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nonsense-mediated decay

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https://www.readbyqxmd.com/read/29348139/dissecting-the-functions-of-smg5-smg7-and-pnrc2-in-nonsense-mediated-mrna-decay-of-human-cells
#1
Pamela Nicholson, Asimina Gkratsou, Christoph Josi, Martino Colombo, Oliver Mühlemann
The term "nonsense-mediated mRNA decay" (NMD) originally described the degradation of mRNAs with premature translation-termination codons (PTCs), but its meaning has recently been extended to be a translation-dependent post-transcriptional regulator of gene expression affecting 3-10 % of all mRNAs. The degradation of NMD target mRNAs involves both exonucleolytic and endonucleolytic pathways in mammalian cells. While the latter is mediated by the endonuclease SMG6, the former pathway has been reported to require a complex of SMG5-SMG7 or SMG5-PNRC2 binding to UPF1...
January 18, 2018: RNA
https://www.readbyqxmd.com/read/29344651/identification-of-genes-and-pathways-in-the-synovia-of-women-with-osteoarthritis-by-bioinformatics-analysis
#2
Bobin Mi, Guohui Liu, Wu Zhou, Huijuan Lv, Yi Liu, Jing Liu
Osteoarthritis (OA) has a high prevalence in female patients and sex may be a key factor affecting the progression of OA. The aim of the present study was to identify genetic signatures in the synovial membranes of female patients with OA and to elucidate the potential associated molecular mechanisms. The gene expression profiles of the GSE55457 and GSE55584 datasets were obtained from the Gene Expression Omnibus database. Data of two synovial membranes from normal female individuals (GSM1337306 and GSM1337310) and two synovial membranes from female patients affected by OA (GSM1337327 and GSM1337330) were obtained from the dataset GSE55457, and those of three synovial membranes from female patients affected by OA (GSM1339628, GSM1339629 and GSM1339632) were obtained from the dataset GSE55584...
January 15, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29343284/extensive-armc5-genetic-variance-in-primary-bilateral-macronodular-adrenal-hyperplasia-that-started-with-exophthalmos-a-case-report
#3
Ping Jin, Muhammad Usman Janjua, Qin Zhang, Chang-Sheng Dong, Youbo Yang, Zhao-Hui Mo
BACKGROUND: Primary bilateral macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome characterized by the presence of bilateral secretory adrenal nodules. Recent studies have shown that primary bilateral macronodular adrenal hyperplasia is caused by combined germline and somatic mutations of the ARMC5 gene. Exophthalmos is an underappreciated sign of Cushing's syndrome. CASE PRESENTATION: A 52-year-old Chinese woman with progressively worsening bilateral proptosis presented to our hospital...
January 18, 2018: Journal of Medical Case Reports
https://www.readbyqxmd.com/read/29334995/antisense-suppression-of-the-nonsense-mediated-decay-factor-upf3b-as-a-potential-treatment-for-diseases-caused-by-nonsense-mutations
#4
Lulu Huang, Audrey Low, Sagar S Damle, Melissa M Keenan, Steven Kuntz, Susan F Murray, Brett P Monia, Shuling Guo
BACKGROUND: About 11% of all human genetic diseases are caused by nonsense mutations that generate premature translation termination codons (PTCs) in messenger RNAs (mRNA). PTCs not only lead to the production of truncated proteins, but also often result in  decreased mRNA abundance due to  nonsense-mediated mRNA decay (NMD). Although pharmacological inhibition of NMD could be an attractive therapeutic approach for the treatment of diseases caused by nonsense mutations, NMD also regulates the expression of 10-20% of the normal transcriptome...
January 15, 2018: Genome Biology
https://www.readbyqxmd.com/read/29322253/identification-of-a-mutation-in-cnnm4-by-whole-exome-sequencing-in-an-amish-family-and-functional-link-between-cnnm4-and-iqcb1
#5
Sisi Li, Quansheng Xi, Xiaoyu Zhang, Dong Yu, Lin Li, Zhenyang Jiang, Qiuyun Chen, Qing K Wang, Elias I Traboulsi
We investigated an Amish family in which three siblings presented with an early-onset childhood retinal dystrophy inherited in an autosomal recessive fashion. Genome-wide linkage analysis identified significant linkage to marker D2S2216 on 2q11 with a two-point LOD score of 1.95 and a multi-point LOD score of 3.76. Whole exome sequencing was then performed for the three affected individuals and identified a homozygous nonsense mutation (c.C1813T, p.R605X) in the cyclin and CBS domain divalent metal cation transport mediator 4 (CNNM4) gene located within the 2p14-2q14 Jalili syndrome locus...
