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Nonsense suppression

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https://www.readbyqxmd.com/read/28432296/aminoglycosides-but-not-ptc124-ataluren-rescue-nonsense-mutations-in-the-leptin-receptor-and-in-luciferase-reporter-genes
#1
Florian Bolze, Sabine Mocek, Anika Zimmermann, Martin Klingenspor
In rare cases, monogenetic obesity is caused by nonsense mutations in genes regulating energy balance. A key factor herein is the leptin receptor. Here, we focus on leptin receptor nonsense variants causing obesity, namely the human W31X, murine Y333X and rat Y763X mutations, and explored their susceptibilities to aminoglycoside and PTC124 mediated translational read-through in vitro. In a luciferase based assay, all mutations - when analysed within the mouse receptor - were prone to aminoglycoside mediated nonsense suppression with the highest susceptibility for W31X, followed by Y763X and Y333X...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28390174/suppression-of-basic-fibroblast-growth-factor-expression-by-antisense-oligonucleotides-inhibits-neural-stem-cell-proliferation-and-differentiation-in-rat-models-with-focal-cerebral-infarction
#2
Chao Li, Li-He Che, Lei Shi, Jin-Lu Yu
This study is designed to investigate the role of basic fibroblast growth factor (bFGF) antisense oligonucleotide (ASODN) on the proliferation and differentiation of neural stem cells (NSCs) in rat models with focal cerebral infarction (CI). Seventy-five Sprague-Dawlay (SD) rats were randomly divided into the control, sham, middle cerebral artery occlusion (MCAO), MCAO + nonsense oligonucleotide (NODN) and MCAO + ASODN groups. Proliferation and differentiation of NSCs were detected by bromodeoxyuridine (BrdU) and immunofluorescence staining, respectively...
April 8, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28367323/nonsense-suppression-as-an-approach-to-treat-lysosomal-storage-diseases
#3
Kim M Keeling
In-frame premature termination codons (PTCs) (also referred to as nonsense mutations) comprise ~10% of all disease-associated gene lesions. PTCs reduce gene expression in two ways. First, PTCs prematurely terminate translation of an mRNA, leading to the production of a truncated polypeptide that often lacks normal function and/or is unstable. Second, PTCs trigger degradation of an mRNA by activating nonsense-mediated mRNA decay (NMD), a cellular pathway that recognizes and degrades mRNAs containing a PTC. Thus, translation termination and NMD are putative therapeutic targets for the development of treatments for genetic diseases caused by PTCs...
December 2016: Diseases (Basel)
https://www.readbyqxmd.com/read/28359917/the-identities-of-stop-codon-reassignments-support-ancestral-trna-stop-codon-decoding-activity-as-a-facilitator-of-gene-duplication-and-evolution-of-novel-function
#4
Steven E Massey
Stop codon reassignments are widely distributed in prokaryotic, eukaryotic and organellar genomes, but are remarkably convergent in terms of the stop codons and amino acids reassigned. Strikingly, the identities of stop codon reassignments are closely matched to the properties of naturally occurring nonsense suppressor (NONS) tRNAs, suggesting that pre-existing nonsense suppression in an ancestral tRNA facilitated the occurrence of stop codon reassignments. Here this idea is expanded, by exploring the mechanism by which the gene duplication of tRNAs has occurred, leading to the reassignment of stop codons...
March 27, 2017: Gene
https://www.readbyqxmd.com/read/28355180/dhx9-suppresses-rna-processing-defects-originating-from-the-alu-invasion-of-the-human-genome
#5
Tuğçe Aktaş, İbrahim Avşar Ilık, Daniel Maticzka, Vivek Bhardwaj, Cecilia Pessoa Rodrigues, Gerhard Mittler, Thomas Manke, Rolf Backofen, Asifa Akhtar
Transposable elements are viewed as 'selfish genetic elements', yet they contribute to gene regulation and genome evolution in diverse ways. More than half of the human genome consists of transposable elements. Alu elements belong to the short interspersed nuclear element (SINE) family of repetitive elements, and with over 1 million insertions they make up more than 10% of the human genome. Despite their abundance and the potential evolutionary advantages they confer, Alu elements can be mutagenic to the host as they can act as splice acceptors, inhibit translation of mRNAs and cause genomic instability...
April 6, 2017: Nature
https://www.readbyqxmd.com/read/28343630/de-novo-truncating-mutations-in-the-last-and-penultimate-exons-of-ppm1d-cause-an-intellectual-disability-syndrome
#6
Sandra Jansen, Sinje Geuer, Rolph Pfundt, Rachel Brough, Priyanka Ghongane, Johanna C Herkert, Elysa J Marco, Marjolein H Willemsen, Tjitske Kleefstra, Mark Hannibal, Joseph T Shieh, Sally Ann Lynch, Frances Flinter, David R FitzPatrick, Alice Gardham, Birgitta Bernhard, Nicola Ragge, Ruth Newbury-Ecob, Raphael Bernier, Malin Kvarnung, E A Helena Magnusson, Marja W Wessels, Marjon A van Slegtenhorst, Kristin G Monaghan, Petra de Vries, Joris A Veltman, Christopher J Lord, Lisenka E L M Vissers, Bert B A de Vries
Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis...
