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Exon skipping

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https://www.readbyqxmd.com/read/28644393/mutations-in-the-genes-for-interphotoreceptor-matrix-proteoglycans-impg1-and-impg2-in-patients-with-vitelliform-macular-lesions
#1
Caroline Brandl, Heidi L Schulz, Peter Charbel Issa, Johannes Birtel, Richard Bergholz, Clemens Lange, Claudia Dahlke, Ditta Zobor, Bernhard H F Weber, Heidi Stöhr
A significant portion of patients diagnosed with vitelliform macular dystrophy (VMD) do not carry causative mutations in the classic VMD genes BEST1 or PRPH2. We therefore performed a mutational screen in a cohort of 106 BEST1/PRPH2-negative VMD patients in two genes encoding secreted interphotoreceptor matrix proteoglycans-1 and -2 (IMPG1 and IMPG2). We identified two novel mutations in IMPG1 in two simplex VMD cases with disease onset in their early childhood, a heterozygous p.(Leu238Pro) missense mutation and a homozygous c...
June 23, 2017: Genes
https://www.readbyqxmd.com/read/28642487/hypoxia-is-a-key-driver-of-alternative-splicing-in-human-breast-cancer-cells
#2
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/28633548/polyquaternium-mediated-delivery-of-morpholino-oligonucleotides-for-exon-skipping-in-vitro-and-in-mdx-mice
#3
Mingxing Wang, Bo Wu, Sapana N Shah, Peijuan Lu, Qilong Lu
Antisense oligonucleotide therapy for Duchenne muscular dystrophy has shown great potential in preclinical and clinical trials, but its therapeutic applications are still limited due to inefficient delivery. In this study, we investigated a few polyquaterniums (PQs) with different size and composition for their potential to improve delivery performance of an antisense phosphorodiamidate morpholino oligomer (PMO) both in vitro and in vivo. The results showed that Luviquat(TM) series, especially PQ-1 and PQ-3, promoted the exon-skipping efficiency comparable to Endoporter-mediated PMO delivery in vitro...
November 2017: Drug Delivery
https://www.readbyqxmd.com/read/28624228/antisense-oligonucleotides-promote-exon-inclusion-and-correct-the-common-c-32-13t-g-gaa-splicing-variant-in-pompe-disease
#4
Erik van der Wal, Atze J Bergsma, Joon M Pijnenburg, Ans T van der Ploeg, W W M Pim Pijnappel
The most common variant causing Pompe disease is c.-32-13T>G (IVS1) in the acid α-glucosidase (GAA) gene, which weakens the splice acceptor of GAA exon 2 and induces partial and complete exon 2 skipping. It also allows a low level of leaky wild-type splicing, leading to a childhood/adult phenotype. We hypothesized that cis-acting splicing motifs may exist that could be blocked using antisense oligonucleotides (AONs) to promote exon inclusion. To test this, a screen was performed in patient-derived primary fibroblasts using a tiling array of U7 small nuclear RNA (snRNA)-based AONs...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28624223/evaluation-of-mybpc3-trans-splicing-and-gene-replacement-as-therapeutic-options-in-human-ipsc-derived-cardiomyocytes
#5
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
#6
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/28615073/crispr-cas9-mediated-genome-editing-induces-exon-skipping-by-alternative-splicing-or-exon-deletion
#7
Haiwei Mou, Jordan L Smith, Lingtao Peng, Hao Yin, Jill Moore, Xiao-Ou Zhang, Chun-Qing Song, Ankur Sheel, Qiongqiong Wu, Deniz M Ozata, Yingxiang Li, Daniel G Anderson, Charles P Emerson, Erik J Sontheimer, Melissa J Moore, Zhiping Weng, Wen Xue
CRISPR is widely used to disrupt gene function by inducing small insertions and deletions. Here, we show that some single-guide RNAs (sgRNAs) can induce exon skipping or large genomic deletions that delete exons. For example, CRISPR-mediated editing of β-catenin exon 3, which encodes an autoinhibitory domain, induces partial skipping of the in-frame exon and nuclear accumulation of β-catenin. A single sgRNA can induce small insertions or deletions that partially alter splicing or unexpected larger deletions that remove exons...
