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Exon skipping

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https://www.readbyqxmd.com/read/29907980/dmd-genotype-correlations-from-duchenneconnect-endogenous-exon-skipping-is-a-factor-in-prolonged-ambulation-for-individuals-with-a-defined-mutation-sub-type
#1
Richard T Wang, Florian Barthelemy, Ann S Martin, Emilie D Douine, Ascia Eskin, Ann Lucas, Jenifer Lavigne, Holly Peay, Negar Khanlou, Lee Sweeney, Rita M Cantor, M Carrie Miceli, Stanley F Nelson
Antisense oligonucleotide (AON) mediated exon skipping is an emerging therapeutic for individuals with Duchenne muscular dystrophy (DMD). Skipping of exons adjacent to common exon deletions in DMD using AONs can produce in-frame transcripts and functional protein. Targeted skipping of DMD exons 8, 44, 45, 50, 51, 52, 53, and 55 are predicted to benefit 47% of affected individuals. We observed a correlation between mutation subgroups and age at loss of ambulation in DuchenneConnect, a large database of phenotypic and genetic data for DMD (N = 765)...
June 16, 2018: Human Mutation
https://www.readbyqxmd.com/read/29907124/exon-skipping-for-duchenne-muscular-dystrophy-a-systematic-review-and-meta-analysis
#2
Yuko Shimizu-Motohashi, Terumi Murakami, En Kimura, Hirofumi Komaki, Norio Watanabe
BACKGROUND: Exon skipping has been considered a promising therapeutic approach for Duchenne muscular dystrophy (DMD). Eteplirsen received conditional approval in the United States in 2016. To date, no systematic reviews or meta-analyses of randomized controlled trials (RCTs) of exon skipping drugs have been published to determine the pooled estimates for the effect of exon skipping in treating DMD. METHODS: A systematic review and meta-analysis of double-blind RCTs comparing exon-skipping drugs with placebo in DMD was performed...
June 15, 2018: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/29893454/a-case-of-inherited-type-1-and-type-2a-von-willebrand-disease-confirmed-by-diagnostic-exome-sequencing
#3
Ye Jee Shim, So Yun Park, Nani Jung, Heung Sik Kim, Jung-Sook Ha, Ja-Hyun Jang
A 10-year-old male and his family members visited a pediatric hematology clinic due to coagulopathy. Laboratory tests indicated von Willebrand disease (vWD) in all the family members. We conducted diagnostic exome sequencing for confirmation. The patient was confirmed to be a compound heterozygote for vWD: c.2574C > G (p.Cys858Trp) from his father (known variant of vWD type 1) and c.3390C > T (p.Pro1127_Gly1180delinsArg) from his mother (variant known to result in exon 26 skipping in vWD type 2A)...
June 12, 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29891534/new-lessons-from-an-old-gene-complex-splicing-and-a-novel-cryptic-exon-in-vhl-gene-cause-erythrocytosis-and-vhl-disease
#4
Marion Lenglet, Florence Robriquet, Klaus Schwarz, Carme Camps, Anne Couturier, David Hoogewijs, Alexandre Buffet, Samantha Jl Knight, Sophie Gad, Sophie Couvé, Franck Chesnel, Mathilde Pacault, Pierre Lindenbaum, Sylvie Job, Solenne Dumont, Thomas Besnard, Marine Cornec, Helene Dreau, Melissa Pentony, Erika Kvikstad, Sophie Deveaux, Nelly Burnichon, Sophie Ferlicot, Mathias Vilaine, Jean-Michaël Mazzella, Fabrice Airaud, Céline Garrec, Laurence Heidet, Sabine Irtan, Elpis Mantadakis, Karim Bouchireb, Klaus-Michael Debatin, Richard Redon, Stéphane Bezieau, Brigitte Bressac-de Paillerets, Bin Tean Teh, François Girodon, Maria-Luigia Randi, Maria Caterina Putti, Vincent Bours, Richard Van Wijk, Joachim R Göthert, Antonis Kattamis, Nicolas Janin, Celeste Bento, Jenny C Taylor, Yannick Arlot-Bonnemains, Stéphane Richard, Anne-Paule Gimenez-Roqueplo, Holger Cario, Betty Gardie
Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau (VHL) gene. Since this discovery, additional VHL mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHL is a major tumor suppressor gene, mutations in which were first described in patients presenting with von Hippel-Lindau disease, which is characterized by the development of highly vascularized tumors...
