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Exon skipping in humans

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https://www.readbyqxmd.com/read/29768479/construction-of-a-tri-chromatic-reporter-cell-line-for-the-rapid-and-simple-screening-of-splice-switching-oligonucleotides-targeting-dmd-exon-51-using-high-content-screening
#1
Takenori Shimo, Keisuke Tachibana, Satoshi Obika
Splice-switching oligonucleotides (SSOs) that can modulate RNA splicing are used for the treatment of many genetic disorders. To enhance the efficacy of modulating splicing, it is important to optimize SSOs with regard to target sites, GC content, melting temperature (Tm value), chemistries, and lengths. Thus, in vitro assay systems that allow for the rapid and simple screening of SSOs are essential for optimizing SSO design. In this study, we established a novel tri-chromatic reporter cell line for SSO screening...
2018: PloS One
https://www.readbyqxmd.com/read/29726989/a-splicing-mutation-in-aryl-hydrocarbon-receptor-associated-with-retinitis-pigmentosa
#2
Yu Zhou, Shijin Li, Lulin Huang, Yeming Yang, Lin Zhang, Mu Yang, Wenjing Liu, Kim Ramasamy, Zhilin Jiang, Periasamy Sundaresan, Xianjun Zhu, Zhenglin Yang
Retinitis pigmentosa (RP) refers to a group of retinal degenerative diseases, which often lead to vision loss. Although 70 genes have been identified in RP patients, the genetic cause of approximately 30% of RP cases remains unknown. We aimed to identify the cause of the disease in a cohort of RP families by whole exome sequencing. A rare homozygous splicing variant, c.1160 + 1G>A, which introduced skipping of exon 9 of the aryl hydrocarbon receptor (AHR), was identified in family RD-134. This variant is very rare in several exome databases and leads to skipping of exon 9 in the transcript...
May 2, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29720576/efficient-exon-skipping-of-sgcg-mutations-mediated-by-phosphorodiamidate-morpholino-oligomers
#3
Eugene J Wyatt, Alexis R Demonbreun, Ellis Y Kim, Megan J Puckelwartz, Andy H Vo, Lisa M Dellefave-Castillo, Quan Q Gao, Mariz Vainzof, Rita C M Pavanello, Mayana Zatz, Elizabeth M McNally
Exon skipping uses chemically modified antisense oligonucleotides to modulate RNA splicing. Therapeutically, exon skipping can bypass mutations and restore reading frame disruption by generating internally truncated, functional proteins to rescue the loss of native gene expression. Limb-girdle muscular dystrophy type 2C is caused by autosomal recessive mutations in the SGCG gene, which encodes the dystrophin-associated protein γ-sarcoglycan. The most common SGCG mutations disrupt the transcript reading frame abrogating γ-sarcoglycan protein expression...
May 3, 2018: JCI Insight
https://www.readbyqxmd.com/read/29701768/exon-specific-u1-snrnas-improve-elp1-exon-20-definition-and-rescue-elp1-protein-expression-in-a-familial-dysautonomia-mouse-model
#4
Irving Donadon, Mirko Pinotti, Katarzyna Rajkowska, Giulia Pianigiani, Elena Barbon, Elisabetta Morini, Helena Motaln, Boris Rogelj, Federico Mingozzi, Susan A Slaugenhaupt, Franco Pagani
Familial dysautonomia (FD) is a rare genetic disease with no treatment, caused by an intronic point mutation (c.2204 + 6T>C) that negatively affects the definition of exon 20 in the Elongator complex protein 1 gene (ELP1 also known as IKBKAP). This substitution modifies the 5' splice site and, in combination with regulatory splicing factors, induces different levels of exon 20 skipping, in various tissues. Here, we evaluated the therapeutic potential of a novel class of U1 snRNA molecules, Exon-Specific U1s (ExSpeU1s), in correcting ELP1 exon 20 recognition...
April 25, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29678492/hmga1a-induces-alternative-splicing-of-estrogen-receptor-alpha-in-mcf-7-human-breast-cancer-cells
#5
Kenji Ohe, Shinsuke Miyajima, Tomoko Tanaka, Yuriko Hamaguchi, Yoshihiro Harada, Yuta Horita, Yuki Beppu, Fumiaki Ito, Takafumi Yamasaki, Hiroki Terai, Masayoshi Mori, Yusuke Murata, Makito Tanabe, Kenji Ashida, Munechika Enjoji, Toshihiko Yanase, Nobuhiro Harada, Toshiaki Utsumi, Akila Mayeda
The high-mobility group A protein 1a (HMGA1a) protein is known as an oncogene whose expression level in cancer tissue correlates with the malignant potential, and known as a component of senescence-related structures connecting it to tumor suppressor networks in fibroblasts. HMGA1 protein binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. Our previous studies have shown that sequence-specific RNA-binding of HMGA1a induces exon-skipping of Presenilin-2 exon 5 in sporadic Alzheimer disease...
