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nonsense-mediated decay

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https://www.readbyqxmd.com/read/28323884/a-system-for-coordinated-analysis-of-translational-readthrough-and-nonsense-mediated-mrna-decay
#1
Stacey L Baker, J Robert Hogg
The nonsense-mediated mRNA decay (NMD) pathway degrades mRNAs containing premature termination codons, limiting the expression of potentially deleterious truncated proteins. This activity positions the pathway as a regulator of the severity of genetic diseases caused by nonsense mutations. Because many genetic diseases result from nonsense alleles, therapeutics inducing readthrough of premature termination codons and/or inhibition of NMD have been of great interest. Several means of enhancing translational readthrough have been reported to concomitantly inhibit NMD efficiency, but tools for systematic analysis of mammalian NMD inhibition by translational readthrough are lacking...
2017: PloS One
https://www.readbyqxmd.com/read/28319091/whole-genome-sequencing-identifies-rare-genotypes-in-comp-and-chadl-associated-with-high-risk-of-hip-osteoarthritis
#2
Unnur Styrkarsdottir, Hannes Helgason, Asgeir Sigurdsson, Gudmundur L Norddahl, Arna B Agustsdottir, Louise N Reynard, Amanda Villalvilla, Gisli H Halldorsson, Aslaug Jonasdottir, Audur Magnusdottir, Asmundur Oddson, Gerald Sulem, Florian Zink, Gardar Sveinbjornsson, Agnar Helgason, Hrefna S Johannsdottir, Anna Helgadottir, Hreinn Stefansson, Solveig Gretarsdottir, Thorunn Rafnar, Ina S Almdahl, Anne Brækhus, Tormod Fladby, Geir Selbæk, Farhad Hosseinpanah, Fereidoun Azizi, Jung Min Koh, Nelson L S Tang, Maryams Danesphour, Jose I Mayordomo, Corrine Welt, Peter S Braund, Nilesh J Samani, Lambertus A Kiemeney, L Stefan Lohmander, Claus Christiansen, Ole A Andreassen, Olafur Magnusson, Gisli Masson, Augustine Kong, Ingileif Jonsdottir, Daniel Gudbjartsson, Patrick Sulem, Helgi Jonsson, John Loughlin, Thorvaldur Ingvarsson, Unnur Thorsteinsdottir, Kari Stefansson
We performed a genome-wide association study of total hip replacements, based on variants identified through whole-genome sequencing, which included 4,657 Icelandic patients and 207,514 population controls. We discovered two rare signals that strongly associate with osteoarthritis total hip replacement: a missense variant, c.1141G>C (p.Asp369His), in the COMP gene (allelic frequency = 0.026%, P = 4.0 × 10(-12), odds ratio (OR) = 16.7) and a frameshift mutation, rs532464664 (p.Val330Glyfs*106), in the CHADL gene that associates through a recessive mode of inheritance (homozygote frequency = 0...
March 20, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28319062/ctcf-genetic-alterations-in-endometrial-carcinoma-are-pro-tumorigenic
#3
A D Marshall, C G Bailey, K Champ, M Vellozzi, P O'Young, C Metierre, Y Feng, A Thoeng, A M Richards, U Schmitz, M Biro, R Jayasinghe, L Ding, L Anderson, E R Mardis, J E J Rasko
CTCF is a haploinsufficient tumour suppressor gene with diverse normal functions in genome structure and gene regulation. However the mechanism by which CTCF haploinsufficiency contributes to cancer development is not well understood. CTCF is frequently mutated in endometrial cancer. Here we show that most CTCF mutations effectively result in CTCF haploinsufficiency through nonsense-mediated decay of mutant transcripts, or loss-of-function missense mutation. Conversely, we identified a recurrent CTCF mutation K365T, which alters a DNA binding residue, and acts as a gain-of-function mutation enhancing cell survival...