June 11, 2018: Blood
https://www.readbyqxmd.com/read/29888056/genetic-variation-affecting-exon-skipping-contributes-to-brain-structural-atrophy-in-alzheimer-s-disease
#5
Younghee Lee, Seonggyun Han, Dongwook Kim, Dokyoon Kim, Emrin Horgousluoglu, Shannon L Risacher, Andrew J Saykin, Kwangsik Nho
Genetic variation in cis-regulatory elements related to splicing machinery and splicing regulatory elements (SREs) results in exon skipping and undesired protein products. We developed a splicing decision model to identify actionable loci among common SNPs for gene regulation. The splicing decision model identified SNPs affecting exon skipping by analyzing sequence-driven alternative splicing (AS) models and by scanning the genome for the regions with putative SRE motifs. We used non-Hispanic Caucasians with neuroimaging, and fluid biomarkers for Alzheimer's disease (AD) and identified 17,088 common exonic SNPs affecting exon skipping...
2018: AMIA Summits on Translational Science Proceedings
https://www.readbyqxmd.com/read/29881398/identification-of-eight-spliceogenic-variants-in-brca2-exon-16-by-minigene-assays
#6
Eugenia Fraile-Bethencourt, Alberto Valenzuela-Palomo, Beatriz Díez-Gómez, Alberto Acedo, Eladio A Velasco
Genetic testing of BRCA1 and BRCA2 identifies a large number of variants of uncertain clinical significance whose functional and clinical interpretations pose a challenge for genetic counseling. Interestingly, a relevant fraction of DNA variants can disrupt the splicing process in cancer susceptibility genes. We have tested more than 200 variants throughout 19 BRCA2 exons mostly by minigene assays, 54% of which displayed aberrant splicing, thus confirming the utility of this assay to check genetic variants in the absence of patient RNA...
2018: Frontiers in Genetics
https://www.readbyqxmd.com/read/29879501/isolation-and-characterization-of-porcine-pilrb-gene-and-its-alternative-splicing-variants
#7
Xiu-Qin Yang, Xiao-Yan Jing, Cai-Xia Zhang, Yan-Fang Song, Di Liu
Paired immunoglobulin-like type 2 receptor (PILR)β regulates inflammatory responses to pathogen infection, and therefore plays an important role in host disease resistance/susceptibility. However porcine PILRβ remains poorly characterized. In this study, we obtained the cDNA (V1) of its encoding gene, PILRB, and three alternative splicing (AS) variants (V2-4). The complete coding sequence of V1 was 621 bp long encoding a polypeptide of 206 aa. Compared with V1, V2 and V3 were formed by exon-skipping in the 3'-untranslated region (UTR), while V4 was formed by alternative 3' splice site of exon 3, resulting in a premature termination codon, combined with exon skipping in the 3'-UTR...
