Multiple cryptic splice sites can be activated by IDS point mutations generating misspliced transcripts

2006 ◽  
Vol 84 (8) ◽  
pp. 692-700 ◽  
Author(s):  
Susanna Lualdi ◽  
Maria G. Pittis ◽  
Stefano Regis ◽  
Rossella Parini ◽  
Anna E. Allegri ◽  
...  
Keyword(s):  
Point Mutations ◽  
Splice Sites ◽  
Cryptic Splice Sites

scholarly journals Induction of cryptic pre-mRNA splice-switching by antisense oligonucleotides

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kristin A. Ham ◽  
Niall P. Keegan ◽  
Craig S. McIntosh ◽  
May T. Aung-Htut ◽  
Khine Zaw ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Antisense Oligonucleotides ◽  
Live Cells ◽  
Splice Sites ◽  
Cryptic Splice Site ◽  
Exon Definition ◽  
Rna Targets ◽  
Cryptic Splice Sites ◽  
Six Genes ◽  
Intended Effect

AbstractAntisense oligomers (AOs) are increasingly being used to modulate RNA splicing in live cells, both for research and for the development of therapeutics. While the most common intended effect of these AOs is to induce skipping of whole exons, rare examples are emerging of AOs that induce skipping of only part of an exon, through activation of an internal cryptic splice site. In this report, we examined seven AO-induced cryptic splice sites in six genes. Five of these cryptic splice sites were discovered through our own experiments, and two originated from other published reports. We modelled the predicted effects of AO binding on the secondary structure of each of the RNA targets, and how these alterations would in turn affect the accessibility of the RNA to splice factors. We observed that a common predicted effect of AO binding was disruption of the exon definition signal within the exon’s excluded segment.

Control of adenovirus E1B mRNA synthesis by a shift in the activities of RNA splice sites

1984 ◽  
Vol 4 (5) ◽  
pp. 966-972
Author(s):  
C Montell ◽  
E F Fisher ◽  
M H Caruthers ◽  
A J Berk
Keyword(s):  
Splice Site ◽  
Rna Splicing ◽  
Early Phase ◽  
Late Phase ◽  
Productive Infection ◽  
Splice Sites ◽  
Mrna Synthesis ◽  
Adenovirus E1b ◽  
Cryptic Splice Sites ◽  
Rna Splice Sites

The primary transcript from adenovirus 2 early region 1B (E1B) is processed by differential RNA splicing into two overlapping mRNAs, 13S and 22S. The 22S mRNA is the major E1B mRNA during the early phase of infection, whereas the 13S mRNA predominates during the late phase. In previous work, it has been shown that this shift in proportions of the E1B mRNAs is influenced by increased cytoplasmic stability of the 13S mRNA at late times in infection. Two observations presented here demonstrate that the increase in proportion of the 13S mRNA at late times is also regulated by a change in the specificity of RNA splicing. First, the relative concentrations of the 13S to 22S nuclear RNAs were not constant throughout infection but increased at late times. Secondly, studies with the mutant, adenovirus 2 pm2250 , provided evidence that there was an increased propensity to utilize a 5' splice in the region of the 13S 5' splice site at late times in infection. Adenovirus 2 pm2250 has a G----C transversion in the first base of E1B 13S mRNA intron preventing splicing of the 13S mRNA but not of the 22S mRNA. During the early phase of a pm2250 infection, the E1B primary transcripts were processed into the 22S mRNA only. However, during the late phase, when the 13S mRNA normally predominates, E1B primary transcripts were also processed by RNA splicing at two formerly unused or cryptic 5' splice sites. Both cryptic splice sites were located much closer to the disrupted 13S 5' splice site than to the 22S 5' splice site. Thus, the temporal increase in proportion of the 13S mRNA to the 22S mRNA is regulated by two processes, an increase in cytoplasmic stability of the 13S mRNA and an increased propensity to utilize the 13S 5' splice site during the late phase of infection. Adenovirus 2 pm2250 was not defective for productive infection of HeLa cells or for transformation of rat cells.

scholarly journals Activation of cryptic splice sites in three patients with chronic granulomatous disease

2019 ◽  
Vol 7 (9) ◽  
Author(s):  
Martin de Boer ◽  
Karin van Leeuwen ◽  
Mathias Hauri‐Hohl ◽  
Dirk Roos
Keyword(s):  
Chronic Granulomatous Disease ◽  
Granulomatous Disease ◽  
Splice Sites ◽  
Cryptic Splice Sites

scholarly journals Synonymous Mutations inRNASEH2ACreate Cryptic Splice Sites Impairing RNase H2 Enzyme Function in Aicardi-Goutières Syndrome

2013 ◽  
Vol 34 (8) ◽  
pp. 1066-1070 ◽  
Author(s):  
Gillian I. Rice ◽  
Martin A.M. Reijns ◽  
Stephanie R. Coffin ◽  
Gabriella M.A. Forte ◽  
Beverley H. Anderson ◽  
...  
Keyword(s):  
Enzyme Function ◽  
Splice Sites ◽  
Synonymous Mutations ◽  
Rnase H2 ◽  
Cryptic Splice Sites

