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Nonsense-mediated mRNA decay

Youn Hee Jee, Nadine Sowada, Thomas C Markello, Iraj Rezvani, Guntram Borck, Jeffrey Baron
Linear growth failure can be caused by many different genetic abnormalities. In many cases, the genetic defect affects not only the growth plate, causing short stature, but also other organs/tissues causing additional clinical abnormalities. The proband was evaluated at 10 years of age for impaired postnatal linear growth (height 113.3 cm, -4.6 SDS), a bone age that was delayed by 5 years, dysmorphic facies, cognitive impairment, and central nervous system anomalies. His younger brother, presented only with growth failure at 10 months of age...
October 17, 2016: Clinical Genetics
Karina Vexler, Miryam A Cymerman, Irina Berezin, Adi Fridman, Linoy Golani, Michal Lasnoy, Helen Saul, Orit Shaul
Nonsense-mediated mRNA decay (NMD) is a eukaryotic RNA surveillance mechanism that degrades aberrant transcripts and controls the levels of many normal mRNAs. It was shown that balanced expression of the NMD factor UPF3 is essential for the maintenance of proper NMD homeostasis in Arabidopsis. UPF3 expression is controlled by a negative feedback loop that exposes UPF3 transcript to NMD. It was shown that the long 3' untranslated region (3' UTR) of UPF3 exposes its transcript to NMD. Long 3' UTRs that subject their transcripts to NMD were identified in several eukaryotic NMD factors...
2016: Frontiers in Plant Science
X Ding, Y Yang, Y Sun, W Xu, B Su, X Zhou
PURPOSE: To investigate the role of miR-585 in the development and progression of non-small-cell lung cancer (NSCLC). METHODS: The expression levels of miR-585 in NSCLC cell lines and clinical samples were measured by quantitative PCR. NSCLC cells, A549 and H1299, were stably transfected with lentiviral vectors of miR-585 mimics or negative control. The effects of miR-585 on cell proliferation were detected both in vitro and in vivo. Cell migration and invasion were evaluated using wound healing assay and Transwell assay...
October 14, 2016: Clinical & Translational Oncology
Andrew J Love, Chulang Yu, Natalia V Petukhova, Natalia O Kalinina, Jianping Chen, Michael E Taliansky
Cajal bodies (CBs) are distinct sub-nuclear structures that are present in eukaryotic living cells and are often associated with the nucleolus. CBs play important roles in RNA metabolism and formation of RNPs involved in transcription, splicing, ribosome biogenesis, and telomere maintenance. Besides these primary roles, CBs appear to be involved in additional functions that may not be directly related to RNA metabolism and RNP biogenesis. In this review, we assess possible roles of plant CBs in RNA regulatory pathways such as nonsense-mediated mRNA decay and RNA silencing...
October 11, 2016: RNA Biology
Atsuko Miki, Josephine Galipon, Satoshi Sawai, Toshifumi Inada, Kunihiro Ohta
Antisense RNA has emerged as a crucial regulator of opposite-strand protein-coding genes in the long noncoding RNA (lncRNA) category, but little is known about their dynamics and decay process in the context of a stress response. Antisense transcripts from the fission yeast fbp1 locus (fbp1-as) are expressed in glucose-rich conditions and anticorrelated with transcription of metabolic stress-induced lncRNA (mlonRNA) and mRNA on the sense strand during glucose starvation. Here, we investigate the localization and decay of antisense RNAs at fbp1 and other loci, and propose a model to explain the rapid switch between antisense and sense mlonRNA/mRNA transcription triggered by glucose starvation...
October 10, 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Maria Francisca Coutinho, Marisa Encarnação, Francisco Laranjeira, Lúcia Lacerda, Maria João Prata, Sandra Alves
While being well known that the diagnosis of many genetic disorders relies on a combination of clinical suspicion and confirmatory genetic testing, not rarely, however, genetic testing needs much perseverance and cunning strategies to identify the causative mutation(s). Here we present a case of a thorny molecular diagnosis of mucolipidosis type III alpha/beta, which is an autosomal recessive lysosomal storage disorder, caused by a defect in the GNPTAB gene that codes for the α/β-subunits of the GlcNAc-1-phosphotransferase...