June 14, 2017: Genome Biology
https://www.readbyqxmd.com/read/28615035/unexpected-consequences-exon-skipping-caused-by-crispr-generated-mutations
#8
Joshua J Sharpe, Thomas A Cooper
A new study finds that splicing disruption is a frequent consequence of mutations generated by CRISPR/Cas9 gene-editing technology, and alleles designed to be null can express aberrant proteins. This new information allows enhanced quality control procedures to select the best mutant alleles generated by CRISPR/Cas9.Please see related Method article: https://www.doi.org/10.1186/s13059-017-1237-8.
June 14, 2017: Genome Biology
https://www.readbyqxmd.com/read/28608266/potentially-pathogenic-germline-chek2-c-319-2t-a-among-multiple-early-onset-cancer-families
#9
Mev Dominguez-Valentin, Sigve Nakken, Hélène Tubeuf, Daniel Vodak, Per Olaf Ekstrøm, Anke M Nissen, Monika Morak, Elke Holinski-Feder, Alexandra Martins, Pål Møller, Eivind Hovig
To study the potential contribution of genes other than BRCA1/2, PTEN, and TP53 to the biological and clinical characteristics of multiple early-onset cancers in Norwegian families, including early-onset breast cancer, Cowden-like and Li-Fraumeni-like syndromes (BC, CSL and LFL, respectively). The Hereditary Cancer Biobank from the Norwegian Radium Hospital was used to identify early-onset BC, CSL or LFL for whom no pathogenic variants in BRCA1/2, PTEN, or TP53 had been found in routine diagnostic DNA sequencing...
June 12, 2017: Familial Cancer
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 12, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28604967/-analysis-of-a-multiple-osteochondroma-case-caused-by-novel-splice-mutation-c-1164-1g-to-a-of-ext1-gene
#11
Xiaoyan Guo, Wenxu Chen, Mingrui Lin, Tengfei Shi, Dianhua Huang, Zhihong Wang
OBJECTIVE: To detect potential mutation of EXT1 gene in a pedigree affected with multiple osteochondroma and explore its pathogenic mechanism. METHODS: The coding regions and their flanking sequences of the EXT1/EXT2 genes were subjected to PCR amplification and Sanger sequencing. Suspected mutations were verified by excluding possible single nucleotide polymorphisms and bioinformatics analysis. Transcripts of the EXT1 gene in the proband were analyzed by TA clone-sequencing, with its abundance compared with that of healthy controls...
June 10, 2017: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
https://www.readbyqxmd.com/read/28595629/identification-and-description-of-three-families-with-familial-alzheimer-disease-that-segregate-variants-in-the-sorl1-gene
#12
Håkan Thonberg, Huei-Hsin Chiang, Lena Lilius, Charlotte Forsell, Anna-Karin Lindström, Charlotte Johansson, Jenny Björkström, Steinunn Thordardottir, Kristel Sleegers, Christine Van Broeckhoven, Annica Rönnbäck, Caroline Graff
Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. The majority of AD cases are sporadic, while up to 5% are families with an early onset AD (EOAD). Mutations in one of the three genes: amyloid beta precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) can be disease causing. However, most EOAD families do not carry mutations in any of these three genes, and candidate genes, such as the sortilin-related receptor 1 (SORL1), have been suggested to be potentially causative...
June 9, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28592875/splice-variants-as-novel-targets-in-pancreatic-ductal-adenocarcinoma
#13
Jun Wang, Laurent Dumartin, Andrea Mafficini, Pinar Ulug, Ajanthah Sangaralingam, Namaa Audi Alamiry, Tomasz P Radon, Roberto Salvia, Rita T Lawlor, Nicholas R Lemoine, Aldo Scarpa, Claude Chelala, Tatjana Crnogorac-Jurcevic
Despite a wealth of genomic information, a comprehensive alternative splicing (AS) analysis of pancreatic ductal adenocarcinoma (PDAC) has not been performed yet. In the present study, we assessed whole exome-based transcriptome and AS profiles of 43 pancreas tissues using Affymetrix exon array. The AS analysis of PDAC indicated on average two AS probe-sets (ranging from 1-28) in 1,354 significantly identified protein-coding genes, with skipped exon and alternative first exon being the most frequently utilised...
June 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28588848/a-case-of-megalencephalic-leukoencephalopathy-with-subcortical-cysts-type-1-was-identified-with-a-novel-compound-heterozygous-alteration-c-135delc-c-423-2dupt-in-china
#14
Cong-Ling Dai, Wen-Bin He, Juan Du, Yue-Qiu Tan, Guang-Xiu Lu, Wen Li
We report a compound heterozygous mutation (c.135delC; c.423+2dupT) of MLC1 gene in a Chinese patient underlying infantile macrocephaly and neurological deterioration in early childhood. Brain MRI revealed diffusion abnormality in swollen white matter and a subcortical cyst. The cDNA sequencing analysis for the c.423+2dupT variant revealed skipping of exon 5.
