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Exon skipping in humans

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https://www.readbyqxmd.com/read/29339778/a-novel-human-muscle-cell-model-of-duchenne-muscular-dystrophy-created-by-crispr-cas9-and-evaluation-of-antisense-mediated-exon-skipping
#1
Takenori Shimo, Kana Hosoki, Yusuke Nakatsuji, Toshifumi Yokota, Satoshi Obika
Oligonucleotide-mediated splicing modulation is a promising therapeutic approach for Duchenne muscular dystrophy (DMD). Recently, eteplirsen, a phosphorodiamidate morpholino oligomer-based splice-switching oligonucleotide (SSO) targeting DMD exon 51, was approved by the U.S. Food and Drug Administration as the first antisense-based drug for DMD patients. For further exploring SSOs targeting other exons in the DMD gene, the efficacy of exon skipping and protein rescue with each SSO sequence needs evaluations in vitro...
January 16, 2018: Journal of Human Genetics
https://www.readbyqxmd.com/read/29329284/identification-of-an-elaborate-nk-specific-system-regulating-hla-c-expression
#2
Hongchuan Li, Martin A Ivarsson, Victoria E Walker-Sperling, Jeff Subleski, Jenna K Johnson, Paul W Wright, Mary Carrington, Niklas K Björkström, Daniel W McVicar, Stephen K Anderson
The HLA-C gene appears to have evolved in higher primates to serve as a dominant source of ligands for the KIR2D family of inhibitory MHC class I receptors. The expression of NK cell-intrinsic MHC class I has been shown to regulate the murine Ly49 family of MHC class I receptors due to the interaction of these receptors with NK cell MHC in cis. However, cis interactions have not been demonstrated for the human KIR and HLA proteins. We report the discovery of an elaborate NK cell-specific system regulating HLA-C expression, indicating an important role for HLA-C in the development and function of NK cells...
January 12, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29243290/a-non-coding-variant-in-ganab-explains-isolated-polycystic-liver-disease-pcld-in-a-large-family
#3
Whitney Besse, Jungmin Choi, Dina Ahram, Shrikant Mane, Simone Sanna-Cherchi, Vicente Torres, Stefan Somlo
Expanded mutation detection and novel gene discovery for isolated polycystic liver disease (PCLD) are necessary as 50% of cases do not have identified mutations in the seven published disease genes. We investigated a family with 5 affected siblings for which no loss of function variants were identified by whole exome sequencing analysis. SNP genotyping and linkage analysis narrowed the candidate regions to ∼8% of the genome, which included two published PCLD genes in close proximity to each other, GANAB and LRP5...
December 15, 2017: Human Mutation
https://www.readbyqxmd.com/read/29231888/analysis-and-prediction-of-exon-skipping-events-from-rna-seq-with-sequence-information-using-rotation-forest
#4
Xiuquan Du, Changlin Hu, Yu Yao, Shiwei Sun, Yanping Zhang
In bioinformatics, exon skipping (ES) event prediction is an essential part of alternative splicing (AS) event analysis. Although many methods have been developed to predict ES events, a solution has yet to be found. In this study, given the limitations of machine learning algorithms with RNA-Seq data or genome sequences, a new feature, called RS (RNA-seq and sequence) features, was constructed. These features include RNA-Seq features derived from the RNA-Seq data and sequence features derived from genome sequences...