October 1, 2016: Journal of Pediatric Endocrinology & Metabolism: JPEM
Ying Li, Yeou-Cherng Bor, Mark P Fitzgerald, Kevin S Lee, David Rekosh, Marie-Louise Hammarskjold
The Nxf1 protein is a major nuclear export receptor for the transport of mRNA and it also is essential for export of retroviral mRNAs with retained introns. In the latter case, it binds to RNA elements known as Constitutive Transport Elements (CTEs) and functions in conjunction with a cofactor known as Nxt1. The NXF1 gene also regulates expression of its own intron-containing RNA through the use of a functional CTE within intron 10. mRNA containing this intron is exported to the cytoplasm where it can be translated into the 356 amino acid short Nxf1(sNxf1) protein, despite the fact that it is a prime candidate for nonsense mediated decay (NMD)...
October 5, 2016: Molecular Biology of the Cell
Vandana Shashi, Loren D M Pena, Katherine Kim, Barbara Burton, Maja Hempel, Kelly Schoch, Magdalena Walkiewicz, Heather M McLaughlin, Megan Cho, Nicholas Stong, Scott E Hickey, Christine M Shuss, Michael S Freemark, Jane S Bellet, Martha Ann Keels, Melanie J Bonner, Maysantoine El-Dairi, Megan Butler, Peter G Kranz, Constance T R M Stumpel, Sylvia Klinkenberg, Karin Oberndorff, Malik Alawi, Rene Santer, Slavé Petrovski, Outi Kuismin, Satu Korpi-Heikkilä, Olli Pietilainen, Palotie Aarno, Mitja I Kurki, Alexander Hoischen, Anna C Need, David B Goldstein, Fanny Kortüm
The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 and ASXL3 have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. ASXL2 has not yet been associated with a human Mendelian disorder...
October 6, 2016: American Journal of Human Genetics
Keiichi Izumikawa, Harunori Yoshikawa, Hideaki Ishikawa, Yuko Nobe, Yoshio Yamauchi, Sjaak Philipsen, Richard J Simpson, Toshiaki Isobe, Nobuhiro Takahashi
Chtop (chromatin target of Prmt1) regulates various aspects of gene expression including transcription and mRNA export. Despite these important functions, the regulatory mechanism underlying Chtop expression remains undetermined. Using Chtop-expressing human cell lines, we demonstrate that Chtop expression is controlled via an autoregulatory negative feedback loop whereby Chtop binds its own mRNA to retain intron 2 during splicing; a premature termination codon present at the 5' end of intron 2 leads to nonsense-mediated decay of the mRNA...
September 28, 2016: Nucleic Acids Research
María Laura Matos, Lara Lapyckyj, Arina Rosso, María José Besso, María Victoria Mencucci, Clara Isabel Marín Briggiler, Silvina Giustina, Laura Inés Furlong, Mónica Hebe Vazquez-Levin
Epithelial Cadherin (E-cadherin) is involved in calcium-dependent cell-cell adhesion and signal transduction. The E-cadherin decrease/loss is a hallmark of Epithelial to Mesenchymal Transition (EMT), a key event in tumor progression. The underlying molecular mechanisms that trigger E-cadherin loss and consequent EMT have not been completely elucidated. This study reports the identification of a novel human E-cadherin variant mRNA produced by alternative splicing. A bioinformatics evaluation of the novel mRNA sequence and biochemical verifications suggest its regulation by Nonsense-Mediated mRNA Decay (NMD)...
September 28, 2016: Journal of Cellular Physiology
Kensuke Ninomiya, Mutsuhito Ohno, Naoyuki Kataoka
Localization of mRNA in neuronal cells is a critical process for spatiotemporal regulation of gene expression. Cytoplasmic localization of mRNA is often conferred by transport elements in 3' untranslated region (UTR). Activity-regulated cytoskeleton-associated protein (arc) mRNA is one of the localizing mRNAs in neuronal cells, and its localization is mediated by dendritic targeting element (DTE). As arc mRNA has introns in its 3' UTR, it was thought that arc mRNA is a natural target of nonsense-mediated mRNA decay (NMD)...
September 23, 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
István Bock, Krisztina Németh, Klára Pentelényi, Péter Balicza, Anna Balázs, Mária Judit Molnár, Viktor Román, József Nagy, György Lévay, Julianna Kobolák, András Dinnyés
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with unknown genetic and environmental causation in most of the affected individuals. On the other hand, there are a growing number of ASD-associated syndromes, where the exact genetic origin can be revealed. Here we report a method, which included the targeted next generation sequencing (NGS) and filtering of 101 ASD associated genes, followed by database search. Next, RNA sequencing was used to study the region of interest at the transcriptional level...
