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Exon skipping in humans

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https://www.readbyqxmd.com/read/27899647/spliceosomal-protein-eftud2-mutation-leads-to-p53-dependent-apoptosis-in-zebrafish-neural-progenitors
#1
Lei Lei, Shou-Yu Yan, Ran Yang, Jia-Yu Chen, Yumei Li, Ye Bu, Nannan Chang, Qinchao Zhou, Xiaojun Zhu, Chuan-Yun Li, Jing-Wei Xiong
Haploinsufficiency of EFTUD2 (Elongation Factor Tu GTP Binding Domain Containing 2) is linked to human mandibulofacial dysostosis, Guion-Almeida type (MFDGA), but the underlying cellular and molecular mechanisms remain to be addressed. We report here the isolation, cloning and functional analysis of the mutated eftud2 (snu114) in a novel neuronal mutant fn10a in zebrafish. This mutant displayed abnormal brain development with evident neuronal apoptosis while the development of other organs appeared less affected...
November 28, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27898092/transposon-mediated-generation-of-cellular-and-mouse-models-of-splicing-mutations-to-assess-the-efficacy-of-snrna-based-therapeutics
#2
Elena Barbon, Mattia Ferrarese, Laetitia van Wittenberghe, Peggy Sanatine, Giuseppe Ronzitti, Fanny Collaud, Pasqualina Colella, Mirko Pinotti, Federico Mingozzi
Disease-causing splicing mutations can be rescued by variants of the U1 small nuclear RNA (U1snRNAs). However, the evaluation of the efficacy and safety of modified U1snRNAs as therapeutic tools is limited by the availability of cellular and animal models specific for a given mutation. Hence, we exploited the hyperactive Sleeping Beauty transposon system (SB100X) to integrate human factor IX (hFIX) minigenes into genomic DNA in vitro and in vivo. We generated stable HEK293 cell lines and C57BL/6 mice harboring splicing-competent hFIX minigenes either wild type (SChFIX-wt) or mutated (SChFIXex5-2C)...
November 29, 2016: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/27885216/a-novel-heterozygous-intronic-mutation-in-pou1f1-is-associated-with-combined-pituitary-hormone-deficiency
#3
Masaki Takagi, Hotaka Kamasaki, Hiroko Yagi, Ryuji Fukuzawa, Satoshi Narumi, Tomonobu Hasegawa
POU class 1 homeobox 1 (POU1F1) regulates pituitary cell-specific gene expression of somatotropes, lactotropes, and thyrotropes. In humans, two POU1F1 isoforms (long and short isoform), which are generated by the alternative use of the splice acceptor site for exon 2, have been identified. To date, more than 30 POU1F1 mutations in patients with combined pituitary hormone deficiency (CPHD) have been described. All POU1F1 variants reported to date affect both the short and long isoforms of the POU1F1 protein; therefore, it is unclear at present whether a decrease in the function of only one of these two isoforms is sufficient for disease onset in humans...
November 22, 2016: Endocrine Journal
https://www.readbyqxmd.com/read/27854228/toxicological-characterization-of-exon-skipping-phosphorodiamidate-morpholino-oligomers-pmos-in-non-human-primates
#4
Michael P Carver, Jay S Charleston, Courtney Shanks, Jianbo Zhang, Mark Mense, Alok K Sharma, Harjeet Kaur, Peter Sazani
BACKGROUND: Phosphorodiamidate morpholino oligomers (PMOs) are a class of exon skipping drugs including eteplirsen, which has shown considerable promise for treatment of the degenerative neuromuscular disease, Duchenne musculardystrophy (DMD). OBJECTIVE: Toxicity studies in non-human primates (NHPs) of 12 weeks duration with two new PMOs for DMD, SRP-4045 and SRP-4053, along with results from a chronic study in NHPs of 39 weeks duration for eteplirsen, are described here...