December 12, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29187847/a-multilayered-control-of-the-human-survival-motor-neuron-gene-expression-by-alu-elements
#5
REVIEW
Eric W Ottesen, Joonbae Seo, Natalia N Singh, Ravindra N Singh
Humans carry two nearly identical copies of Survival Motor Neuron gene: SMN1 and SMN2. Mutations or deletions of SMN1, which codes for SMN, cause spinal muscular atrophy (SMA), a leading genetic disease associated with infant mortality. Aberrant expression or localization of SMN has been also implicated in other pathological conditions, including male infertility, inclusion body myositis, amyotrophic lateral sclerosis and osteoarthritis. SMN2 fails to compensate for the loss of SMN1 due to skipping of exon 7, leading to the production of SMNΔ7, an unstable protein...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29167380/self-oligomerization-regulates-stability-of-survival-motor-neuron-smn-protein-isoforms-by-sequestering-an-scf-slmb-degron
#6
Kelsey M Gray, Kevin A Kaifer, David Baillat, Ying Wen, Thomas R Bonacci, Allison D Ebert, Amanda C Raimer, Ashlyn M Spring, Sara Ten Have, Jacqueline J Glascock, Kushol Gupta, Gregory D Van Duyne, Michael J Emanuele, Angus I Lamond, Eric J Wagner, Christian L Lorson, A Gregory Matera
Spinal muscular atrophy (SMA) is caused by homozygous mutations in human SMN1 Expression of a duplicate gene (SMN2) primarily results in skipping of exon 7 and production of an unstable protein isoform, SMNΔ7. Although SMN2 exon skipping is the principal contributor to SMA severity, mechanisms governing stability of SMN isoforms are poorly understood. We used a Drosophila model system and label-free proteomics to identify the SCF(Slmb) ubiquitin E3 ligase complex as a novel SMN binding partner. SCF(Slmb) interacts with a phospho-degron embedded within the human and fruitfly SMN YG-box oligomerization domains...
November 22, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29162642/abca4-midigenes-reveal-the-full-splice-spectrum-of-all-reported-noncanonical-splice-site-variants-in-stargardt-disease
#7
Riccardo Sangermano, Mubeen Khan, Stéphanie S Cornelis, Valerie Richelle, Silvia Albert, Alejandro Garanto, Duaa Elmelik, Raheel Qamar, Dorien Lugtenberg, L Ingeborgh van den Born, Rob W J Collin, Frans P M Cremers
Stargardt disease is caused by variants in the ABCA4 gene, a significant part of which are noncanonical splice site (NCSS) variants. In case a gene of interest is not expressed in available somatic cells, small genomic fragments carrying potential disease-associated variants are tested for splice abnormalities using in vitro splice assays. We recently discovered that when using small minigenes lacking the proper genomic context, in vitro results do not correlate with splice defects observed in patient cells...
November 21, 2017: Genome Research
https://www.readbyqxmd.com/read/29122468/an-intronic-variation-in-slc52a1-causes-exon-skipping-and-transient-riboflavin-responsive-multiple-acyl-coa-dehydrogenation-deficiency
#8
Signe Mosegaard, Gitte Hoffmann Bruun, Karen Freund Flyvbjerg, Yngve Thomas Bliksrud, Niels Gregersen, Maja Dembic, Ellen Annexstad, Trine Tangeraas, Rikke Katrine Jentoft Olsen, Brage S Andresen
Vitamin B2, riboflavin is essential for cellular function, as it participates in a diversity of redox reactions central to human metabolism, through its role as precursor for the cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are electron carriers. The electron transfer flavoprotein (ETF) and its dehydrogenase (ETFDH), uses FAD as cofactor. The ETF and ETFDH are forming the electron transport pathway for many mitochondrial flavoprotein dehydrogenases involved in fatty acid, amino acid and choline metabolism...
November 2, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29121990/identification-of-functional-single-nucleotide-polymorphisms-in-the-branchpoint-site
#9
Hung-Lun Chiang, Jer-Yuarn Wu, Yuan-Tsong Chen
BACKGROUND: The human genome contains millions of single nucleotide polymorphisms (SNPs); many of these SNPs are intronic and have unknown functional significance. SNPs occurring within intron branchpoint sites, especially at the adenine (A), would presumably affect splicing; however, this has not been systematically studied. We employed a splicing prediction tool to identify human intron branchpoint sites and screened dbSNP for identifying SNPs located in the predicted sites to generate a genome-wide branchpoint site SNP database...