June 4, 2018: Gene
https://www.readbyqxmd.com/read/29878199/integrating-glycomics-and-genomics-uncovers-slc10a7-as-essential-factor-for-bone-mineralization-by-regulating-post-golgi-protein-transport-and-glycosylation
#8
Angel Ashikov, Nurulamin Abu Bakar, Xiao-Yan Wen, Marco Niemeijer, Glentino Rodrigues Pinto Osorio, Koroboshka Brand-Arzamendi, Linda Hasadsri, Hana Hansikova, Kimiyo Raymond, Dorothée Vicogne, Marleen E H Simon, Rolph Pfundt, Sharita Timal, Roel Beumers, Christophe Biot, Roel Smeets, Marjan Kersten, Karin Huijben, Peter Ta Linders, Geert van den Bogaart, Sacha A F T van Hijum, Richard Rodenburg, Lambertus P van den Heuvel, Francjan van Spronsen, Tomas Honzik, Francois Foulquier, Monique van Scherpenzeel, Dirk J Lefeber
Genomics methodologies have significantly improved elucidation of Mendelian disorders. The combination with high-throughput functional-omics technologies potentiates the identification and confirmation of causative genetic variants, especially in singleton families of recessive inheritance. In a cohort of 99 individuals with abnormal Golgi glycosylation, 47 of which being unsolved, glycomics profiling was performed of total plasma glycoproteins. Combination with whole-exome sequencing in 31 cases revealed a known genetic defect in 15 individuals...
June 5, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29860876/the-macrophage-as-a-trojan-horse-for-antisense-oligonucleotide-delivery
#9
James S Novak, Jyoti K Jaiswal, Terence A Partridge
No abstract text is available yet for this article.
June 7, 2018: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29858054/saponins-as-natural-adjuvant-for-antisense-morpholino-oligonucleotides-delivery-in-vitro-and-in-mdx-mice
#10
Mingxing Wang, Bo Wu, Sapana N Shah, Peijuan Lu, Qilong Lu
Antisense oligonucleotide (AON) therapy for Duchenne muscular dystrophy has drawn great attention in preclinical and clinical trials, but its therapeutic applications are still limited due to inefficient delivery. In this study, we investigated a few saponins for their potential to improve delivery performance of an antisense phosphorodiamidate morpholino oligomer (PMO) both in vitro and in vivo. The results showed that these saponins, especially digitonin and tomatine, improve the delivery efficiency of PMO comparable to Endo-Porter-mediated PMO delivery in vitro...
June 1, 2018: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/29858053/repurposing-dantrolene-for-long-term-combination-therapy-to-potentiate-antisense-mediated-dmd-exon-skipping-in-the-mdx-mouse
#11
Derek W Wang, Ekaterina I Mokhonova, Genevieve C Kendall, Diana Becerra, Yalda B Naeini, Rita M Cantor, Melissa J Spencer, Stanley F Nelson, M Carrie Miceli
Duchenne muscular dystrophy (DMD) is caused by mutations in DMD, resulting in loss of dystrophin, which is essential to muscle health. DMD "exon skipping" uses anti-sense oligo-nucleotides (AONs) to force specific exon exclusion during mRNA processing to restore reading frame and rescue of partially functional dystrophin protein. Although exon-skipping drugs in humans show promise, levels of rescued dystrophin protein remain suboptimal. We previously identified dantrolene as a skip booster when combined with AON in human DMD cultures and short-term mdx dystrophic mouse studies...
June 1, 2018: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/29850846/a-survey-of-transcriptome-complexity-in-sus-scrofa-using-single-molecule-long-read-sequencing
#12
Yao Li, Chengchi Fang, Yuhua Fu, An Hu, Cencen Li, Cheng Zou, Xinyun Li, Shuhong Zhao, Chengjun Zhang, Changchun Li
Alternative splicing (AS) and fusion transcripts produce a vast expansion of transcriptomes and proteomes diversity. However, the reliability of these events and the extend of epigenetic mechanisms have not been adequately addressed due to its limitation of uncertainties about the complete structure of mRNA. Here we combined single-molecule real-time sequencing, Illumina RNA-seq and DNA methylation data to characterize the landscapes of DNA methylation on AS, fusion isoforms formation and lncRNA feature and further to unveil the transcriptome complexity of pig...
