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Nonsense mediated mrna decay

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https://www.readbyqxmd.com/read/29131862/optimized-approach-for-the-identification-of-highly-efficient-correctors-of-nonsense-mutations-in-human-diseases
#1
Hana Benhabiles, Sara Gonzalez-Hilarion, Séverine Amand, Christine Bailly, Anne Prévotat, Philippe Reix, Dominique Hubert, Eric Adriaenssens, Sylvie Rebuffat, David Tulasne, Fabrice Lejeune
About 10% of patients with a genetic disease carry a nonsense mutation causing their pathology. A strategy for correcting nonsense mutations is premature termination codon (PTC) readthrough, i.e. incorporation of an amino acid at the PTC position during translation. PTC-readthrough-activating molecules appear as promising therapeutic tools for these patients. Unfortunately, the molecules shown to induce PTC readthrough show low efficacy, probably because the mRNAs carrying a nonsense mutation are scarce, as they are also substrates of the quality control mechanism called nonsense-mediated mRNA decay (NMD)...
2017: PloS One
https://www.readbyqxmd.com/read/29122854/the-substrates-of-nonsense-mediated-mrna-decay-in-caenorhabditis-elegans
#2
Virginia S Muir, Audrey P Gasch, Philip Anderson
Nonsense-mediated mRNA decay (NMD) is a conserved pathway that strongly influences eukaryotic gene expression.  Inactivating or inhibiting NMD affects the abundance of a substantial fraction of the transcriptome in numerous species.  Transcripts whose abundance is altered in NMD-deficient cells may represent either direct substrates of NMD or indirect effects of inhibiting NMD.  We present a genome-wide investigation of the direct substrates of NMD in Caenorhabditis elegans  Our goals were (i) to identify mRNA substrates of NMD and (ii) to distinguish those mRNAs from others whose abundance is indirectly influenced by the absence of NMD...
November 9, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29121514/nonsense-mediated-mrna-decay-and-cancer
#3
REVIEW
Maximilian W Popp, Lynne E Maquat
Nonsense-mediated mRNA decay (NMD) is a conserved mRNA surveillance pathway that cells use to ensure the quality of transcripts and to fine-tune transcript abundance. The role of NMD in cancer development is complex. In some cases, tumors have exploited NMD to downregulate gene expression by apparently selecting for mutations causing destruction of key tumor-suppressor mRNAs. In other cases, tumors adjust NMD activity to adapt to their microenvironment. Understanding how particular tumors exploit NMD for their benefit may augment the development of new therapeutic interventions...
November 7, 2017: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/29115704/recessive-distal-motor-neuropathy-with-pyramidal-signs-in-an-omani-kindred-underlying-novel-mutation-in-the-sigmar1-gene
#4
Ramachandiran Nandhagopal, Douja Meftah, Sami Al-Kalbani, Patrick Scott
BACKGROUND: Distal hereditary motor neuropathy (dHMN) due to sigma nonopiod intracellular receptor 1 gene (SIGMAR1) mutation (OMIM 601978.0003) is a rare neuromuscular disorder characterized by prominent amyotrophic distal limb weakness and co-existing pyramidal signs initially described in a Chinese family in the recent year. We report an extended consanguineous Omani family segregating dHMN with pyramidal signs in an autosomal recessive pattern and describe a novel mutation in the SIGMAR1 gene underlying this motor phenotype...
November 8, 2017: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
https://www.readbyqxmd.com/read/29107646/spastic-paraplegia-type-31-a-novel-reep1-splice-site-donor-variant-and-expansion-of-the-phenotype-variability
#5
Masaki Kamada, Toshitaka Kawarai, Ryosuke Miyamoto, Rie Kawakita, Yuki Tojima, Celeste Montecchiani, Laura D'Onofrio, Carlo Caltagirone, Antonio Orlacchio, Ryuji Kaji
Mutations in REEP1 have been identified in three types of neurological disorders, autosomal dominant form of Hereditary Spastic Paraplegia type 31 (SPG31), autosomal dominant distal hereditary motor neuronopathy type VB (HMN5B), and autosomal recessive form of congenital axonal neuropathy and diaphragmatic palsy. Previous studies demonstrated different molecular pathogenesis in SPG31, including loss-of-function, gain-of-function and haploinsufficiency. A four-generation family from Japan, including 12 members, was investigated clinically and genetically...
