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Exon skipping in humans

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https://www.readbyqxmd.com/read/28756020/identification-and-characterization-of-the-tyrosinase-gene-tyr-and-its-transcript-variants-tyr_1-and-tyr_2-in-the-crab-eating-macaque-macaca-fascicularis
#1
Young-Hyun Kim, Sang-Je Park, Se-Hee Choe, Ja-Rang Lee, Hyeon-Mu Cho, Sun-Uk Kim, Ji-Su Kim, Bo-Woong Sim, Bong-Seok Song, Youngjeon Lee, Yeung Bae Jin, Jung-Joo Hong, Kang-Jin Jeong, Philyong Kang, Seung-Ho Baek, Sang-Rae Lee, Jae-Won Huh, Kyu-Tae Chang
Tyrosinase is a copper-containing enzyme that regulates melanin biosynthesis and is encoded by the tyrosinase (TYR) gene. Previous studies demonstrated that mutations in TYR could lead to oculocutaneous albinism type 1 (OCA1) owing to the failure of melanin formation. Although a previous study found that albinism in the rhesus monkey was derived from a mutation in TYR, the identification and characterization of this gene in non-human primates has not been achieved thus far. Thus, using the rapid amplification of cDNA ends (RACE) and internal reverse transcription PCR (RT-PCR) we identified the full-length sequence of TYR in the crab-eating macaque, and two different transcript variants (TYR_1 and TYR_2)...
July 26, 2017: Gene
https://www.readbyqxmd.com/read/28742140/short-16-mer-locked-nucleic-acid-splice-switching-oligonucleotides-restore-dystrophin-production-in-duchenne-muscular-dystrophy-myotubes
#2
Vanessa Borges Pires, Ricardo Simões, Kamel Mamchaoui, Célia Carvalho, Maria Carmo-Fonseca
Splice-switching antisense oligonucleotides (SSOs) offer great potential for RNA-targeting therapies, and two SSO drugs have been recently approved for treating Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA). Despite promising results, new developments are still needed for more efficient chemistries and delivery systems. Locked nucleic acid (LNA) is a chemically modified nucleic acid that presents several attractive properties, such as high melting temperature when bound to RNA, potent biological activity, high stability and low toxicity in vivo...
2017: PloS One
https://www.readbyqxmd.com/read/28705773/recent-progress-in-circular-rnas-in-human-cancers
#3
Guanqun Huang, Shuaihu Li, Nuo Yang, Yongdong Zou, Duo Zheng, Tian Xiao
Circular RNAs (circRNAs) are a large class of endogenous RNAs, formed by exon skipping or back-splicing events as covalently closed loops, which are expressed abundantly in mammalian cells. Although their biological functions remain largely unknown, recent studies show that circRNAs have three main functions in mammalian cells. First, circRNAs can regulate transcription and RNA splicing. Second, circRNAs function as microRNA (miRNA) sponges. Third, they can be translated into protein driven by N(6)-methyladenosine modification...
July 11, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28684740/hur-dependent-editing-of-a-new-mineralocorticoid-receptor-splice-variant-reveals-an-osmoregulatory-loop-for-sodium-homeostasis
#4
Ingrid Lema, Larbi Amazit, Khadija Lamribet, Jérôme Fagart, Anne Blanchard, Marc Lombès, Nadia Cherradi, Say Viengchareun
Aldosterone and the Mineralocorticoid Receptor (MR) control hydroelectrolytic homeostasis and alterations of mineralocorticoid signaling pathway are involved in the pathogenesis of numerous human diseases, justifying the need to decipher molecular events controlling MR expression level. Here, we show in renal cells that the RNA-Binding Protein, Human antigen R (HuR), plays a central role in the editing of MR transcript as revealed by a RNA interference strategy. We identify a novel Δ6 MR splice variant, which lacks the entire exon 6, following a HuR-dependent exon skipping event...
July 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28679766/sym015-a-highly-efficacious-antibody-mixture-against-met-amplified-tumors
#5
Thomas Tuxen Poulsen, Michael M Grandal, Niels Jørgen Ø Skartved, Rikke Hald, Lene Alifrangis, Klaus Koefoed, Trine Lindsted, Camilla Fröhlich, Sofie Ellebæk Pollmann, Karsten W Eriksen, Anna Dahlman, Helle J Jacobsen, Thomas Bouquin, Mikkel Wandahl Pedersen, Ivan D Horak, Johan Lantto, Michael Kragh
<span style="text-decoration: underline;">Purpose:</span> Activation of the receptor tyrosine kinase MET is associated with poor clinical outcome in certain cancers. To target MET more effectively, we developed an antagonistic antibody mixture, Sym015, consisting of two humanized monoclonal antibodies directed against non-overlapping epitopes of MET. <p><span style="text-decoration: underline;">Experimental Design/Results:</span> We screened a large panel of well-annotated human cancer cell lines and identified a subset with highly elevated MET expression...