August 30, 2016: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/27826023/allele-specific-splicing-effects-on-dkkl1-and-znf419-transcripts-in-hela-cells
#5
Grace Martin, S Duygu Selcuklu, Katherine Schouest, Victoria Nembaware, Peter C McKeown, Cathal Seoighe, Charles Spillane
Allele-specific splicing is the production of different RNA isoforms from different alleles of a gene. Altered splicing patterns such as exon skipping can have a dramatic effect on the final protein product yet have traditionally proven difficult to predict. We investigated the splicing effects of a set of nine single nucleotide polymorphisms (SNPs) which are predicted to have a direct impact on mRNA splicing, each in a different gene. Predictions were based on SNP location relative to splice junctions and intronic/exonic splicing elements, combined with an analysis of splice isoform expression data from public sources...
November 5, 2016: Gene
https://www.readbyqxmd.com/read/27820807/the-ribosome-engaged-landscape-of-alternative-splicing
#6
Robert J Weatheritt, Timothy Sterne-Weiler, Benjamin J Blencowe
High-throughput RNA sequencing (RNA-seq) has revealed an enormous complexity of alternative splicing (AS) across diverse cell and tissue types. However, it is currently unknown to what extent repertoires of splice-variant transcripts are translated into protein products. Here, we surveyed AS events engaged by the ribosome. Notably, at least 75% of human exon-skipping events detected in transcripts with medium-to-high abundance in RNA-seq data were also detected in ribosome profiling data. Furthermore, relatively small subsets of functionally related splice variants are engaged by ribosomes at levels that do not reflect their absolute abundance, thus indicating a role for AS in modulating translational output...
November 7, 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27788395/in-silico-investigation-of-the-impact-of-synonymous-variants-in-abcb4-gene-on-mrna-stability-structure-splicing-accuracy-and-codon-usage-potential-contribution-to-pfic3-disease
#7
Boudour Khabou, Olfa Siala-Sahnoun, Lamia Gargouri, Emna Mkaouar-Rebai, Leila Keskes, Mongia Hachicha, Faiza Fakhfakh
Progressive Familial Intrahepatic Cholestasis type 3 (PFIC3) is an autosomal-recessive liver disease due to mutations in the ABCB4 gene encoding for the MDR3 protein. In the present study, we performed molecular and bioinformatic analyses in PFIC3 patients in order to understand the molecular basis of the disease. The three studied patients with PFIC3 were screened by PCR amplification followed by direct sequencing of the 27 coding exons of ABCB4. In silico analysis was performed by bioinformatic programs. We revealed three synonymous polymorphisms c...
October 22, 2016: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/27779620/double-target-antisense-u1snrnas-correct-mis-splicing-due-to-c-639-861c-t-and-c-639-919g-a-gla-deep-intronic-mutations
#8
Lorenzo Ferri, Giuseppina Covello, Anna Caciotti, Renzo Guerrini, Michela Alessandra Denti, Amelia Morrone
Fabry disease is a rare X-linked lysosomal storage disorder caused by deficiency of the α-galactosidase A (α-Gal A) enzyme, which is encoded by the GLA gene. GLA transcription in humans produces a major mRNA encoding α-Gal A and a minor mRNA of unknown function, which retains a 57-nucleotide-long cryptic exon between exons 4 and 5, bearing a premature termination codon. NM_000169.2:c.639+861C>T and NM_000169.2:c.639+919G>A GLA deep intronic mutations have been described to cause Fabry disease by inducing overexpression of the alternatively spliced mRNA, along with a dramatic decrease in the major one...