April 6, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28323884/a-system-for-coordinated-analysis-of-translational-readthrough-and-nonsense-mediated-mrna-decay
#7
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/28318500/mutations-in-tmem260-cause-a-pediatric-neurodevelopmental-cardiac-and-renal-syndrome
#8
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...
April 6, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28289221/gentamicin-b1-is-a-minor-gentamicin-component-with-major-nonsense-mutation-suppression-activity
#9
Alireza Baradaran-Heravi, Jürgen Niesser, Aruna D Balgi, Kunho Choi, Carla Zimmerman, Andrew P South, Hilary J Anderson, Natalie C Strynadka, Marcel B Bally, Michel Roberge
Nonsense mutations underlie about 10% of rare genetic disease cases. They introduce a premature termination codon (PTC) and prevent the formation of full-length protein. Pharmaceutical gentamicin, a mixture of several related aminoglycosides, is a frequently used antibiotic in humans that can induce PTC readthrough and suppress nonsense mutations at high concentrations. However, testing of gentamicin in clinical trials has shown that safe doses of this drug produce weak and variable readthrough activity that is insufficient for use as therapy...
March 28, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28277935/the-pre-mrna-retention-and-splicing-complex-controls-expression-of-the-mediator-subunit-med20
#10
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/28264986/a-truncating-mutation-in-cep55-is-the-likely-cause-of-march-a-novel-syndrome-affecting-neuronal-mitosis
#11
Patrick Frosk, Heleen H Arts, Julien Philippe, Carter S Gunn, Emma L Brown, Bernard Chodirker, Louise Simard, Jacek Majewski, Somayyeh Fahiminiya, Chad Russell, Yangfan P Liu, Robert Hegele, Nicholas Katsanis, Conrad Goerz, Marc R Del Bigio, Erica E Davis
BACKGROUND: Hydranencephaly is a congenital anomaly leading to replacement of the cerebral hemispheres with a fluid-filled cyst. The goals of this work are to describe a novel autosomal-recessive syndrome that includes hydranencephaly (multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia and hydranencephaly (MARCH)); to identify its genetic cause(s) and to provide functional insight into pathomechanism. METHODS: We used homozygosity mapping and exome sequencing to identify recessive mutations in a single family with three affected fetuses...
March 6, 2017: Journal of Medical Genetics
https://www.readbyqxmd.com/read/28264473/future-of-the-genetic-code
#12
REVIEW
Hong Xue, J Tze-Fei Wong
The methods for establishing synthetic lifeforms with rewritten genetic codes comprising non-canonical amino acids (NCAA) in addition to canonical amino acids (CAA) include proteome-wide replacement of CAA, insertion through suppression of nonsense codon, and insertion via the pyrrolysine and selenocysteine pathways. Proteome-wide reassignments of nonsense codons and sense codons are also under development. These methods enable the application of NCAAs to enrich both fundamental and applied aspects of protein chemistry and biology...
February 28, 2017: Life
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
#13
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
https://www.readbyqxmd.com/read/28178277/paucity-of-intact-non-induced-provirus-with-early-long-term-antiretroviral-therapy-of-perinatal-hiv-infection
#14
Kaitlin Rainwater-Lovett, Carrie Ziemniak, Douglas Watson, Katherine Luzuriaga, George Siberry, Ann Petru, YaHui Chen, Priyanka Uprety, Margaret McManus, Ya-Chi Ho, Susanna L Lamers, Deborah Persaud
The latent reservoir is a major barrier to HIV eradication. Reservoir size is emerging as an important biomarker to assess the likelihood of HIV remission in the absence of antiretroviral therapy (ART) and may be reduced by earlier initiation of ART that restricts HIV spread into CD4+ T cells. Reservoir size is traditionally measured with a quantitative viral outgrowth assay (QVOA) that induces replication-competent HIV production through in vitro stimulation of resting CD4+ T cells. However, the recent identification of replication-intact, non-induced proviral genomes (NIPG) suggests the QVOA significantly underestimates (by 62-fold) latent reservoir size in chronically-infected adults...