July 5, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28663100/a-new-aav10-u7-mediated-gene-therapy-prolongs-survival-and-restores-function-in-an-als-mouse-model
#6
Maria Grazia Biferi, Mathilde Cohen-Tannoudji, Ambra Cappelletto, Benoit Giroux, Marianne Roda, Stéphanie Astord, Thibaut Marais, Corinne Bos, Thomas Voit, Arnaud Ferry, Martine Barkats
One of the most promising therapeutic approaches for familial amyotrophic lateral sclerosis linked to superoxide dismutase 1 (SOD1) is the suppression of toxic mutant SOD1 in the affected tissues. Here, we report an innovative molecular strategy for inducing substantial, widespread, and sustained reduction of mutant human SOD1 (hSOD1) levels throughout the body of SOD1(G93A) mice, leading to therapeutic effects in animals. Adeno-associated virus serotype rh10 vectors (AAV10) were used to mediate exon skipping of the hSOD1 pre-mRNA by expression of exon-2-targeted antisense sequences embedded in a modified U7 small-nuclear RNA (AAV10-U7-hSOD)...
June 26, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28642487/hypoxia-is-a-key-driver-of-alternative-splicing-in-human-breast-cancer-cells
#7
Jian Han, Jia Li, Jolene Caifeng Ho, Grace Sushin Chia, Hiroyuki Kato, Sudhakar Jha, Henry Yang, Lorenz Poellinger, Kian Leong Lee
Adaptation to hypoxia, a hallmark feature of many tumors, is an important driver of cancer cell survival, proliferation and the development of resistance to chemotherapy. Hypoxia-induced stabilization of hypoxia-inducible factors (HIFs) leads to transcriptional activation of a network of hypoxia target genes involved in angiogenesis, cell growth, glycolysis, DNA damage repair and apoptosis. Although the transcriptional targets of hypoxia have been characterized, the alternative splicing of transcripts that occurs during hypoxia and the roles they play in oncogenesis are much less understood...
June 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28624223/evaluation-of-mybpc3-trans-splicing-and-gene-replacement-as-therapeutic-options-in-human-ipsc-derived-cardiomyocytes
#8
Maksymilian Prondzynski, Elisabeth Krämer, Sandra D Laufer, Aya Shibamiya, Ole Pless, Frederik Flenner, Oliver J Müller, Julia Münch, Charles Redwood, Arne Hansen, Monica Patten, Thomas Eschenhagen, Giulia Mearini, Lucie Carrier
Gene therapy is a promising option for severe forms of genetic diseases. We previously provided evidence for the feasibility of trans-splicing, exon skipping, and gene replacement in a mouse model of hypertrophic cardiomyopathy (HCM) carrying a mutation in MYBPC3, encoding cardiac myosin-binding protein C (cMyBP-C). Here we used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from an HCM patient carrying a heterozygous c.1358-1359insC MYBPC3 mutation and from a healthy donor. HCM hiPSC-CMs exhibited ∼50% lower MYBPC3 mRNA and cMyBP-C protein levels than control, no truncated cMyBP-C, larger cell size, and altered gene expression, thus reproducing human HCM features...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28624186/gaa-deficiency-in-pompe-disease-is-alleviated-by-exon-inclusion-in-ipsc-derived-skeletal-muscle-cells
#9
Erik van der Wal, Atze J Bergsma, Tom J M van Gestel, Stijn L M In 't Groen, Holm Zaehres, Marcos J Araúzo-Bravo, Hans R Schöler, Ans T van der Ploeg, W W M Pim Pijnappel
Pompe disease is a metabolic myopathy caused by deficiency of the acid α-glucosidase (GAA) enzyme and results in progressive wasting of skeletal muscle cells. The c.-32-13T>G (IVS1) GAA variant promotes exon 2 skipping during pre-mRNA splicing and is the most common variant for the childhood/adult disease form. We previously identified antisense oligonucleotides (AONs) that promoted GAA exon 2 inclusion in patient-derived fibroblasts. It was unknown how these AONs would affect GAA splicing in skeletal muscle cells...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28607084/systems-guided-forward-genetic-screen-reveals-a-critical-role-of-the-replication-stress-response-protein-etaa1-in-t-cell-clonal-expansion
#10
Lisa A Miosge, Yovina Sontani, Aaron Chuah, Keisuke Horikawa, Tiffany A Russell, Yan Mei, Mayura V Wagle, Debbie R Howard, Anselm Enders, David C Tscharke, Christopher C Goodnow, Ian A Parish
T-cell immunity requires extremely rapid clonal proliferation of rare, antigen-specific T lymphocytes to form effector cells. Here we identify a critical role for ETAA1 in this process by surveying random germ line mutations in mice using exome sequencing and bioinformatic annotation to prioritize mutations in genes of unknown function with potential effects on the immune system, followed by breeding to homozygosity and testing for immune system phenotypes. Effector CD8(+) and CD4(+) T-cell formation following immunization, lymphocytic choriomeningitis virus (LCMV) infection, or herpes simplex virus 1 (HSV1) infection was profoundly decreased despite normal immune cell development in adult mice homozygous for two different Etaa1 mutations: an exon 2 skipping allele that deletes Gly78-Leu119, and a Cys166Stop truncating allele that eliminates most of the 877-aa protein...