October 21, 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/29106929/gentamicin-induced-readthrough-and-nonsense-mediated-mrna-decay-of-serpinb7-nonsense-mutant-transcripts
#6
Yuka Ohguchi, Toshifumi Nomura, Shotaro Suzuki, Masae Takeda, Toshinari Miyauchi, Osamu Mizuno, Satoru Shinkuma, Yasuyuki Fujita, Osamu Nemoto, Kota Ono, W H Irwin McLean, Hiroshi Shimizu
Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive skin disorder with a high, unmet medical need that is caused by mutations in SERPINB7. Almost all NPPK patients carry the founder nonsense mutation c.796C>T (p.Arg266Ter) in the last exon of SERPINB7. Here we sought to determine whether topical "nonsense-suppression (readthrough)" therapy using gentamicin is applicable to NPPK. First, we demonstrated that gentamicin enhanced readthrough activity in cells transfected with SERPINB7 cDNA carrying the mutation and promoted full-length SERPINB7 protein synthesis in NPPK keratinocytes...
October 26, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29080838/the-smn1-common-variant-c-22-dupa-in-chinese-patients-causes-spinal-muscular-atrophy-by-nonsense-mediated-mrna-decay-in-humans
#7
Bai JinLi, Qu YuJin, Cao YanYan, Yang Lan, Ge Lin, Jin YuWei, Wang Hong, Song Fang
Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is mostly caused by homozygous deletion of the SMN1 gene. Approximately 5%-10% of SMA patients are believed to have SMN1 variants. c.22 dupA (p.Ser8lysfs*23) has been identified as the most frequent variant in the Chinese SMA population and to be associated with a severe phenotype. However, the exact molecular mechanism of the variant on the pathogenesis of SMA is unclear. We observed that SMN1 mRNA and the SMN protein in the peripheral blood cells of a patient with c...
October 25, 2017: Gene
https://www.readbyqxmd.com/read/29077258/whole-exome-sequencing-identifies-a-novel-mutation-of-gpd1l-r189x-associated-with-familial-conduction-disease-and-sudden-death
#8
Hao Huang, Ya-Qin Chen, Liang-Liang Fan, Shuai Guo, Jing-Jing Li, Jie-Yuan Jin, Rong Xiang
Cardiac conduction disease (CCD) is a serious disorder and the leading cause of mortality worldwide. It is characterized by arrhythmia, syncope or even sudden cardiac death caused by the dysfunction of cardiac voltage-gated channel. Previous study has demonstrated that mutations in genes encoding voltage-gated channel and related proteins were the crucial genetic lesion of CCD. In this study, we employed whole-exome sequencing to explore the potential causative genes in a Chinese family with ventricular tachycardia and syncope...
October 27, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29058182/nonsense-mediated-mrna-decay-of-herg-mutations-in-long-qt-syndrome
#9
Qiuming Gong, Zhengfeng Zhou
Long QT syndrome type 2 (LQT2) is caused by mutations in the human ether-à-go-go related gene (hERG), which encodes the Kv11.1 potassium channel in the heart. Over 30% of identified LQT2 mutations are nonsense or frameshift mutations that introduce premature termination codons (PTCs). Contrary to intuition, the predominant consequence of LQT2 nonsense and frameshift mutations is not the production of truncated proteins, but rather the degradation of mutant mRNA by nonsense-mediated mRNA decay (NMD), an RNA surveillance mechanism that selectively eliminates the mRNA transcripts that contain PTCs...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29057815/further-insights-into-the-ciliary-gene-and-protein-kiz-and-its-murine-ortholog-plk1s1-mutated-in-rod-cone-dystrophy
#10
Said El Shamieh, Cécile Méjécase, Matteo Bertelli, Angélique Terray, Christelle Michiels, Christel Condroyer, Stéphane Fouquet, Maxime Sadoun, Emmanuelle Clérin, Binqian Liu, Thierry Léveillard, Olivier Goureau, José-Alain Sahel, Isabelle Audo, Christina Zeitz
We identified herein additional patients with rod-cone dystrophy (RCD) displaying mutations in KIZ, encoding the ciliary centrosomal protein kizuna and performed functional characterization of the respective protein in human fibroblasts and of its mouse ortholog PLK1S1 in the retina. Mutation screening was done by targeted next generation sequencing and subsequent Sanger sequencing validation. KIZ mRNA levels were assessed on blood and serum-deprived human fibroblasts from a control individual and a patient, compound heterozygous for the c...