January 10, 2018: Molecular Genetics and Genomics: MGG
https://www.readbyqxmd.com/read/29282598/upf-proteins-highly-conserved-factors-involved-in-nonsense-mrna-mediated-decay
#6
REVIEW
Puneet Gupta, Yan-Ruide Li
Over 10% of genetic diseases are caused by mutations that introduce a premature termination codon in protein-coding mRNA. Nonsense-mediated mRNA decay (NMD) is an essential cellular pathway that degrades these mRNAs to prevent the accumulation of harmful partial protein products. NMD machinery is also increasingly appreciated to play a role in other essential cellular functions, including telomere homeostasis and the regulation of normal mRNA turnover, and is misregulated in numerous cancers. Hence, understanding and designing therapeutics targeting NMD is an important goal in biomedical science...
December 27, 2017: Molecular Biology Reports
https://www.readbyqxmd.com/read/29247835/amlexanox-provides-a-potential-therapy-for-nonsense-mutations-in-the-lysosomal-storage-disorder-aspartylglucosaminuria
#7
Antje Banning, Manuel Schiff, Ritva Tikkanen
Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by mutations in the gene for aspartylglucosaminidase (AGA). This enzyme participates in glycoprotein degradation in lysosomes. AGU results in progressive mental retardation, and no curative therapy is currently available. We have here characterized the consequences of AGA gene mutations in a compound heterozygous patient who exhibits a missense mutation producing a Ser72Pro substitution in one allele, and a nonsense mutation Trp168X in the other...
December 13, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29246305/induced-decay-of-glycine-decarboxylase-transcripts-as-an-anticancer-therapeutic-strategy-for-non-small-cell-lung-carcinoma
#8
Jing Lin, Jia Hui Jane Lee, Kathirvel Paramasivam, Elina Pathak, Zhenxun Wang, Zacharias Aloysius Dwi Pramono, Bing Lim, Keng Boon Wee, Uttam Surana
Self-renewing tumor-initiating cells (TICs) are thought to be responsible for tumor recurrence and chemo-resistance. Glycine decarboxylase, encoded by the GLDC gene, is reported to be overexpressed in TIC-enriched primary non-small-cell lung carcinoma (NSCLC). GLDC is a component of the mitochondrial glycine cleavage system, and its high expression is required for growth and tumorigenic capacity. Currently, there are no therapeutic agents against GLDC. As a therapeutic strategy, we have designed and tested splicing-modulating steric hindrance antisense oligonucleotides (shAONs) that efficiently induce exon skipping (half maximal inhibitory concentration [IC50] at 3...
December 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/29236296/rna-decay-factor-upf1-promotes-protein-decay-a-hidden-talent
#9
REVIEW
Terra-Dawn M Plank, Miles F Wilkinson
The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay (NMD) pathway. Feng et al. now report a new function for UPF1-it is an E3 ubiquitin ligase that specifically promotes the decay of a key pro-muscle transcription factor: MYOD. UPF1 achieves this through its RING-like domain, which confers ubiquitin E3 ligase activity. Feng et al. provide evidence that the ability of UPF1 to destabilize MYOD represses myogenesis. In the future, it will be important to define other protein substrates of UPF1-driven ubiquitination and to determine whether this biochemical activity is responsible for some of UPF1's previously defined biological functions, including in development and stress responses...