October 25, 2016: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/27754488/antisense-oligonucleotide-mediated-exon-skipping-as-a-systemic-therapeutic-approach-for-recessive-dystrophic-epidermolysis-bullosa
#9
Jeroen Bremer, Olivier Bornert, Alexander Nyström, Antoni Gostynski, Marcel F Jonkman, Annemieke Aartsma-Rus, Peter C van den Akker, Anna Mg Pasmooij
The "generalized severe" form of recessive dystrophic epidermolysis bullosa (RDEB-gen sev) is caused by bi-allelic null mutations in COL7A1, encoding type VII collagen. The absence of type VII collagen leads to blistering of the skin and mucous membranes upon the slightest trauma. Because most patients carry exonic point mutations or small insertions/deletions, most exons of COL7A1 are in-frame, and low levels of type VII collagen already drastically improve the disease phenotype, this gene seems a perfect candidate for antisense oligonucleotide (AON)-mediated exon skipping...
October 18, 2016: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/27754374/endogenous-multiple-exon-skipping-and-back-splicing-at-the-dmd-mutation-hotspot
#10
Hitoshi Suzuki, Yoshitsugu Aoki, Toshiki Kameyama, Takashi Saito, Satoru Masuda, Jun Tanihata, Tetsuya Nagata, Akila Mayeda, Shin'ichi Takeda, Toshifumi Tsukahara
Duchenne muscular dystrophy (DMD) is a severe muscular disorder. It was reported that multiple exon skipping (MES), targeting exon 45-55 of the DMD gene, might improve patients' symptoms because patients who have a genomic deletion of all these exons showed very mild symptoms. Thus, exon 45-55 skipping treatments for DMD have been proposed as a potential clinical cure. Herein, we detected the expression of endogenous exons 44-56 connected mRNA transcript of the DMD using total RNAs derived from human normal skeletal muscle by reverse transcription polymerase chain reaction (RT-PCR), and identified a total of eight types of MES products around the hotspot...
October 13, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27748560/insecticide-resistance-mediated-by-an-exon-skipping-event
#11
Madeleine Berger, Alin Mirel Puinean, Emma Randall, Christoph T Zimmer, Wellington M Silva, Pablo Bielza, Linda M Field, David Hughes, Ian Mellor, Keywan Hassani-Pak, Herbert A A Siqueira, Martin S Williamson, Chris Bass
Many genes increase coding capacity by alternate exon usage. The gene encoding the insect nicotinic acetylcholine receptor (nAChR) α6 subunit, target of the bio-insecticide spinosad, is one example of this and expands protein diversity via alternative splicing of mutually exclusive exons. Here, we show that spinosad resistance in the tomato leaf miner, Tuta absoluta is associated with aberrant regulation of splicing of Taα6 resulting in a novel form of insecticide resistance mediated by exon skipping. Sequencing of the α6 subunit cDNA from spinosad selected and unselected strains of T...
November 2016: Molecular Ecology
https://www.readbyqxmd.com/read/27736885/dynamic-asxl1-exon-skipping-and-alternative-circular-splicing-in-single-human-cells
#12
Winston Koh, Veronica Gonzalez, Sivaraman Natarajan, Robert Carter, Patrick O Brown, Charles Gawad
Circular RNAs comprise a poorly understood new class of noncoding RNA. In this study, we used a combination of targeted deletion, high-resolution splicing detection, and single-cell sequencing to deeply probe ASXL1 circular splicing. We found that efficient circular splicing required the canonical transcriptional start site and inverted AluSx elements. Sequencing-based interrogation of isoforms after ASXL1 overexpression identified promiscuous linear splicing between all exons, with the two most abundant non-canonical linear products skipping the exons that produced the circular isoforms...
2016: PloS One
https://www.readbyqxmd.com/read/27721063/hydrogen-peroxide-triggers-a-novel-alternative-splicing-of-arsenic-3%C3%A2-oxidation-state-methyltransferase-gene
#13
Daigo Sumi, Chieri Takeda, Daiki Yasuoka, Seiichiro Himeno
We previously reported that two splicing variants of human AS3MT mRNA, exon-3 skipping form (Δ3) and exons-4 and -5 skipping form (Δ4,5), were detected in HepG2 cells and that both variants lacked arsenic methylation activity (Sumi et al., 2011). Here we studied whether hydrogen peroxide (H2O2) triggers alternative splicing of AS3MT mRNA. The results showed that exposure of HepG2 cells to H2O2 resulted in increased levels of a novel spliced form skipping exon-3 to exon-10 (Δ3-10) in an H2O2-concentration-dependent manner, although no change was detected in the mRNA levels of Δ3 AS3MT...