October 18, 2017: Genes
https://www.readbyqxmd.com/read/29046474/human-alternative-klotho-mrna-is-a-nonsense-mediated-mrna-decay-target-inefficiently-spliced-in-renal-disease
#11
Rik Mencke, Geert Harms, Jill Moser, Matijs van Meurs, Arjan Diepstra, Henri G Leuvenink, Jan-Luuk Hillebrands
Klotho is a renal protein involved in phosphate homeostasis, which is downregulated in renal disease. It has long been considered an antiaging factor. Two Klotho gene transcripts are thought to encode membrane-bound and secreted Klotho. Indeed, soluble Klotho is detectable in bodily fluids, but the relative contributions of Klotho secretion and of membrane-bound Klotho shedding are unknown. Recent advances in RNA surveillance reveal that premature termination codons, as present in alternative Klotho mRNA (for secreted Klotho), prime mRNAs for degradation by nonsense-mediated mRNA decay (NMD)...
October 19, 2017: JCI Insight
https://www.readbyqxmd.com/read/29038333/germ-granule-mediated-rna-regulation-in-male-germ-cells
#12
Tiina Lehtiniemi, Noora Kotaja
Germ cells have exceptionally diverse transcriptomes. Furthermore, the progress of spermatogenesis is accompanied by dramatic changes in gene expression patterns, the most drastic of them being near-to-complete transcriptional silencing during the final steps of differentiation. Therefore, accurate RNA regulatory mechanisms are critical for normal spermatogenesis. Cytoplasmic germ cell-specific ribonucleoprotein (RNP) granules, known as germ granules, participate in posttranscriptional regulation in developing male germ cells...
October 16, 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/29036709/deep-learning-of-the-splicing-epi-genetic-code-reveals-a-novel-candidate-mechanism-linking-histone-modifications-to-esc-fate-decision
#13
Yungang Xu, Yongcui Wang, Jiesi Luo, Weiling Zhao, Xiaobo Zhou
Alternative splicing (AS) is a genetically and epigenetically regulated pre-mRNA processing to increase transcriptome and proteome diversity. Comprehensively decoding these regulatory mechanisms holds promise in getting deeper insights into a variety of biological contexts involving in AS, such as development and diseases. We assembled splicing (epi)genetic code, DeepCode, for human embryonic stem cell (hESC) differentiation by integrating heterogeneous features of genomic sequences, 16 histone modifications with a multi-label deep neural network...
September 28, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29034140/regulation-of-gene-expression-by-translation-factor-eif5a-hypusine-modified-eif5a-enhances-nonsense-mediated-mrna-decay-in-human-cells
#14
Mainul Hoque, Ji Yeon Park, Yun-Juan Chang, Augusto D Luchessi, Tavane D Cambiaghi, Raghavendra Shamanna, Hartmut M Hanauske-Abel, Bart Holland, Tsafi Pe'ery, Bin Tian, Michael B Mathews
Nonsense-mediated mRNA decay (NMD) couples protein synthesis to mRNA turnover. It eliminates defective transcripts and controls the abundance of certain normal mRNAs. Our study establishes a connection between NMD and the translation factor eIF5A (eukaryotic initiation factor 5A) in human cells. eIF5A modulates the synthesis of groups of proteins (the eIF5A regulon), and undergoes a distinctive two-step post-translational modification (hypusination) catalyzed by deoxyhypusine synthase and deoxyhypusine hydroxylase...
2017: Translation
https://www.readbyqxmd.com/read/29020934/transcriptome-analyses-reveal-sr45-to-be-a-neutral-splicing-regulator-and-a-suppressor-of-innate-immunity-in-arabidopsis-thaliana
#15
Xiao-Ning Zhang, Yifei Shi, Jordan J Powers, Nikhil B Gowda, Chong Zhang, Heba M M Ibrahim, Hannah B Ball, Samuel L Chen, Hua Lu, Stephen M Mount
BACKGROUND: Regulation of pre-mRNA splicing diversifies protein products and affects many biological processes. Arabidopsis thaliana Serine/Arginine-rich 45 (SR45), regulates pre-mRNA splicing by interacting with other regulatory proteins and spliceosomal subunits. Although SR45 has orthologs in diverse eukaryotes, including human RNPS1, the sr45-1 null mutant is viable. Narrow flower petals and reduced seed formation suggest that SR45 regulates genes involved in diverse processes, including reproduction...