December 13, 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/29236262/studying-nonsense-mediated-mrna-decay-in-mammalian-cells-using-a-multicolored-bioluminescence-based-reporter-system
#10
Andrew Nickless, Zhongsheng You
The nonsense-mediated mRNA decay (NMD) pathway degrades aberrant transcripts containing premature translation termination codons (PTCs) and also regulates the levels of many normal mRNAs containing NMD-inducing features. The activity of this pathway varies considerably in different cell types and can change in response to developmental and environmental cues. Modulating NMD activity represents a potential therapeutic avenue for certain genetic disorders and cancers. Simple reporter systems capable of faithfully assessing NMD activity in mammalian cells greatly facilitate both basic and translational research on NMD...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29236261/reactivation-assay-to-identify-direct-targets-of-the-nonsense-mediated-mrna-decay-pathway-in-drosophila
#11
Jonathan O Nelson, Mark M Metzstein
Transcriptome analysis provides a snapshot of cellular gene expression and is used to determine how cells and organisms respond to genetic or environmental changes. Identifying the transcripts whose expression levels are regulated directly by the manipulation being examined from those whose expression changes as a secondary cause from the primary changes requires additional analyses. Here we present a technique used to distinguish direct targets of the nonsense-mediated mRNA decay (NMD) pathway in Drosophila from secondary gene expression effects caused by loss of this pathway...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29236260/generation-of-cell-lines-stably-expressing-a-fluorescent-reporter-of-nonsense-mediated-mrna-decay-activity
#12
Nadezhda M Markina, Anton P Pereverzev, Dmitry B Staroverov, Konstantin A Lukyanov, Nadya G Gurskaya
Nonsense-mediated mRNA decay (NMD) is a mechanism of mRNA surveillance ubiquitous among eukaryotes. Importantly, NMD not only removes aberrant transcripts with premature stop codons, but also regulates expression of many normal genes. A recently introduced dual-color fluorescent protein-based reporter enables analysis of NMD activity in live cells. In this chapter we describe the method to generate stable transgenic cell lines expressing the splicing-dependent NMD reporter using consecutive steps of lentivirus transduction and Tol2 transposition...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29236259/identifying-cellular-nonsense-mediated-mrna-decay-nmd-targets-immunoprecipitation-of-phosphorylated-upf1-followed-by-rna-sequencing-p-upf1-rip-seq
#13
Tatsuaki Kurosaki, Mainul Hoque, Lynne E Maquat
Recent progress in the technology of transcriptome-wide high-throughput sequencing has revealed that nonsense-mediated mRNA decay (NMD) targets ~10% of physiologic transcripts for the purpose of tuning gene expression in response to various environmental conditions. Regardless of the eukaryote studied, NMD requires the ATP-dependent RNA helicase upframeshift 1 (UPF1). It was initially thought that cellular NMD targets could be defined by their binding to steady-state UPF1, which is largely hypophosphorylated...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29236258/using-tet-off-cells-and-rnai-knockdown-to-assay-mrna-decay
#14
Thomas D Baird, J Robert Hogg
Cellular mRNA levels are determined by the competing forces of transcription and decay. A wide array of cellular mRNA decay pathways carry out RNA turnover either on a constitutive basis or in response to changing cellular conditions. Here, we outline a method to investigate mRNA decay that employs RNAi knockdown of known or putative decay factors in commercially available Tet-off cell systems. Reporter mRNAs of interest are expressed under the control of a tetracycline-regulated promoter, allowing pulse-chase mRNA decay assays to be conducted...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29235495/identification-of-nonsense-mediated-mrna-decay-pathway-as-a-critical-regulator-of-p53-isoform-%C3%AE
#15
Lauren E Cowen, Yi Tang
Human TP53 gene encodes the tumor suppressor p53 and, via alternative splicing, the p53β and γ isoforms. Numerous studies have shown that p53β/γ can modulate p53 functions and are critically involved in regulation of cellular response to stress conditions. However, it is not fully understood how the β and γ isoforms are regulated following splicing. Using gene targeting and RNAi, we showed that depletion of the nonsense-mediated mRNA decay (NMD) factor SMG7 or UPF1 significantly induced p53β but had minimal effect on p53γ...
December 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29229843/machine-learning-shows-association-between-genetic-variability-in-pparg-and-cerebral-connectivity-in-preterm-infants
#16
Michelle L Krishnan, Zi Wang, Paul Aljabar, Gareth Ball, Ghazala Mirza, Alka Saxena, Serena J Counsell, Joseph V Hajnal, Giovanni Montana, A David Edwards
Preterm infants show abnormal structural and functional brain development, and have a high risk of long-term neurocognitive problems. The molecular and cellular mechanisms involved are poorly understood, but novel methods now make it possible to address them by examining the relationship between common genetic variability and brain endophenotype. We addressed the hypothesis that variability in the Peroxisome Proliferator Activated Receptor (PPAR) pathway would be related to brain development. We employed machine learning in an unsupervised, unbiased, combined analysis of whole-brain diffusion tractography together with genomewide, single-nucleotide polymorphism (SNP)-based genotypes from a cohort of 272 preterm infants, using Sparse Reduced Rank Regression (sRRR) and correcting for ethnicity and age at birth and imaging...