March 20, 2017: Oncogene
https://www.readbyqxmd.com/read/28318500/mutations-in-tmem260-cause-a-pediatric-neurodevelopmental-cardiac-and-renal-syndrome
#4
Asaf Ta-Shma, Tahir N Khan, Asaf Vivante, Jason R Willer, Pavle Matak, Chaim Jalas, Ben Pode-Shakked, Yishay Salem, Yair Anikster, Friedhelm Hildebrandt, Nicholas Katsanis, Orly Elpeleg, Erica E Davis
Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon...
March 11, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28298237/irfinder-assessing-the-impact-of-intron-retention-on-mammalian-gene-expression
#5
Robert Middleton, Dadi Gao, Aubin Thomas, Babita Singh, Amy Au, Justin J-L Wong, Alexandra Bomane, Bertrand Cosson, Eduardo Eyras, John E J Rasko, William Ritchie
Intron retention (IR) occurs when an intron is transcribed into pre-mRNA and remains in the final mRNA. We have developed a program and database called IRFinder to accurately detect IR from mRNA sequencing data. Analysis of 2573 samples showed that IR occurs in all tissues analyzed, affects over 80% of all coding genes and is associated with cell differentiation and the cell cycle. Frequently retained introns are enriched for specific RNA binding protein sites and are often retained in clusters in the same gene...
March 15, 2017: Genome Biology
https://www.readbyqxmd.com/read/28288699/longevity-regulation-by-nmd-mediated-mrna-quality-control
#6
Heehwa G Son, Seung-Jae V Lee
Proper maintenance of biological components is crucial for longevity and healthy aging. Although the role of homeostatic maintenance systems for DNA and protein in longevity is established, it remained largely unknown for RNA. In our recent work, we show that nonsense-mediated mRNA decay (NMD) promotes longevity in the roundworm C. elegans by enhancing RNA quality control. We find that the activity of NMD decreases during aging, raising the possibility that RNA quality declines in old animals. We then show that key components of NMD complex are required for long lifespan in C...
March 14, 2017: BMB Reports
https://www.readbyqxmd.com/read/28277935/the-pre-mrna-retention-and-splicing-complex-controls-expression-of-the-mediator-subunit-med20
#7
Yang Zhou, Marcus J O Johansson
The heterotrimeric pre-mRNA retention and splicing (RES) complex, consisting of Bud13p, Snu17p and Pml1p, promotes splicing and nuclear retention of a subset of intron-containing pre-mRNAs. Yeast cells deleted for individual RES genes show growth defects that are exacerbated at elevated temperatures. Although the growth phenotypes correlate to the splicing defects in the individual mutants, the underlying mechanism is unknown. Here, we show that the temperature sensitive (Ts) growth phenotype of bud13Δ and snu17Δ cells is a consequence of inefficient splicing of MED20 pre-mRNA, which codes for a subunit of the Mediator complex; a co-regulator of RNA polymerase II transcription...
February 17, 2017: RNA Biology
https://www.readbyqxmd.com/read/28276498/the-impact-of-the-rbm4-initiated-splicing-cascade-on-modulating-the-carcinogenic-signature-of-colorectal-cancer-cells
#8
Jung-Chun Lin, Yuan-Chii Lee, Yu-Chih Liang, Yang C Fann, Kory R Johnson, Ying-Ju Lin
A growing body of studies has demonstrated that dysregulated splicing profiles constitute pivotal mechanisms for carcinogenesis. In this study, we identified discriminative splicing profiles of colorectal cancer (CRC) cells compared to adjacent normal tissues using deep RNA-sequencing (RNA-seq). The RNA-seq results and cohort studies indicated a relatively high ratio of exon 4-excluded neuro-oncological ventral antigen 1 (Nova1(-4)) and intron 2-retained SRSF6 (SRSF6(+intron 2)) transcripts in CRC tissues and cell lines...