April 17, 2018: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29672717/antisense-oligonucleotides-correct-the-familial-dysautonomia-splicing-defect-in-ikbkap-transgenic-mice
#6
Rahul Sinha, Young Jin Kim, Tomoki Nomakuchi, Kentaro Sahashi, Yimin Hua, Frank Rigo, C Frank Bennett, Adrian R Krainer
Familial dysautonomia (FD) is a rare inherited neurodegenerative disorder caused by a point mutation in the IKBKAP gene that results in defective splicing of its pre-mRNA. The mutation weakens the 5' splice site of exon 20, causing this exon to be skipped, thereby introducing a premature termination codon. Though detailed FD pathogenesis mechanisms are not yet clear, correcting the splicing defect in the relevant tissue(s), thus restoring normal expression levels of the full-length IKAP protein, could be therapeutic...
April 17, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29598826/the-complexity-of-titin-splicing-pattern-in-human-adult-skeletal-muscles
#7
Marco Savarese, Per Harald Jonson, Sanna Huovinen, Lars Paulin, Petri Auvinen, Bjarne Udd, Peter Hackman
BACKGROUND: Mutations in the titin gene (TTN) cause a large spectrum of diseases affecting skeletal and/or cardiac muscle. TTN includes 363 coding exons, a repeated region with a high degree of complexity, isoform-specific elements, and metatranscript-only exons thought to be expressed only during fetal development. Although three main classes of isoforms have been described so far, alternative splicing events (ASEs) in different tissues or in different developmental and physiological states have been reported...
March 29, 2018: Skeletal Muscle
https://www.readbyqxmd.com/read/29567830/cardiac-circrnas-arise-mainly-from-constitutive-exons-rather-than-alternatively-spliced-exons
#8
Simona Aufiero, Maarten M G van den Hoogenhof, Yolan J Reckman, Abdelaziz Beqqali, Ingeborg van der Made, Jolanda Kluin, Mohsin A F Khan, Yigal M Pinto, Esther E Creemers
Circular RNAs (circRNAs) are a relatively new class of RNA molecules, and knowledge about their biogenesis and function is still in its infancy. It was recently shown that alternative splicing underlies the formation of circular RNAs (circRNA) arising from the Titin (TTN) gene. Since the main mechanism by which circRNAs are formed is still unclear, we hypothesized that alternative splicing, and in particular exon skipping, is a major driver of circRNA production. We performed RNA sequencing on human and mouse hearts, mapped alternative splicing events and overlaid these with expressed circRNAs at exon-level resolution...
March 22, 2018: RNA
https://www.readbyqxmd.com/read/29560374/-de-novo-variants-in-camk2a-and-camk2b-cause-neurodevelopmental-disorders
#9
Tenpei Akita, Kazushi Aoto, Mitsuhiro Kato, Masaaki Shiina, Hiroki Mutoh, Mitsuko Nakashima, Ichiro Kuki, Shin Okazaki, Shinichi Magara, Takashi Shiihara, Kenji Yokochi, Kaori Aiba, Jun Tohyama, Chihiro Ohba, Satoko Miyatake, Noriko Miyake, Kazuhiro Ogata, Atsuo Fukuda, Naomichi Matsumoto, Hirotomo Saitsu
Objective: α ( CAMK2A ) and β ( CAMK2B ) isoforms of Calcium/calmodulin-dependent protein kinase II (CaMKII) play a pivotal role in neuronal plasticity and in learning and memory processes in the brain. Here, we explore the possible involvement of α - and β -CaMKII variants in neurodevelopmental disorders. Methods: Whole-exome sequencing was performed for 976 individuals with intellectual disability, developmental delay, and epilepsy. The effect of CAMK2A and CAMK2B variants on CaMKII structure and firing of neurons was evaluated by computational structural analysis, immunoblotting, and electrophysiological analysis...
March 2018: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/29523794/complementarity-of-assembly-first-and-mapping-first-approaches-for-alternative-splicing-annotation-and-differential-analysis-from-rnaseq-data
#10
Clara Benoit-Pilven, Camille Marchet, Emilie Chautard, Leandro Lima, Marie-Pierre Lambert, Gustavo Sacomoto, Amandine Rey, Audric Cologne, Sophie Terrone, Louis Dulaurier, Jean-Baptiste Claude, Cyril F Bourgeois, Didier Auboeuf, Vincent Lacroix
Genome-wide analyses estimate that more than 90% of multi exonic human genes produce at least two transcripts through alternative splicing (AS). Various bioinformatics methods are available to analyze AS from RNAseq data. Most methods start by mapping the reads to an annotated reference genome, but some start by a de novo assembly of the reads. In this paper, we present a systematic comparison of a mapping-first approach (FARLINE) and an assembly-first approach (KISSPLICE). We applied these methods to two independent RNAseq datasets and found that the predictions of the two pipelines overlapped (70% of exon skipping events were common), but with noticeable differences...