2017: PloS One
https://www.readbyqxmd.com/read/28165652/candidate-susceptibility-variants-for-esophageal-squamous-cell-carcinoma
#15
Iikki Donner, Riku Katainen, Tomas Tanskanen, Eevi Kaasinen, Mervi Aavikko, Kristian Ovaska, Miia Artama, Eero Pukkala, Lauri A Aaltonen
Esophageal cancer is common worldwide, and often fatal. The major histological subtype is esophageal squamous cell carcinoma (ESCC). ESCC shows familial aggregation and high heritability. Mutations in RHBDF2 cause tylosis, a very rare disorder characterized by high life-time risk of ESCC, but no other well-established predisposition genes have been identified. To identify candidate susceptibility variants for ESCC we utilized the Population Information System and the Finnish cancer registry to find study materials by clustering ESCC patients by family name at birth and municipality at birth...
February 6, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28145797/characterization-of-new-generation-aminoglycoside-promoting-premature-termination-codon-readthrough-in-cancer-cells
#16
Laure Bidou, Olivier Bugaud, Valery Belakhov, Timor Baasov, Olivier Namy
Nonsense mutations, generating premature termination codons (PTCs), account for 10% to 30% of the mutations in tumor suppressor genes. Nonsense translational suppression, induced by small molecules including gentamicin and G418, has been suggested as a potential therapy to counteract the deleterious effects of nonsense mutations in several genetic diseases and cancers. We describe here that NB124, a synthetic aminoglycoside derivative recently developed especially for PTC suppression, strongly induces apoptosis in human tumor cells by promoting high level of PTC readthrough...
March 4, 2017: RNA Biology
https://www.readbyqxmd.com/read/28121133/probing-the-structural-mechanism-of-partial-agonism-in-glycine-receptors-using-the-fluorescent-artificial-amino-acid-anap
#17
Ming S Soh, Argel Estrada-Mondragon, Nela Durisic, Angelo Keramidas, Joseph W Lynch
The efficacy of an agonist at a pentameric ligand-gated ion channel is determined by the rate at which it induces a conformational change from the resting closed state to a preopen ("flip") state. If the ability of an agonist to promote this isomerization is sufficiently low, then it becomes a partial agonist. As partial agonists at pentameric ligand-gated ion channels show considerable promise as therapeutics, understanding the structural basis of the resting-flip-state isomerization may provide insight into therapeutic design...
March 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28105933/haploid-yeast-cells-undergo-a-reversible-phenotypic-switch-associated-with-chromosome-ii-copy-number
#18
Polina Drozdova, Ludmila Mironova, Galina Zhouravleva
BACKGROUND: SUP35 and SUP45 are essential genes encoding polypeptide chain release factors. However, mutants for these genes may be viable but display pleiotropic phenotypes which include, but are not limited to, nonsense suppressor phenotype due to translation termination defect. [PSI (+)] prion formation is another Sup35p-associated mechanism leading to nonsense suppression through decreased availability of functional Sup35p. [PSI (+)] differs from genuine sup35 mutations by the possibility of its elimination and subsequent re-induction...
December 22, 2016: BMC Genetics
https://www.readbyqxmd.com/read/28096462/unique-contributions-of-an-arginine-side-chain-to-ligand-recognition-in-a-glutamate-gated-chloride-channel
#19
Timothy Lynagh, Vitaly V Komnatnyy, Stephan A Pless
Glutamate recognition by neurotransmitter receptors often relies on Arg residues in the binding site, leading to the assumption that charge-charge interactions underlie ligand recognition. However, assessing the precise chemical contribution of Arg side chains to protein function and pharmacology has proven to be exceedingly difficult in such large and complex proteins. Using the in vivo nonsense suppression approach, we report the first successful incorporation of the isosteric, titratable Arg analog, canavanine, into a neurotransmitter receptor in a living cell, utilizing a glutamate-gated chloride channel from the nematode Haemonchus contortus Our data unveil a surprisingly small contribution of charge at a conserved arginine side chain previously suggested to form a salt bridge with the ligand, glutamate...
March 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28077719/suppressing-n-acetyl-l-aspartate-synthesis-prevents-loss-of-neurons-in-a-murine-model-of-canavan-leukodystrophy
#20
Jiho Sohn, Peter Bannerman, Fuzheng Guo, Travis Burns, Laird Miers, Christopher Croteau, Naveen K Singhal, Jennifer A McDonough, David Pleasure
Canavan disease is a leukodystrophy caused by aspartoacylase (ASPA) deficiency. The lack of functional ASPA, an enzyme enriched in oligodendroglia that cleaves N-acetyl-l-aspartate (NAA) to acetate and l-aspartic acid, elevates brain NAA and causes "spongiform" vacuolation of superficial brain white matter and neighboring gray matter. In children with Canavan disease, neuroimaging shows early-onset dysmyelination and progressive brain atrophy. Neuron loss has been documented at autopsy in some cases. Prior studies have shown that mice homozygous for the Aspa nonsense mutation Nur7 also develop brain vacuolation...
January 11, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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