October 11, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28984438/engineering-the-genetic-code-in-cells-and-animals-biological-considerations-and-impacts
#16
Lei Wang
Expansion of the genetic code allows unnatural amino acids (Uaas) to be site-specifically incorporated into proteins in live biological systems, thus enabling novel properties selectively introduced into target proteins in vivo for basic biological studies and for engineering of novel biological functions. Orthogonal components including tRNA and aminoacyl-tRNA synthetase (aaRS) are expressed in live cells to decode a unique codon (often the amber stop codon UAG) as the desired Uaa. Initially developed in E...
October 6, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28983119/the-gbap1-pseudogene-acts-as-a-cerna-for-the-glucocerebrosidase-gene-gba-by-sponging-mir-22-3p
#17
Letizia Straniero, Valeria Rimoldi, Maura Samarani, Stefano Goldwurm, Alessio Di Fonzo, Rejko Krüger, Michela Deleidi, Massimo Aureli, Giulia Soldà, Stefano Duga, Rosanna Asselta
Mutations in the GBA gene, encoding lysosomal glucocerebrosidase, represent the major predisposing factor for Parkinson's disease (PD), and modulation of the glucocerebrosidase activity is an emerging PD therapy. However, little is known about mechanisms regulating GBA expression. We explored the existence of a regulatory network involving GBA, its expressed pseudogene GBAP1, and microRNAs. The high level of sequence identity between GBA and GBAP1 makes the pseudogene a promising competing-endogenous RNA (ceRNA), functioning as a microRNA sponge...
October 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28977534/fractionation-iclip-detects-persistent-sr-protein-binding-to-conserved-retained-introns-in-chromatin-nucleoplasm-and-cytoplasm
#18
Mattia Brugiolo, Valentina Botti, Na Liu, Michaela Müller-McNicoll, Karla M Neugebauer
RNA binding proteins (RBPs) regulate the lives of all RNAs from transcription, processing, and function to decay. How RNA-protein interactions change over time and space to support these roles is poorly understood. Towards this end, we sought to determine how two SR proteins-SRSF3 and SRSF7, regulators of pre-mRNA splicing, nuclear export and translation-interact with RNA in different cellular compartments. To do so, we developed Fractionation iCLIP (Fr-iCLIP), in which chromatin, nucleoplasmic and cytoplasmic fractions are prepared from UV-crosslinked cells and then subjected to iCLIP...
October 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28959040/endoplasmic-reticulum-stress-preconditioning-modifies-intracellular-mercury-content-by-upregulating-membrane-transporters
#19
Fusako Usuki, Masatake Fujimura, Akio Yamashita
Endoplasmic reticulum (ER) stress preconditioning protects cells against methylmercury (MeHg) cytotoxicity by inducing integrated stress responses such as eIF2α phosphorylation, ATF4 accumulation, and nonsense-mediated mRNA decay (NMD) suppression. Here we demonstrated that ER stress preconditioning results in the upregulation of membrane transporters, leading to a decrease in intracellular mercury content. Our analyses showed that ER stress preconditioning upregulated the expression of methionine transporters that affect the cellular influx of MeHg, LAT1, LAT3, and SNAT2; and a membrane transporter that affects the efflux of MeHg, ABCC4, in MeHg-susceptible myogenic cells...
September 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28950212/p-val19glyfs-21-and-p-leu228-variants-in-the-survival-of-motor-neuron-1-trigger-nonsense-mediated-mrna-decay-causing-the-smn1-ptc-transcripts-degradation
#20
Yu-Jin Qu, Lin Ge, Jin-Li Bai, Yan-Yan Cao, Yu-Wei Jin, Hong Wang, Lan Yang, Fang Song
Spinal Muscular Atrophy (SMA) results from loss-of-function mutations in the survival of motor neuron 1 (SMN1) gene. Our previous research showed that 40% of variants were nonsense or frameshift variants and SMN1 mRNA levels in the patients carrying these variants were significantly decreased. Here we selected one rare variant (p.Val19Glyfs*21) and one common variant (p.Leu228*) to explore the degradation mechanism of mutant transcripts. The levels of full-length (FL)-SMN1 transcripts and SMN protein in the cell lines from the patients with these variants were both significantly reduced (p<0...
September 15, 2017: Mutation Research
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