March 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29515135/genome-wide-transcriptome-analysis-identifies-alternative-splicing-regulatory-network-and-key-splicing-factors-in-mouse-and-human-psoriasis
#11
Jin Li, Peng Yu
Psoriasis is a chronic inflammatory disease that affects the skin, nails, and joints. For understanding the mechanism of psoriasis, though, alternative splicing analysis has received relatively little attention in the field. Here, we developed and applied several computational analysis methods to study psoriasis. Using psoriasis mouse and human datasets, our differential alternative splicing analyses detected hundreds of differential alternative splicing changes. Our analysis of conservation revealed many exon-skipping events conserved between mice and humans...
March 7, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29500230/ethanolamine-phosphotransferase-1-selenoprotein-i-is-critical-for-the-neural-development-and-maintenance-of-plasmalogen-in-human
#12
Yasuhiro Horibata, Orly Elpeleg, Ayelet Eran, Yoshio Hirabayashi, David Savitzki, Galit Tal, Hanna Mandel, Hiroyuki Sugimoto
Ethanolamine phosphotransferase 1 (EPT1), also known as selenoprotein 1 (SELENOI), is an enzyme that transfers phosphoethanolamine from cytidine diphosphate (CDP)-ethanolamine to lipid acceptors to produce ethanolamine glycerophospholipids such as diacyl-linked phosphatidylethanolamine (PE) and ether-linked plasmalogen (plasmenyl-PE). However, to date there has been no analysis of the metabolomic consequence of the mutation of EPT1 on the concentration of ethanolamine glycerophospholipids in mammalian cells...
March 2, 2018: Journal of Lipid Research
https://www.readbyqxmd.com/read/29499940/rna-seq-analysis-of-an-antisense-sequence-optimized-for-exon-skipping-in-duchenne-patients-reveals-no-off-target-effect
#13
Claire Domenger, Marine Allais, Virginie François, Adrien Léger, Emilie Lecomte, Marie Montus, Laurent Servais, Thomas Voit, Philippe Moullier, Yann Audic, Caroline Le Guiner
Non-coding uridine-rich small nuclear RNAs (UsnRNAs) have emerged in recent years as effective tools for exon skipping for the treatment of Duchenne muscular dystrophy (DMD), a degenerative muscular genetic disorder. We recently showed the high capacity of a recombinant adeno-associated virus (rAAV)-U7snRNA vector to restore the reading frame of the DMD mRNA in the muscles of DMD dogs. We are now moving toward a phase I/II clinical trial with an rAAV-U7snRNA-E53, carrying an antisense sequence designed to hybridize exon 53 of the human DMD messenger...
March 2, 2018: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/29473878/alternative-mrna-splicing-in-the-pathogenesis-of-obesity
#14
REVIEW
Chi-Ming Wong, Lu Xu, Mabel Yin-Chun Yau
Alternative mRNA splicing is an important mechanism in expansion of proteome diversity by production of multiple protein isoforms. However, emerging evidence indicates that only a limited number of annotated protein isoforms by alternative splicing are detected, and the coding sequence of alternative splice variants usually is only slightly different from that of the canonical sequence. Nevertheless, mis-splicing is associated with a large array of human diseases. Previous reviews mainly focused on hereditary and somatic mutations in cis-acting RNA sequence elements and trans-acting splicing factors...
February 23, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29466448/a-dystrophic-duchenne-mouse-model-for-testing-human-antisense-oligonucleotides
#15
Marcel Veltrop, Laura van Vliet, Margriet Hulsker, Jill Claassens, Conny Brouwers, Cor Breukel, Jos van der Kaa, Margot M Linssen, Johan T den Dunnen, Sjef Verbeek, Annemieke Aartsma-Rus, Maaike van Putten
Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disease generally caused by reading frame disrupting mutations in the DMD gene resulting in loss of functional dystrophin protein. The reading frame can be restored by antisense oligonucleotide (AON)-mediated exon skipping, allowing production of internally deleted, but partially functional dystrophin proteins as found in the less severe Becker muscular dystrophy. Due to genetic variation between species, mouse models with mutations in the murine genes are of limited use to test and further optimize human specific AONs in vivo...