March 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28276441/rna-surveillance-via-nonsense-mediated-mrna-decay-is-crucial-for-longevity-in-daf-2-insulin-igf-1-mutant-c-elegans
#9
Heehwa G Son, Mihwa Seo, Seokjin Ham, Wooseon Hwang, Dongyeop Lee, Seon Woo A An, Murat Artan, Keunhee Seo, Rachel Kaletsky, Rachel N Arey, Youngjae Ryu, Chang Man Ha, Yoon Ki Kim, Coleen T Murphy, Tae-Young Roh, Hong Gil Nam, Seung-Jae V Lee
Long-lived organisms often feature more stringent protein and DNA quality control. However, whether RNA quality control mechanisms, such as nonsense-mediated mRNA decay (NMD), which degrades both abnormal as well as some normal transcripts, have a role in organismal aging remains unexplored. Here we show that NMD mediates longevity in C. elegans strains with mutations in daf-2/insulin/insulin-like growth factor 1 receptor. We find that daf-2 mutants display enhanced NMD activity and reduced levels of potentially aberrant transcripts...
March 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28272342/the-characterization-of-gsdmb-splicing-and-backsplicing-profiles-identifies-novel-isoforms-and-a-circular-rna-that-are-dysregulated-in-multiple-sclerosis
#10
Giulia Cardamone, Elvezia Maria Paraboschi, Valeria Rimoldi, Stefano Duga, Giulia Soldà, Rosanna Asselta
Abnormalities in alternative splicing (AS) are emerging as recurrent features in autoimmune diseases (AIDs). In particular, a growing body of evidence suggests the existence of a pathogenic association between a generalized defect in splicing regulatory genes and multiple sclerosis (MS). Moreover, several studies have documented an unbalance in alternatively-spliced isoforms in MS patients possibly contributing to the disease etiology. In this work, using a combination of PCR-based techniques (reverse-transcription (RT)-PCR, fluorescent-competitive, real-time, and digital RT-PCR assays), we investigated the alternatively-spliced gene encoding Gasdermin B, GSDMB, which was repeatedly associated with susceptibility to asthma and AIDs...
March 7, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28270101/deciphering-alternative-splicing-and-nonsense-mediated-decay-modulate-expression-in-primary-lymphoid-tissues-of-birds-infected-with-avian-pathogenic-e-coli-apec
#11
Hongyan Sun
BACKGROUND: Avian pathogenic E. coli (APEC) can lead to a loss in millions of dollars in poultry annually because of mortality and produce contamination. Studies have verified that many immune-related genes undergo changes in alternative splicing (AS), along with nonsense mediated decay (NMD), to regulate the immune system under different conditions. Therefore, the splicing profiles of primary lymphoid tissues with systemic APEC infection need to be comprehensively examined. RESULTS: Gene expression in RNAseq data were obtained for three different immune tissues (bone marrow, thymus, and bursa) from three phenotype birds (non-challenged, resistant, and susceptible birds) at two time points...