May 29, 2018: DNA Research: An International Journal for Rapid Publication of Reports on Genes and Genomes
https://www.readbyqxmd.com/read/29849037/further-evidence-for-gain-of-function-mechanism-of-dfna5-related-hearing-loss
#13
Hongyang Wang, Jing Guan, Liping Guan, Ju Yang, Kaiwen Wu, Qiongfen Lin, Wenping Xiong, Lan Lan, Cui Zhao, Linyi Xie, Lan Yu, Dan Bing, Lidong Zhao, Dayong Wang, Qiuju Wang
To report two DFNA5 pathogenic splice-site variations and a novel benign frameshift variation to further support the gain-of-function mechanism of DFNA5 related hearing impairment, targeted genes capture and next generation sequencing were performed on selected members from Family 1007208, 1007081 and a sporadic case with sensorineural hearing loss. Reverse transcriptase polymerase chain reaction was conducted on the proband from Family 1007208 to test how the splice-site variation affects the transcription in RNA level...
May 30, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29847600/mutation-spectrum-analysis-of-duchenne-becker-muscular-dystrophy-in-68-families-in-kuwait-the-era-of-personalized-medicine
#14
Fawziah Mohammed, Alaa Elshafey, Haya Al-Balool, Hayat Alaboud, Mohammed Al Ben Ali, Adel Baqer, Laila Bastaki
Duchenne and Becker muscular dystrophies (DMD/BMD) are X-linked recessive neuromuscular disorders characterized by progressive irreversible muscle weakness and atrophy that affect both skeletal and cardiac muscles. DMD/BMD is caused by mutations in the Dystrophin gene on the X chromosome, leading to the absence of the essential muscle protein Dystrophin in DMD. In BMD, Dystrophin is partially functioning with a shorter protein product. Recent advances in molecular therapies for DMD require precise genetic diagnoses because most therapeutic strategies are mutation-specific...
2018: PloS One
https://www.readbyqxmd.com/read/29845112/-anxa11-mutations-prevail-in-chinese-als-patients-with-and-without-cognitive-dementia
#15
Kang Zhang, Qing Liu, Keqiang Liu, Dongchao Shen, Hongfei Tai, Shi Shu, Qingyun Ding, Hanhui Fu, Shuangwu Liu, Zhili Wang, Xiaoguang Li, Mingsheng Liu, Xue Zhang, Liying Cui
Objective: To investigate the genetic contribution of ANXA11 , a gene associated with amyotrophic lateral sclerosis (ALS), in Chinese ALS patients with and without cognitive dementia. Methods: Sequencing all the coding exons of ANXA11 and intron-exon boundaries in 18 familial amyotrophic lateral sclerosis (FALS), 353 unrelated sporadic amyotrophic lateral sclerosis (SALS), and 12 Chinese patients with ALS-frontotemporal lobar dementia (ALS-FTD). The transcripts in peripheral blood generated from a splicing mutation were examined by reverse transcriptase PCR...
June 2018: Neurology. Genetics
https://www.readbyqxmd.com/read/29844105/inhibition-of-sf3b1-by-molecules-targeting-the-spliceosome-results-in-massive-aberrant-exon-skipping
#16
Gang Wu, Liying Fan, Michael N Edmondson, Timothy Shaw, Kristy Boggs, John Easton, Michael C Rusch, Thomas R Webb, Jinghui Zhang, Philip M Potter
The recent identification of compounds that interact the spliceosome (sudemycins, spliceostatin A, and meamycin) indicate that these molecules modulate alternative splicing via SF3B1 inhibition. Through whole transcriptome sequencing, we have demonstrated that treatment of Rh18 cells with sudemycin leads to exon skipping as the predominant aberrant splicing event. This was also observed following reanalysis of published RNAseq datasets derived from Hela cells after spliceostatin A exposure. These results are in contrast to previous reports that indicate that intron retention was the major consequence of SF3B1 inhibition...