October 6, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27701399/an-exon-specific-u1snrna-induces-a-robust-factor-ix-activity-in-mice-expressing-multiple-human-fix-splicing-mutants
#14
Dario Balestra, Daniela Scalet, Franco Pagani, Malgorzata Ewa Rogalska, Rosella Mari, Francesco Bernardi, Mirko Pinotti
In cellular models we have demonstrated that a unique U1snRNA targeting an intronic region downstream of a defective exon (Exon-specific U1snRNA, ExSpeU1) can rescue multiple exon-skipping mutations, a relevant cause of genetic disease. Here, we explored in mice the ExSpeU1 U1fix9 toward two model Hemophilia B-causing mutations at the 5' (c.519A > G) or 3' (c.392-8T > G) splice sites of F9 exon 5. Hydrodynamic injection of wt-BALB/C mice with plasmids expressing the wt and mutant (hFIX-2G(5'ss) and hFIX-8G(3'ss)) splicing-competent human factor IX (hFIX) cassettes resulted in the expression of hFIX transcripts lacking exon 5 in liver, and in low plasma levels of inactive hFIX...
October 4, 2016: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/27672039/concerted-effects-of-heterogeneous-nuclear-ribonucleoprotein-c1-c2-to-control-vitamin-d-directed-gene-transcription-and-rna-splicing-in-human-bone-cells
#15
Rui Zhou, Juw Won Park, Rene F Chun, Thomas S Lisse, Alejandro J Garcia, Kathryn Zavala, Jessica L Sea, Zhi-Xiang Lu, Jianzhong Xu, Yi Xing, John S Adams, Martin Hewison
Traditionally recognized as an RNA splicing regulator, heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC1/C2) can also bind to double-stranded DNA and function in trans as a vitamin D response element (VDRE)-binding protein. As such, hnRNPC1/C2 may couple transcription induced by the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) with subsequent RNA splicing. In MG63 osteoblastic cells, increased expression of the 1,25(OH)2D target gene CYP24A1 involved immunoprecipitation of hnRNPC1/C2 with CYP24A1 chromatin and RNA...
September 26, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27639833/exploring-splicing-switching-molecules-for-seckel-syndrome-therapy
#16
Daniela Scalet, Dario Balestra, Sara Rohban, Matteo Bovolenta, Daniela Perrone, Francesco Bernardi, Stefano Campaner, Mirko Pinotti
The c.2101A>G synonymous change (p.G674G) in the gene for ATR, a key player in the DNA-damage response, has been the first identified genetic cause of Seckel Syndrome (SS), an orphan disease characterized by growth and mental retardation. This mutation mainly causes exon 9 skipping, through an ill-defined mechanism. Through ATR minigene expression studies, we demonstrated that the detrimental effect of this mutation (6±1% of correct transcripts only) depends on the poor exon 9 definition (47±4% in the ATR(wt) context), because the change was ineffective when the weak 5' or the 3' splice sites (ss) were strengthened (scores from 0...
September 14, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27588452/bi-allelic-truncating-mutations-in-cep78-encoding-centrosomal-protein-78-cause-cone-rod-degeneration-with-sensorineural-hearing-loss
#17
Prasanthi Namburi, Rinki Ratnapriya, Samer Khateb, Csilla H Lazar, Yael Kinarty, Alexey Obolensky, Inbar Erdinest, Devorah Marks-Ohana, Eran Pras, Tamar Ben-Yosef, Hadas Newman, Menachem Gross, Anand Swaroop, Eyal Banin, Dror Sharon
Inherited retinal diseases (IRDs) are a diverse group of genetically and clinically heterogeneous retinal abnormalities. The present study was designed to identify genetic defects in individuals with an uncommon combination of autosomal recessive progressive cone-rod degeneration accompanied by sensorineural hearing loss (arCRD-SNHL). Homozygosity mapping followed by whole-exome sequencing (WES) and founder mutation screening revealed two truncating rare variants (c.893-1G>A and c.534delT) in CEP78, which encodes centrosomal protein 78, in six individuals of Jewish ancestry with CRD and SNHL...