November 9, 2017: Human Genomics
https://www.readbyqxmd.com/read/29059470/banf1-plod3-sf3b4-as-early-stage-cancer-decision-markers-and-drivers-of-hepatocellular-carcinoma
#10
Qingyu Shen, Jung Woo Eun, Kyungbun Lee, Hyung Seok Kim, Hee Doo Yang, Sang Yean Kim, Eun Kyung Lee, Taemook Kim, Keunsoo Kang, Seongchan Kim, Dal-Hee Min, Soon-Nam Oh, Young-Joon Lee, Hyuk Moon, Simon Weonsang Ro, Won Sang Park, Jung Young Lee, Suk Woo Nam
An accurate tool enabling early diagnosis of hepatocellular carcinoma (HCC) is clinically important, since early detection of HCC markedly improves survival. We aimed to investigate the molecular markers underlying early progression of HCC that can be detected in precancerous lesions. We designed a gene selection strategy to identify potential driver genes by integrative analysis of transcriptome and clinicopathologic data of human multi-stage HCC tissues including precancerous lesions, low- and high-grade dysplastic nodules...
October 23, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29025893/disease-specific-biases-in-alternative-splicing-and-tissue-specific-dysregulation-revealed-by-multitissue-profiling-of-lymphocyte-gene-expression-in-type-1-diabetes
#11
Jeremy R B Newman, Ana Conesa, Matthew Mika, Felicia N New, Suna Onengut-Gumuscu, Mark A Atkinson, Stephen S Rich, Lauren M McIntyre, Patrick Concannon
Genome-wide association studies (GWAS) have identified multiple, shared allelic associations with many autoimmune diseases. However, the pathogenic contributions of variants residing in risk loci remain unresolved. The location of the majority of shared disease-associated variants in noncoding regions suggests they contribute to risk of autoimmunity through effects on gene expression in the immune system. In the current study, we test this hypothesis by applying RNA sequencing to CD4(+), CD8(+), and CD19(+) lymphocyte populations isolated from 81 subjects with type 1 diabetes (T1D)...
November 2017: Genome Research
https://www.readbyqxmd.com/read/28984045/differentially-expressed-alternatively-spliced-genes-in-skeletal-muscle-from-cancer-patients-with-cachexia
#12
Ashok Narasimhan, Russell Greiner, Oliver F Bathe, Vickie Baracos, Sambasivarao Damaraju
BACKGROUND: Alternative splicing (AS) is a post-transcriptional gene regulatory mechanism that contributes to proteome diversity. Aberrant splicing mechanisms contribute to various cancers and muscle-related conditions such as Duchenne muscular dystrophy. However, dysregulation of AS in cancer cachexia (CC) remains unexplored. Our objectives were (i) to profile alternatively spliced genes (ASGs) on a genome-wide scale and (ii) to identify differentially expressed alternatively spliced genes (DASGs) associated with CC...
October 6, 2017: Journal of Cachexia, Sarcopenia and Muscle
https://www.readbyqxmd.com/read/28973015/a-small-molecule-drug-promoting-mirna-processing-induces-alternative-splicing-of-mdmx-transcript-and-rescues-p53-activity-in-human-cancer-cells-overexpressing-mdmx-protein
#13
Georgios Valianatos, Barbora Valcikova, Katerina Growkova, Amandine Verlande, Jitka Mlcochova, Lenka Radova, Monika Stetkova, Michaela Vyhnakova, Ondrej Slaby, Stjepan Uldrijan
MdmX overexpression contributes to the development of cancer by inhibiting tumor suppressor p53. A switch in the alternative splicing of MdmX transcript, leading to the inclusion of exon 6, has been identified as the primary mechanism responsible for increased MdmX protein levels in human cancers, including melanoma. However, there are no approved drugs, which could translate these new findings into clinical applications. We analyzed the anti-melanoma activity of enoxacin, a fluoroquinolone antibiotic inhibiting the growth of some human cancers in vitro and in vivo by promoting miRNA maturation...
