for PLS3, by analyzing expression levels in peripheral blood.ResultsWe identified 2 exonic variants in FUS exons 5 and 6 (p.R216C and p.S135N) in 2 unrelated patients, but clinical effects were not evident. We identified 8 intronic variants in PLS3 in 33 patients. Five PLS3 variants (c.1511+82T>C; c.748+130 G>A; c.367+182C>T; c.891-25T>C (rs145269469); c.1355+17A>G (rs150802596)) potentially alter exonic splice silencer or exonic splice enhancer sites. The variant c.367+182C>T, but not RNA expression levels, corresponded with a more severe phenotype in 1 family. However, this variant or level of PLS3 expression did not consistently correspond with a milder or more severe phenotype in other families or the overall cohort. We found 3 heterozygous, intronic variants in PFN2 and TDP-43 with no correlation with clinical phenotype or effects on splicing.ConclusionsPLS3 and FUS sequence variants do not modify SMA severity at the population level. Specific variants in individual patients or families do not consistently correlate with disease severity.

Why there is more to protein evolution than protein function: splicing, nucleosomes and dual-coding sequence

2009 ◽  
Vol 37 (4) ◽  
pp. 756-761 ◽  
Author(s):  
Tobias Warnecke ◽  
Claudia C. Weber ◽  
Laurence D. Hurst
Keyword(s):  
Amino Acid ◽  
Protein Evolution ◽  
Protein Function ◽  
Dual Coding ◽  
Splice Enhancer ◽  
Dna And Rna ◽  
Rates Of Evolution ◽  
Exonic Splice ◽  
Production History

There is considerable variation in the rate at which different proteins evolve. Why is this? Classically, it has been considered that the density of functionally important sites must predict rates of protein evolution. Likewise, amino acid choice is usually assumed to reflect optimal protein function. In the present article, we briefly review evidence suggesting that this protein function-centred view is too simplistic. In particular, we concentrate on how selection acting during the protein's production history can also affect protein evolutionary rates and amino acid choice. Exploring the role of selection at the DNA and RNA level, we specifically address how the need (i) to specify exonic splice enhancer motifs in pre-mRNA, and (ii) to ensure nucleosome positioning on DNA have an impact on amino acid choice and rates of evolution. For both, we review evidence that sequence affected by more than one coding demand is particularly constrained. Strikingly, in mammals, splicing-related constraints are quantitatively as important as expression parameters in predicting rates of protein evolution. These results indicate that there is substantially more to protein evolution than protein functional constraints.

scholarly journals The effect of disease-associated HRPT2 mutations on splicing

2009 ◽  
Vol 201 (3) ◽  
pp. 387-396 ◽  
Author(s):  
Michael A Hahn ◽  
Julie McDonnell ◽  
Deborah J Marsh
Keyword(s):  
Splice Site ◽  
Hot Spot ◽  
Splice Sites ◽  
Loss Of Function ◽  
Splice Enhancer ◽  
Aberrant Splicing ◽  
Acceptor Splice Site ◽  
Web Based ◽  
Exonic Splice

Mutations in the tumour suppressor HRPT2 occur in patients with parathyroid carcinoma, kidney tumours and Hyperparathyroidism–Jaw Tumour syndrome. Disruption of exonic splicing through mutation of donor/acceptor splice sites or exonic splice enhancer (ESE) sites leads to loss of function of a number of major tumour suppressors including BRCA1, APC and MLH1. Given that the effect of HRPT2 mutations on splicing has not been widely studied, we used an in vitro splicing assay to determine whether 17 HRPT2 mutations located in hot-spot and other exons predicted to disrupt ESE consensus sites led to aberrant splicing. Using two independent web-based prediction programs, the majority of these mutations were predicted to disrupt ESE consensus sites; however, aberrant splicing of HRPT2 transcripts was not observed. Canonical donor or acceptor splice site mutations were also investigated using this splicing assay and transcripts assessed from tumour tissue. Splice site mutations were shown to lead to either exon skipping or retention of intronic sequences through the use of cryptic splice sites comprised of non-classical splicing signals. Aberrant splicing caused by disruption of ESE sites does not appear to have a major role in HRPT2-associated disease; however, premature truncation of parafibromin as the result of canonical donor or acceptor splice site mutations is associated with pathogenicity. Functional splicing assays must be undertaken in order to confirm web-based software predictions of the modification of putative ESE sites by disease-associated mutations.

Sign in / Sign up

Export Citation Format

Share Document