June 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28588571/genome-wide-transcriptome-analysis-reveals-extensive-alternative-splicing-events-in-the-protoscoleces-of-echinococcus-granulosus-and-echinococcus-multilocularis
#11
Shuai Liu, Xiaosu Zhou, Lili Hao, Xianyu Piao, Nan Hou, Qijun Chen
Alternative splicing (AS), as one of the most important topics in the post-genomic era, has been extensively studied in numerous organisms. However, little is known about the prevalence and characteristics of AS in Echinococcus species, which can cause significant health problems to humans and domestic animals. Based on high-throughput RNA-sequencing data, we performed a genome-wide survey of AS in two major pathogens of echinococcosis-Echinococcus granulosus and Echinococcus multilocularis. Our study revealed that the prevalence and characteristics of AS in protoscoleces of the two parasites were generally consistent with each other...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28570605/frameshift-indels-introduced-by-genome-editing-can-lead-to-in-frame-exon-skipping
#12
Simon Lalonde, Oliver A Stone, Samuel Lessard, Adam Lavertu, Jessica Desjardins, Mélissa Beaudoin, Manuel Rivas, Didier Y R Stainier, Guillaume Lettre
The introduction of frameshift indels by genome editing has emerged as a powerful technique to study the functions of uncharacterized genes in cell lines and model organisms. Such mutations should lead to mRNA degradation owing to nonsense-mediated mRNA decay or the production of severely truncated proteins. Here, we show that frameshift indels engineered by genome editing can also lead to skipping of "multiple of three nucleotides" exons. Such splicing events result in in-frame mRNA that may encode fully or partially functional proteins...
2017: PloS One
https://www.readbyqxmd.com/read/28566768/moving-towards-successful-exon-skipping-therapy-for-duchenne-muscular-dystrophy
#13
REVIEW
Akinori Nakamura
Duchenne muscular dystrophy (DMD) is an X chromosome-linked lethal muscular disorder with progressing muscle wasting and weakness caused by mutations in the gene encoding a subsarcolemmal protein dystrophin. For a long time, there was no effective cure; however, advances in molecular biology have allowed the development of radical treatment approaches. Among them, exon-skipping therapy using antisense oligonucleotides is very promising, because it corrects the reading frame of the dystrophin-encoding gene and restores protein expression, resulting in the conversion of DMD to a clinically milder form, Becker muscular dystrophy (BMD)...
June 1, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28541300/splicing-modulators-act-at-the-branch-point-adenosine-binding-pocket-defined-by-the-phf5a-sf3b-complex
#14
Teng Teng, Jennifer Hc Tsai, Xiaoling Puyang, Michael Seiler, Shouyong Peng, Sudeep Prajapati, Daniel Aird, Silvia Buonamici, Benjamin Caleb, Betty Chan, Laura Corson, Jacob Feala, Peter Fekkes, Baudouin Gerard, Craig Karr, Manav Korpal, Xiang Liu, Jason T Lowe, Yoshiharu Mizui, James Palacino, Eunice Park, Peter G Smith, Vanitha Subramanian, Zhenhua Jeremy Wu, Jian Zou, Lihua Yu, Agustin Chicas, Markus Warmuth, Nicholas Larsen, Ping Zhu
Pladienolide, herboxidiene and spliceostatin have been identified as splicing modulators that target SF3B1 in the SF3b subcomplex. Here we report that PHF5A, another component of this subcomplex, is also targeted by these compounds. Mutations in PHF5A-Y36, SF3B1-K1071, SF3B1-R1074 and SF3B1-V1078 confer resistance to these modulators, suggesting a common interaction site. RNA-seq analysis reveals that PHF5A-Y36C has minimal effect on basal splicing but inhibits the global action of splicing modulators. Moreover, PHF5A-Y36C alters splicing modulator-induced intron-retention/exon-skipping profile, which correlates with the differential GC content between adjacent introns and exons...