2017: PloS One
https://www.readbyqxmd.com/read/28934498/widespread-intra-dependencies-in-the-removal-of-introns-from-human-transcripts
#14
Seong Won Kim, Allison J Taggart, Claire Heintzelman, Kamil J Cygan, Caitlin G Hull, Jing Wang, Barsha Shrestha, William G Fairbrother
Research into the problem of splice site selection has followed a reductionist approach focused on how individual splice sites are recognized. Early applications of information theory uncovered an inconsistency. Human splice signals do not contain enough information to explain the observed fidelity of splicing. Here, we conclude that introns do not necessarily contain 'missing' information but rather may require definition from neighboring processing events. For example, there are known cases where an intronic mutation disrupts the splicing of not only the local intron but also adjacent introns...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28932105/changes-in-alternative-splicing-as-pharmacodynamic-markers-for-sudemycin-d6
#15
Morgan Thurman, Jacob van Doorn, Barbara Danzer, Thomas R Webb, Stefan Stamm
OBJECTIVE: The aim of the study was to define pharmacodynamic markers for sudemycin D6, an experimental cancer drug that changes alternative splicing in human blood. METHODS: Blood samples from 12 donors were incubated with sudemycin D6 for up to 24 hours, and at several time points total RNA from lymphocytes was prepared and the pre-messenger RNA (mRNA) splicing patterns were analyzed with reverse transcription-polymerase chain reaction. RESULTS: Similar to immortalized cells, blood lymphocytes change alternative splicing due to sudemycin D6 treatment...
2017: Biomarker Insights
https://www.readbyqxmd.com/read/28916811/an-enu-induced-splice-site-mutation-of-mouse-col1a1-causing-recessive-osteogenesis-imperfecta-and-revealing-a-novel-splicing-rescue
#16
Koichi Tabeta, Xin Du, Kei Arimatsu, Mai Yokoji, Naoki Takahashi, Norio Amizuka, Tomoka Hasegawa, Karine Crozat, Tomoki Maekawa, Sayuri Miyauchi, Yumi Matsuda, Takako Ida, Masaru Kaku, Kasper Hoebe, Kinji Ohno, Hiromasa Yoshie, Kazuhisa Yamazaki, Eva Marie Y Moresco, Bruce Beutler
GU-AG consensus sequences are used for intron recognition in the majority of cases of pre-mRNA splicing in eukaryotes. Mutations at splice junctions often cause exon skipping, short deletions, or insertions in the mature mRNA, underlying one common molecular mechanism of genetic diseases. Using N-ethyl-N-nitrosourea, a novel recessive mutation named seal was produced, associated with fragile bones and susceptibility to fractures (spine and limbs). A single nucleotide transversion (T → A) at the second position of intron 36 of the Col1a1 gene, encoding the type I collagen, α1 chain, was responsible for the phenotype...
September 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28865998/quantitative-antisense-screening-and-optimization-for-exon-51-skipping-in-duchenne-muscular-dystrophy
#17
Yusuke Echigoya, Kenji Rowel Q Lim, Nhu Trieu, Bo Bao, Bailey Miskew Nichols, Maria Candida Vila, James S Novak, Yuko Hara, Joshua Lee, Aleksander Touznik, Kamel Mamchaoui, Yoshitsugu Aoki, Shin'ichi Takeda, Kanneboyina Nagaraju, Vincent Mouly, Rika Maruyama, William Duddy, Toshifumi Yokota
Duchenne muscular dystrophy (DMD), the most common lethal genetic disorder, is caused by mutations in the dystrophin (DMD) gene. Exon skipping is a therapeutic approach that uses antisense oligonucleotides (AOs) to modulate splicing and restore the reading frame, leading to truncated, yet functional protein expression. In 2016, the US Food and Drug Administration (FDA) conditionally approved the first phosphorodiamidate morpholino oligomer (morpholino)-based AO drug, eteplirsen, developed for DMD exon 51 skipping...
November 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
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
#18
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)...
September 30, 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
#19
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
#20
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...
September 28, 2017: Cancer Letters
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