June 2017: Clinical Case Reports
https://www.readbyqxmd.com/read/28588571/genome-wide-transcriptome-analysis-reveals-extensive-alternative-splicing-events-in-the-protoscoleces-of-echinococcus-granulosus-and-echinococcus-multilocularis
#15
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/28587017/case-series-of-met-exon-14-skipping-mutation-positive-non-small-cell-lung-cancers-and-response-to-crizotinib
#16
S X Wang, B Zhang, H A Wakelee, M Diehn, C Kunder, J W Neal
No abstract text is available yet for this article.
May 1, 2017: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/28586478/autoregulation-of-rbm10-and-cross-regulation-of-rbm10-rbm5-via-alternative-splicing-coupled-nonsense-mediated-decay
#17
Yue Sun, Yufang Bao, Wenjian Han, Fan Song, Xianfeng Shen, Jiawei Zhao, Ji Zuo, David Saffen, Wei Chen, Zefeng Wang, Xintian You, Yongbo Wang
Mutations in the spliceosomal RNA binding protein RBM10 cause TARP syndrome and are frequently observed in lung adenocarcinoma (LUAD). We have previously shown that RBM10 enhances exon skipping of its target genes, including its paralog RBM5. Here, we report that RBM10 negatively regulates its own mRNA and protein expression and that of RBM5 by promoting alternative splicing-coupled nonsense-mediated mRNA decay (AS-NMD). Through computational analysis and experimental validation, we identified RBM10-promoted skipping of exon 6 or 12 in RBM10 and exon 6 or 16 in RBM5 as the underlying AS-NMD events...
June 6, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28582853/investigating-the-exon-6-sequence-changes-of-interleukin-7-receptor-a-il7ra-gene-in-patients-with-relapsing-remitting-multiple-sclerosis
#18
Mohammad Taheri, Arezou Sayad
BACKGROUND: Interleukin 7 receptor alpha (IL7RA) gene that encodes a subunit of IL7 receptor has been reported to be associated with different immunologic disease. OBJECTIVE: Multiple Sclerosis (MS) patients have shown an aberrant blood level of soluble form of IL7R protein. The genomic changes in the sequence of this gene have been suggested to be correlated with its altered splicing specially, variants in the exon 6 of the gene have been reported to influence the maintenance or skipping of this exon and control the soluble or insoluble form of the final product...
May 12, 2017: Human Antibodies
https://www.readbyqxmd.com/read/28577945/systematic-identification-of-cancer-related-long-noncoding-rnas-and-aberrant-alternative-splicing-of-quintuple-negative-lung-adenocarcinoma-through-rna-seq
#19
Lu Zhang, Shiyong Li, Yoon-La Choi, Jinseon Lee, Zhuolin Gong, Xiaoqiao Liu, Yunfei Pei, Awei Jiang, Mingzhi Ye, Mao Mao, Xuegong Zhang, Jhingook Kim, Ronghua Chen
OBJECTIVES: Lung adenocarcinoma (LUAD) is a common subtype of non-small cell lung cancer prevalent in Asia. There is a dearth of understanding regarding the transcriptome landscape of LUAD without primary known driver mutations. In this study, LUAD samples without well-known driver mutations occurring in EGFR, KRAS, ALK, ROS1 or RET (quintuple-negative) were used for transcriptome study with a focus on long noncoding RNAs (lncRNAs), alternative splicing and gene fusions. MATERIALS AND METHODS: 24 pairs of LUAD and adjacent normal samples and 13 tumor-only samples derived from 37 quintuple-negative patients were used...
July 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28575652/mutations-in-kdsr-cause-recessive-progressive-symmetric-erythrokeratoderma
#20
Lynn M Boyden, Nicholas G Vincent, Jing Zhou, Ronghua Hu, Brittany G Craiglow, Susan J Bayliss, Ilana S Rosman, Anne W Lucky, Luis A Diaz, Lowell A Goldsmith, Amy S Paller, Richard P Lifton, Susan J Baserga, Keith A Choate
The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet...
June 1, 2017: American Journal of Human Genetics
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