March 7, 2017: BMC Genetics
https://www.readbyqxmd.com/read/28261246/possible-role-of-mads-affecting-flowering-3-and-b-box-domain-protein-19-in-flowering-time-regulation-of-arabidopsis-mutants-with-defects-in-nonsense-mediated-mrna-decay
#12
Zeeshan Nasim, Muhammad Fahim, Ji Hoon Ahn
Eukaryotic cells use nonsense-mediated mRNA decay (NMD) to clear aberrant mRNAs from the cell, thus preventing the accumulation of truncated proteins. In Arabidopsis, two UP-Frameshift (UPF) proteins, UPF1 and UPF3, play a critical role in NMD. Although deficiency of UPF1 and UPF3 leads to various developmental defects, little is known about the mechanism underlying the regulation of flowering time by NMD. Here, we showed that the upf1-5 and upf3-1 mutants had a late-flowering phenotype under long-day conditions and the upf1-5 upf3-1 double mutants had an additive effect in delaying flowering time...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28259707/clinical-and-molecular-phenotyping-of-a-child-with-hermansky-pudlak-syndrome-7-an-uncommon-genetic-type-of-hps
#13
Melanie M Bryan, Nathanial J Tolman, Karen L Simon, Marjan Huizing, Robert B Hufnagel, Brian P Brooks, Vladislav Speransky, James C Mullikin, William A Gahl, May Christine V Malicdan, Bernadette R Gochuico
PURPOSE: Hermansky-Pudlak syndrome (HPS) is a rare inherited disorder with ten reported genetic types; each type has defects in subunits of either Adaptor Protein-3 complex or Biogenesis of Lysosome-related Organelles Complex (BLOC)-1, -2, or -3. Very few patients with BLOC-1 deficiency (HPS-7, -8, and -9 types) have been diagnosed. We report results of comprehensive clinical testing and molecular analyses of primary fibroblasts from a new case of HPS-7. RESULTS: A 6-year old Paraguayan male presented with hypopigmentation, ocular albinism, nystagmus, reduced visual acuity, and easy bruising...
February 27, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28236339/mutations-of-the-aminoacyl-trna-synthetases-sars-and-wars2-are-implicated-in-the-aetiology-of-autosomal-recessive-intellectual-disability
#14
Luciana Musante, Lucia Püttmann, Kimia Kahrizi, Masoud Garshasbi, Hao Hu, Henning Stehr, Bettina Lipkowitz, Sabine Otto, Lars R Jensen, Andreas Tzschach, Payman Jamali, Thomas Wienker, Hossein Najmabadi, Hans Hilger Ropers, Andreas W Kuss
Intellectual disability (ID) is the hallmark of an extremely heterogeneous group of disorders that comprises a wide variety of syndromic and non-syndromic phenotypes. Here we report on mutations in two aminoacyl-tRNA synthetases that are associated with ID in two unrelated Iranian families. In the first family, we identified a homozygous missense mutation (c.514G>A, p.Asp172Asn) in the cytoplasmic seryl-tRNA synthetase (SARS) gene. The mutation affects the enzymatic core domain of the protein and impairs its enzymatic activity, probably leading to reduced cytoplasmic tRNA(Ser) concentrations...
February 25, 2017: Human Mutation
https://www.readbyqxmd.com/read/28235824/a-nonsense-variant-in-the-st14-gene-in-akhal-teke-horses-with-naked-foal-syndrome
#15
Anina Bauer, Theresa Hiemesch, Vidhya Jagannathan, Markus Neuditschko, Iris Bachmann, Stefan Rieder, Sofia Mikko, M Cecilia Penedo, Nadja Tarasova, Martina Vitková, Nicolò Sirtori, Paola Roccabianca, Tosso Leeb, Monika M Welle
Naked foal syndrome (NFS) is a genodermatosis in the Akhal-Teke horse breed. We provide the first scientific description of this phenotype. Affected horses had almost no hair and showed a mild ichthyosis. So far, all known NFS affected horses died between a few weeks and 3 years of age. It is not clear whether a specific pathology caused the premature deaths. NFS is inherited as a monogenic autosomal recessive trait. We mapped the disease causing genetic variant to two segments on chromosomes 7 and 27 in the equine genome...
February 24, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28231257/targeted-sequencing-identifies-a-novel-sh2d1a-pathogenic-variant-in-a-chinese-family-carrier-screening-and-prenatal-genetic-testing
#16
Jun-Yu Zhang, Song-Chang Chen, Yi-Yao Chen, Shu-Yuan Li, Lan-Lan Zhang, Ying-Hua Shen, Chun-Xin Chang, Yu-Qian Xiang, He-Feng Huang, Chen-Ming Xu
X-linked lymphoproliferative disease type 1 (XLP1) is a rare primary immunodeficiency characterized by a clinical triad consisting of severe EBV-induced hemophagocytic lymphohistiocytosis, B-cell lymphoma, and dysgammaglobulinemia. Mutations in SH2D1A gene have been revealed as the cause of XLP1. In this study, a pregnant woman with recurrence history of birthing immunodeficiency was screened for pathogenic variant because the proband sample was unavailable. We aimed to clarify the genetic diagnosis and provide prenatal testing for the family...