Generation of a Novel Mouse Model of Cooley’s Anemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3654-3654
Author(s):  
Yongliang Huo ◽  
Sean McConnell ◽  
Chiao-Wang Sun ◽  
Li-Chen Wu ◽  
Thomas M. Ryan
Keyword(s):  
Blood Transfusion ◽  
Mouse Model ◽  
Adult Mouse ◽  
Globin Gene ◽  
Marker Gene ◽  
Gene Replacement ◽  
Globin Genes ◽  
Splice Sites ◽  
Cooley's Anemia ◽  
Cryptic Splice Sites

Abstract A novel mouse model of Cooley’s Anemia (CA) has been generated by targeted gene replacement of the adult murine α-globin genes with human α-globin and the adult mouse β-globin genes with a human γ- to β-globin gene switching cassette containing a β0 thalassemic allele. A positive-negative gene replacement construct was designed to simultaneously delete both of the adult mouse α-globin genes by inserting a 3.8kb human α1-globin gene and a hygromycin marker gene flanked by loxP sites in murine embryonic stem (ES) cells. Both adult murine β-globin genes were deleted by insertion of an Hprt marker gene that was later replaced by a 5.6kb human Aγ-globin gene, 4.1kb human β0-globin gene, and a loxP flanked hygromycin marker gene by a “tag and exchange” strategy. The human β0-globin knock-in allele contains a single G to A nucleotide mutation in the first base of intervening sequence 1 [β0-IVS1(GtoA)-globin]. This single base change destroys the splice donor site of IVS-1 resulting in the recruitment of several cryptic splice sites. Use of these cryptic splice sites produces a frameshift in the mRNA that results in no functional β-globin polypeptide synthesis from this allele. This β0-IVS1(GtoA)-globin gene mutation is a naturally occurring β0 thalassemia allele found in Mediterranean populations. Chimeric mice were generated from both the α- and β-globin targeted cells lines. After germline transmission the α- and β-globin targeted mice were bred to cre recombinase transgenic mice to remove the marker genes. Heterozygous CA mice exhibit β thalassemia intermedia. The α- and β-globin targeted mice were interbred to produce animals homozygous for the human α1- and γβ0-globin knock-in alleles. Instead of dying early in fetal life as all current homozygous β0 thalassemia mouse models, these novel homozygous CA mice survive solely on high levels of human fetal hemoglobin (α2γ2) throughout fetal development. Newborn homozygous CA mice are blood transfusion dependent similar to β thalassemia major infants. This novel model of CA has multiple improvements over existing models of β thalassemia. Namely, CA mice express 100% human hemoglobin in their RBCs, mimic the human γ- to β-globin gene switch, synthesize no functional β-globin chains after birth, have a single mutant human β0-globin knock-in allele at each β-globin locus, and are blood transfusion dependent for life after birth.

scholarly journals Cryptic splice sites and split genes

2011 ◽  
Vol 39 (14) ◽  
pp. 5837-5844 ◽  
Author(s):  
Yuri Kapustin ◽  
Elcie Chan ◽  
Rupa Sarkar ◽  
Frederick Wong ◽  
Igor Vorechovsky ◽  
...  
Keyword(s):  
Splice Sites ◽  
Cryptic Splice Sites

scholarly journals Two novel splicing mutations in the SLC45A2 gene cause Oculocutaneous Albinism Type IV by unmasking cryptic splice sites

2015 ◽  
Vol 60 (9) ◽  
pp. 467-471 ◽  
Author(s):  
Letizia Straniero ◽  
Valeria Rimoldi ◽  
Giulia Soldà ◽  
Lucia Mauri ◽  
Emanuela Manfredini ◽  
...  
Keyword(s):  
Oculocutaneous Albinism ◽  
Splice Sites ◽  
Type Iv ◽  
Splicing Mutations ◽  
Slc45a2 Gene ◽  
Cryptic Splice Sites

scholarly journals ADAR and hnRNPC deficiency synergize in activating endogenous dsRNA-induced type I IFN responses

2021 ◽  
Vol 218 (9) ◽  
Author(s):  
Anna-Maria Herzner ◽  
Zia Khan ◽  
Eric L. Van Nostrand ◽  
Sara Chan ◽  
Trinna Cuellar ◽  
...  
Keyword(s):  
Repetitive Element ◽  
Type I ◽  
Type I Ifn ◽  
Rna Seq ◽  
Splice Sites ◽  
Double Stranded Rna ◽  
Alu Elements ◽  
Synergistic Induction ◽  
Plausible Mechanism ◽  
Cryptic Splice Sites

Cytosolic double-stranded RNA (dsRNA) initiates type I IFN responses. Endogenous retroelements, notably Alu elements, constitute a source of dsRNA. Adenosine-to-inosine (A-to-I) editing by ADAR induces mismatches in dsRNA and prevents recognition by MDA5 and autoinflammation. To identify additional endogenous dsRNA checkpoints, we conducted a candidate screen in THP-1 monocytes and found that hnRNPC and ADAR deficiency resulted in synergistic induction of MDA5-dependent IFN responses. RNA-seq analysis demonstrated dysregulation of Alu-containing introns in hnRNPC-deficient cells via utilization of unmasked cryptic splice sites, including introns containing ADAR-dependent A-to-I editing clusters. These putative MDA5 ligands showed reduced editing in the absence of ADAR, providing a plausible mechanism for the combined effects of hnRNPC and ADAR. This study contributes to our understanding of the control of repetitive element–induced autoinflammation and suggests that patients with hnRNPC-mutated tumors might maximally benefit from ADAR inhibition-based immunotherapy.

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