September 1, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27565344/cell-type-specific-alternative-splicing-governs-cell-fate-in-the-developing-cerebral-cortex
#18
Xiaochang Zhang, Ming Hui Chen, Xuebing Wu, Andrew Kodani, Jean Fan, Ryan Doan, Manabu Ozawa, Jacqueline Ma, Nobuaki Yoshida, Jeremy F Reiter, Douglas L Black, Peter V Kharchenko, Phillip A Sharp, Christopher A Walsh
Alternative splicing is prevalent in the mammalian brain. To interrogate the functional role of alternative splicing in neural development, we analyzed purified neural progenitor cells (NPCs) and neurons from developing cerebral cortices, revealing hundreds of differentially spliced exons that preferentially alter key protein domains-especially in cytoskeletal proteins-and can harbor disease-causing mutations. We show that Ptbp1 and Rbfox proteins antagonistically govern the NPC-to-neuron transition by regulating neuron-specific exons...
August 25, 2016: Cell
https://www.readbyqxmd.com/read/27556805/read-split-run-an-improved-bioinformatics-pipeline-for-identification-of-genome-wide-non-canonical-spliced-regions-using-rna-seq-data
#19
Yongsheng Bai, Jeff Kinne, Brandon Donham, Feng Jiang, Lizhong Ding, Justin R Hassler, Randal J Kaufman
BACKGROUND: Most existing tools for detecting next-generation sequencing-based splicing events focus on generic splicing events. Consequently, special types of non-canonical splicing events of short mRNA regions (IRE1α targeted) have not yet been thoroughly addressed at a genome-wide level using bioinformatics approaches in conjunction with next-generation technologies. During endoplasmic reticulum (ER) stress, the gene encoding the RNase Ire1α is known to splice out a short 26 nt region from the mRNA of the transcription factor Xbp1 non-canonically within the cytosol...
August 22, 2016: BMC Genomics
https://www.readbyqxmd.com/read/27545674/biallelic-variants-in-uba5-link-dysfunctional-ufm1%C3%A2-ubiquitin-like-modifier-pathway-to-severe-infantile-onset-encephalopathy
#20
Mikko Muona, Ryosuke Ishimura, Anni Laari, Yoshinobu Ichimura, Tarja Linnankivi, Riikka Keski-Filppula, Riitta Herva, Heikki Rantala, Anders Paetau, Minna Pöyhönen, Miki Obata, Takefumi Uemura, Thomas Karhu, Norihisa Bizen, Hirohide Takebayashi, Shane McKee, Michael J Parker, Nadia Akawi, Jeremy McRae, Matthew E Hurles, Outi Kuismin, Mitja I Kurki, Anna-Kaisa Anttonen, Keiji Tanaka, Aarno Palotie, Satoshi Waguri, Anna-Elina Lehesjoki, Masaaki Komatsu
The ubiquitin fold modifier 1 (UFM1) cascade is a recently identified evolutionarily conserved ubiquitin-like modification system whose function and link to human disease have remained largely uncharacterized. By using exome sequencing in Finnish individuals with severe epileptic syndromes, we identified pathogenic compound heterozygous variants in UBA5, encoding an activating enzyme for UFM1, in two unrelated families. Two additional individuals with biallelic UBA5 variants were identified from the UK-based Deciphering Developmental Disorders study and one from the Northern Finland Intellectual Disability cohort...
September 1, 2016: American Journal of Human Genetics
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