2017: PloS One
https://www.readbyqxmd.com/read/28224650/androgen-receptor-splice-variants-are-not-substrates-of-nonsense-mediated-decay
#17
Atinuke S Ajiboye, David Esopi, Srinivasan Yegnasubramanian, Samuel R Denmeade
BACKGROUND: Androgen receptor (AR) splice variants have been clinically associated with progressive cancer, castration-resistance, and resistance to AR antagonists and androgen synthesis inhibitors. AR variants can be generated by genomic alterations and alternative splicing, and their expression is androgen-regulated. There has been a suggestion that AR variants bearing premature termination codons and coding for truncated proteins should be regulated by the nonsense-mediated decay (NMD) mRNA surveillance pathway, suggesting that either the NMD pathway is dysfunctional in variant-expressing cell lines or that variants are somehow able to evade degradation by NMD...
February 22, 2017: Prostate
https://www.readbyqxmd.com/read/28219207/-mutations-of-vitamin-d-receptor-gene-found-in-patients-with-multiple-myeloma
#18
Y Liu, H B Rui
Objective: To explore the mutations of vitamin D receptor (VDR) gene in patients with multiple myeloma (MM). Methods: Polymerase chain reaction (PCR) and direct DNA sequencing were used to detect the mutations of VDR gene(loci Fok Ⅰ, Bsm Ⅰ, Apa Ⅰ, Taq Ⅰ) in forty MM cases and 84 healthy control subjects. Results: A synonymous mutation (ATC→ATA , both encode isoleucine) at cDNA codon1421 of VDR gene was found in one MM patients, which correlated to a better therapeutic response. Rare Bsm Ⅰ AA genotype and Taq Ⅰ CC genotype were detected in a MM patient, which might be related to the relapsing and refracfory disease...
February 23, 2017: Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology]
https://www.readbyqxmd.com/read/28209632/high-resolution-profiling-of-nmd-targets-in-yeast-reveals-translational-fidelity-as-a-basis-for-substrate-selection
#19
Alper Celik, Richard Baker, Feng He, Allan Jacobson
Nonsense-mediated mRNA decay (NMD) plays an important role in eukaryotic gene expression yet the scope and the defining features of NMD-targeted transcripts remain elusive. To address these issues, we re-evaluated the genome-wide expression of annotated transcripts in yeast cells harboring deletions of the UPF1, UPF2, or UPF3 genes. Our new RNA-Seq analyses confirm previous results of microarray studies, but also uncover hundreds of new NMD-regulated transcripts that had escaped previous detection, including many intron-containing pre-mRNAs and several non-coding RNAs...
February 16, 2017: RNA
https://www.readbyqxmd.com/read/28188297/alternative-splicing-in-the-cytochrome-p450-superfamily-expands-protein-diversity-to-augment-gene-function-and-redirect-human-drug-metabolism
#20
Andrew J Annalora, Craig B Marcus, Patrick L Iversen
The human genome encodes 57 cytochrome P450 (CYP) genes whose enzyme products metabolize hundreds of drugs, thousands of xenobiotics and unknown numbers of endogenous compounds including steroids, retinoids and icosinoids. Indeed, CYP genes are the first line of defense against daily environmental chemical challenges in a manner that parallels the immune system. Several databases, including PubMed, AceView, and Ensembl, were queried to establish a comprehensive analysis of the full human CYP transcriptome. This review describes a remarkable diversification of the 57 human CYP genes, which may be alternatively processed into nearly 1000 distinct mRNA transcripts to shape an individual's CYP proteome...
February 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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