December 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29210071/whole-exome-sequencing-of-sickle-cell-disease-patients-with-hyperhemolysis-syndrome-suggests-a-role-for-rare-variation-in-disease-predisposition
#17
Savannah Mwesigwa, Joann M Moulds, Alice Chen, Jonathan Flanagan, Vivien A Sheehan, Alex George, Neil A Hanchard
BACKGROUND: Hyperhemolysis syndrome (HHS) is an uncommon, but life-threatening, transfusion-related complication of red blood cell transfusion. HHS has predominantly been described in patients with sickle cell disease (SCD) and is difficult to diagnose and treat. The pathogenesis of HHS, including its occurrence in only a subset of apparently susceptible individuals, is poorly understood. We undertook whole-exome sequencing (WES) of 12 SCD-HHS patients to identify shared genetic variants that might be relevant to the development of HHS...
December 6, 2017: Transfusion
https://www.readbyqxmd.com/read/29208651/a-12-3-kb-duplication-within-the-vwf-gene-in-pigs-affected-by-von-willebrand-disease-type-3
#18
Stefanie Lehner, Mahnaz Ekhlasi-Hundrieser, Carsten Detering, Hanna Allerkamp, Christiane Pfarrer, Mario von Depka Prondzinski
Von Willebrand Disease (VWD) type 3 is a serious and sometimes fatal hereditary bleeding disorder. In pigs, the disease has been known for decades and affected animals are used as models for the human disease. Due to the recessive mode of inheritance of VWD type 3, severe bleeding is typically seen in homozygous individuals. We sequenced the complete porcine VWF (Von Willebrand Factor) cDNA and detected a tandem duplication of exons 17 and 18, causing a frameshift and a premature termination codon (p.Val814LeufsTer3) in the affected pig...
December 5, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29198722/a-recurrent-de-novo-nonsense-variant-in-zswim6-results-in-severe-intellectual-disability-without-frontonasal-or-limb-malformations
#19
Elizabeth E Palmer, Raman Kumar, Christopher T Gordon, Marie Shaw, Laurence Hubert, Renee Carroll, Marlène Rio, Lucinda Murray, Melanie Leffler, Tracy Dudding-Byth, Myriam Oufadem, Seema R Lalani, Andrea M Lewis, Fan Xia, Allison Tam, Richard Webster, Susan Brammah, Francesca Filippini, John Pollard, Judy Spies, Andre E Minoche, Mark J Cowley, Sarah Risen, Nina N Powell-Hamilton, Jessica E Tusi, LaDonna Immken, Honey Nagakura, Christine Bole-Feysot, Patrick Nitschké, Alexandrine Garrigue, Geneviève de Saint Basile, Emma Kivuva, Richard H Scott, Augusto Rendon, Arnold Munnich, William Newman, Bronwyn Kerr, Claude Besmond, Jill A Rosenfeld, Jeanne Amiel, Michael Field, Jozef Gecz
A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations...
November 23, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29192227/conservation-of-nonsense-mediated-mrna-decay-complex-components-throughout-eukaryotic-evolution
#20
Barry Causier, Zhen Li, Riet De Smet, James P B Lloyd, Yves Van de Peer, Brendan Davies
Nonsense-mediated mRNA decay (NMD) is an essential eukaryotic process regulating transcript quality and abundance, and is involved in diverse processes including brain development and plant defenses. Although some of the NMD machinery is conserved between kingdoms, little is known about its evolution. Phosphorylation of the core NMD component UPF1 is critical for NMD and is regulated in mammals by the SURF complex (UPF1, SMG1 kinase, SMG8, SMG9 and eukaryotic release factors). However, since SMG1 is reportedly missing from the genomes of fungi and the plant Arabidopsis thaliana, it remains unclear how UPF1 is activated outside the metazoa...
November 30, 2017: Scientific Reports
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