May 25, 2017: Nature Communications
https://www.readbyqxmd.com/read/28536242/mutation-in-tdrd9-causes-non-obstructive-azoospermia-in-infertile-men
#15
Maram Arafat, Iris Har-Vardi, Avi Harlev, Eliahu Levitas, Atif Zeadna, Maram Abofoul-Azab, Victor Dyomin, Val C Sheffield, Eitan Lunenfeld, Mahmoud Huleihel, Ruti Parvari
BACKGROUND: Azoospermia is diagnosed when sperm cells are completely absent in the ejaculate even after centrifugation. It is identified in approximately 1% of all men and in 10%-20% of infertile males. Non-obstructive azoospermia (NOA) is characterised by the absence of sperm due to either a Sertoli cell-only pattern, maturation arrest, hypospermatogenesis or mixed patterns. NOA is a severe form of male infertility, with limited treatment options and low fertility success rates. In the majority of patients, the cause for NOA is not known and mutations in only a few genes were shown to be causative...
May 23, 2017: Journal of Medical Genetics
https://www.readbyqxmd.com/read/28526070/the-golden-retriever-model-of-duchenne-muscular-dystrophy
#16
REVIEW
Joe N Kornegay
Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the DMD gene and loss of the protein dystrophin. The absence of dystrophin leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and contractures. Affected boys typically die in their second or third decade due to either respiratory failure or cardiomyopathy. Despite extensive attempts to develop definitive therapies for DMD, the standard of care remains prednisone, which has only palliative benefits. Animal models, mainly the mdx mouse and golden retriever muscular dystrophy (GRMD) dog, have played a key role in studies of DMD pathogenesis and treatment development...
May 19, 2017: Skeletal Muscle
https://www.readbyqxmd.com/read/28524599/modulation-of-nuclear-rest-by-alternative-splicing-a-potential-therapeutic-target-for-huntington-s-disease
#17
Guo-Lin Chen, Qi Ma, Dharmendra Goswami, Jianyu Shang, Gregory M Miller
Huntington's disease (HD) is caused by a genetically mutated huntingtin (mHtt) protein with expanded polyQ stretch, which impairs cytosolic sequestration of the repressor element-1 silencing transcription factor (REST), resulting in excessive nuclear REST and subsequent repression of neuronal genes. We recently demonstrated that REST undergoes extensive, context-dependent alternative splicing, of which exon-3 skipping (∆E3 )-a common event in human and nonhuman primates-causes loss of a motif critical for REST nuclear targeting...
May 19, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28522754/met-exon-14-mutation-encodes-an-actionable-therapeutic-target-in-lung-adenocarcinoma
#18
Xinyuan Lu, Nir Peled, John Greer, Wei Wu, Peter Choi, Alice H Berger, Sergio Wong, Kuang-Yu Jen, Youngho Seo, Byron Hann, Angela Brooks, Matthew Meyerson, Eric A Collisson
Targeting somatically activated oncogenes has revolutionized the treatment of non-small cell lung cancer (NSCLC). Mutations in the gene mesenchymal-epithelial transition (MET) near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (METΔ14). Here we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. METΔ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a Hepatocyte growth factor (HGF)-dependent manner...
May 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28505980/creation-of-a-novel-humanized-dystrophic-mouse-model-of-duchenne-muscular-dystrophy-and-application-of-a-crispr-cas9-gene-editing-therapy
#19
Courtney S Young, Ekaterina Mokhonova, Marbella Quinonez, April D Pyle, Melissa J Spencer
Duchenne muscular dystrophy is caused by mutations in DMD which disrupt the reading frame. Therapeutic strategies that restore DMD's reading frame, such as exon skipping and CRISPR/Cas9, need to be tested in the context of the human DMD sequence in vivo. We have developed a novel dystrophic mouse model by using CRISPR/Cas9 to delete exon 45 in the human DMD gene in hDMD mice, which places DMD out-of-frame. We have utilized this model to demonstrate that our clinically-relevant CRISPR/Cas9 platform, which targets deletion of human DMD exons 45-55, can be directly applied in vivo to restore dystrophin...
2017: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/28504715/human-dbr1-modulates-the-recycling-of-snrnps-to-affect-alternative-rna-splicing-and-contributes-to-the-suppression-of-cancer-development
#20
B Han, H K Park, T Ching, J Panneerselvam, H Wang, Y Shen, J Zhang, L Li, R Che, L Garmire, P Fei
The contribution of RNA processing to tumorigenesis is understudied. Here, we report that the human RNA debranching enzyme (hDBR1), when inappropriately regulated, induces oncogenesis by causing RNA processing defects, for example, splicing defects. We found that wild-type p53 and hypoxia-inducible factor 1 co-regulate hDBR1 expression, and insufficient hDBR1 leads to a higher rate of exon skipping. Transcriptomic sequencing confirmed the effect of hDBR1 on RNA splicing, and metabolite profiling supported the observation that neoplasm is triggered by a decrease in hDBR1 expression both in vitro and in vivo...
May 15, 2017: Oncogene
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