2018: PloS One
https://www.readbyqxmd.com/read/29461686/atp-binding-cassette-subfamily-a-member-4-intronic-variants-c-4773-3a-g-and-c-5461-10t-c-cause-stargardt-disease-due-to-defective-splicing
#16
Frida Jonsson, Ida Maria Westin, Lennart Österman, Ola Sandgren, Marie Burstedt, Monica Holmberg, Irina Golovleva
PURPOSE: Inherited retinal dystrophies (IRDs) represent a group of progressive conditions affecting the retina. There is a great genetic heterogeneity causing IRDs, and to date, more than 260 genes are associated with IRDs. Stargardt disease, type 1 (STGD1) or macular degeneration with flecks, STGD1 represents a disease with early onset, central visual impairment, frequent appearance of yellowish flecks and mutations in the ATP-binding cassette subfamily A, member 4 (ABCA4) gene. A large number of intronic sequence variants in ABCA4 have been considered pathogenic although their functional effect was seldom demonstrated...
February 20, 2018: Acta Ophthalmologica
https://www.readbyqxmd.com/read/29454830/the-discrepancy-function-of-nlrc5-isoforms-in-antiviral-and-antibacterial-immune-responses
#17
Lu Cao, Xiao Man Wu, Yi Wei Hu, Na Na Xue, Pin Nie, Ming Xian Chang
NOD-like receptors (NLRs) are a family of intracellular pattern recognition receptors (PRRs) that play critical roles in innate immunity against pathogens infection. NLRC5, the largest member of NLR family, has been characterized as a regulator of innate immunity and MHC class I expression. Alternative splicing of NLRC5 is only reported in human and zebrafish. However, the function of NLRC5 isoforms in the innate immune responses remains unknown. In the present study, we report the functional characterization of zfNLRC5a and zfNLRC5d, two splicing isoforms of zebrafish NLRC5...
July 2018: Developmental and Comparative Immunology
https://www.readbyqxmd.com/read/29404407/correction-of-diverse-muscular-dystrophy-mutations-in-human-engineered-heart-muscle-by-single-site-genome-editing
#18
Chengzu Long, Hui Li, Malte Tiburcy, Cristina Rodriguez-Caycedo, Viktoriia Kyrychenko, Huanyu Zhou, Yu Zhang, Yi-Li Min, John M Shelton, Pradeep P A Mammen, Norman Y Liaw, Wolfram-Hubertus Zimmermann, Rhonda Bassel-Duby, Jay W Schneider, Eric N Olson
Genome editing with CRISPR/Cas9 is a promising new approach for correcting or mitigating disease-causing mutations. Duchenne muscular dystrophy (DMD) is associated with lethal degeneration of cardiac and skeletal muscle caused by more than 3000 different mutations in the X-linked dystrophin gene ( DMD ). Most of these mutations are clustered in "hotspots." There is a fortuitous correspondence between the eukaryotic splice acceptor and splice donor sequences and the protospacer adjacent motif sequences that govern prokaryotic CRISPR/Cas9 target gene recognition and cleavage...
January 2018: Science Advances
https://www.readbyqxmd.com/read/29397868/sf3b4-as-an-early-stage-diagnostic-marker-and-driver-of-hepatocellular-carcinoma
#19
Qingyu Shen, Suk Woo Nam
An accurate diagnostic marker for detecting early-stage hepatocellular carcinoma (eHCC) is clinically important, since early detection of HCC remarkably improves patient survival. From the integrative analysis of the transcriptome and clinicopathologic data of human multi-stage HCC tissues, we were able to identify barrier-to-autointegration factor 1 (BANF1), procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) and splicing factor 3b subunit 4 (SF3B4) as early HCC biomarkers which could be detected in precancerous lesions of HCC, with superior capabilities to diagnose eHCC compared to the currently popular HCC diagnostic biomarkers: GPC3, GS, and HSP70...
February 2018: BMB Reports
https://www.readbyqxmd.com/read/29353404/dna-methylation-rather-than-single-nucleotide-polymorphisms-regulates-the-production-of-an-aberrant-splice-variant-of-il6r-in-mastitic-cows
#20
Yan Zhang, Xiuge Wang, Qiang Jiang, Haisheng Hao, Zhihua Ju, Chunhong Yang, Yan Sun, Changfa Wang, Jifeng Zhong, Jinming Huang, Huabin Zhu
Interleukin-6 receptor-alpha (IL6R) interacts with IL6 and forms a ligand-receptor complex, which can stimulate various cellular responses, such as cell proliferation, cell differentiation, and activation of inflammatory processes. Both genetic mutation and epigenetic modification regulate gene transcription. We identified a novel splice variant of bovine IL6R, designated as IL6R-TV, which is characterized by the skipping of exon 2 of the NCBI-referenced IL6R gene (IL6R-reference). The expression levels of IL6R-TV and IL6R-reference transcripts were lower in normal mammary gland tissues...
January 20, 2018: Cell Stress & Chaperones
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