May 29, 2018: RNA
https://www.readbyqxmd.com/read/29802995/autoregulation-of-the-human-splice-factor-kinase-clk1-through-exon-skipping-and-intron-retention
#17
Simon Uzor, Panagiota Zorzou, Elizabeth Bowler, Sean Porazinski, Ian Wilson, Michael Ladomery
Alternative splicing is a key process required for the regulation of gene expression in normal development and physiology. It is regulated by splice factors whose activities are in turn regulated by splice factor kinases and phosphatases. The CDC-like protein kinases are a widespread family of splice factor kinases involved in normal physiology and in several diseases including cancer. In humans they include the CLK1, CLK2, CLK3 and CLK4 genes. The expression of CLK1 is regulated through alternative splicing producing both full-length catalytically active and truncated catalytically inactive isoforms, CLKT1 (arising from exon 4 skipping) and CLKT2 (arising from intron 4 retention)...
May 23, 2018: Gene
https://www.readbyqxmd.com/read/29801479/splicing-defect-in-fkbp10-gene-causes-autosomal-recessive-osteogenesis-imperfecta-disease-a-case-report
#18
Fatemeh Maghami, Seyed Mohammad Bagher Tabei, Hossein Moravej, Hassan Dastsooz, Farzaneh Modarresi, Mohammad Silawi, Mohammad Ali Faghihi
BACKGROUND: Osteogenesis imperfecta (OI) is a group of connective tissue disorder caused by mutations of genes involved in the production of collagen and its supporting proteins. Although the majority of reported OI variants are in COL1A1 and COL1A2 genes, recent reports have shown problems in other non-collagenous genes involved in the post translational modifications, folding and transport, transcription and proliferation of osteoblasts, bone mineralization, and cell signaling. Up to now, 17 types of OI have been reported in which types I to IV are the most frequent cases with autosomal dominant pattern of inheritance...
May 25, 2018: BMC Medical Genetics
https://www.readbyqxmd.com/read/29799103/c-835-5t-g-variant-in-smn1-gene-causes-transcript-exclusion-of-exon-7-and-spinal-muscular-atrophy
#19
Shuang Wu, Yun-Lu Li, Ning-Yi Cheng, Chong Wang, En-Lin Dong, Ying-Qian Lu, Jin-Jing Li, Xin-Xin Guo, Xiang Lin, Lu-Lu Lai, Zhi-Wei Liu, Ning Wang, Wan-Jin Chen
Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder caused by survival motor neuron (SMN) protein deficiency leading the loss of motor neurons in the anterior horns of the spinal cord and brainstem. More than 95% of SMA patients are attributed to the homozygous deletion of survival motor neuron 1 (SMN1) gene, and approximately 5% are caused by compound heterozygous with a SMN1 deletion and a subtle mutation. Here, we identified a rare variant c.835-5T>G in intron 6 of SMN1 in a patient affected with type I SMA...
May 24, 2018: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/29797630/histopathological-analysis-of-aggressive-renal-cell-carcinoma-harboring-a-unique-germline-mutation-in-fumarate-hydratase
#20
Kana Matsumoto, Naoko Udaka, Hisashi Hasumi, Noboru Nakaigawa, Yoji Nagashima, Reiko Tanaka, Ikuma Kato, Masahiro Yao, Mitsuko Furuya
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare genetic disorder characterized by cutaneous and uterine leiomyomatosis with RCC. This disorder is caused by a germline mutation in the fumarate hydratase (FH) gene, which encodes an important enzyme of the tricarboxylic acid (TCA) cycle. This mutation distinguishes HLRCC from sporadic RCCs. Herein, we investigated a case of HLRCC in a 32-year-old man who underwent nephrectomy for treatment of a solid-cystic tumor in the left kidney. Histopathology demonstrated a variegated architecture of papillary, tubulocystic and cribriform patterns composed of high-grade tumor cells with enlarged nuclei and eosinophilic nucleoli...
May 24, 2018: Pathology International
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