September 17, 2016: Gene
Yong-Jin Park, Seog-Ki Lee, Seong-Ho Kang, Sook-Jin Jang, Dae-Soo Moon, Geon Park
A novel FLCN c.1489_1490delTG (p.Val497Glyfs*22) mutation at the genomic DNA and mRNA levels was identified in a 43-year-old woman with complaining of recurrent primary spontaneous pneumothorax. The aberrant FLCN mRNA escaped the nonsense-mediated decay system (NMD) because of a premature termination code located in an NMD-incompetent region. To the best of our knowledge, this is the first case report of an FLCN mutation escaping the NMD.
September 2016: Annals of Clinical and Laboratory Science
Anne A Blanchard, Teresa Zelinski, Jiuyong Xie, Steven Cooper, Carla Penner, Etienne Leygue, Yvonne Myal
BACKGROUND: The claudin 1 tight junction protein, solely responsible for the barrier function of epithelial cells, is frequently down regulated in invasive human breast cancer. The underlying mechanism is largely unknown, and no obvious mutations in the claudin 1 gene (CLDN1) have been identified to date in breast cancer. Since many genes have been shown to undergo deregulation through splicing and mis-splicing events in cancer, the current study was undertaken to investigate the occurrence of transcript variants for CLDN1 in human invasive breast cancer...
2016: PloS One
Alice Luddi, Laura Crifasi, Angela Capaldo, Paola Piomboni, Elvira Costantino-Ceccarini
Krabbe's disease (KD) is a degenerative lysosomal storage disease resulting from deficiency of β-galactocerebrosidase activity. Over 100 mutations are known to cause the disease, and these usually occur in compound heterozygote patterns. In affected patients, nonsense mutations leading to a nonfunctional enzyme are often found associated with other mutations. The twitcher mouse is a naturally occurring model of KD, containing in β-galactocerebrosidase a premature stop codon, W339X. Recent studies have shown that selected compounds may induce the ribosomal bypass of premature stop codons without affecting the normal termination codons...
November 2016: Journal of Neuroscience Research
Laura Bianciardi, Valentina Imperatore, Erika Fernandez-Vizarra, Angela Lopomo, Micol Falabella, Simone Furini, Paolo Galluzzi, Salvatore Grosso, Massimo Zeviani, Alessandra Renieri, Francesca Mari, Elisa Frullanti
We report here the case of a young male who started to show verbal fluency disturbance, clumsiness and gait anomalies at the age of 3.5years and presented bilateral striatal necrosis. Clinically, the diagnosis was compatible with Leigh syndrome but the underlying molecular defect remained elusive even after exome analysis using autosomal/X-linked recessive or de novo models. Dosage of respiratory chain activity on fibroblasts, but not in muscle, underlined a deficit in complex I. Re-analysis of heterozygous probably pathogenic variants, inherited from one healthy parent, identified the p...
September 3, 2016: Molecular Genetics and Metabolism
Rik G H Lindeboom, Fran Supek, Ben Lehner
Premature termination codons (PTCs) cause a large proportion of inherited human genetic diseases. PTC-containing transcripts can be degraded by an mRNA surveillance pathway termed nonsense-mediated mRNA decay (NMD). However, the efficiency of NMD varies; it is inefficient when a PTC is located downstream of the last exon junction complex (EJC). We used matched exome and transcriptome data from 9,769 human tumors to systematically elucidate the rules of NMD targeting in human cells. An integrated model incorporating multiple rules beyond the canonical EJC model explains approximately three-fourths of the non-random variance in NMD efficiency across thousands of PTCs...
October 2016: Nature Genetics
Vladyslav S Bondarenko, Mikhail S Gelfand
A typical eukaryotic gene is comprised of alternating stretches of regions, exons and introns, retained in and spliced out a mature mRNA, respectively. Although the length of introns may vary substantially among organisms, a large fraction of genes contains short introns in many species. Notably, some Ciliates (Paramecium and Nyctotherus) possess only ultra-short introns, around 25 bp long. In Paramecium, ultra-short introns with length divisible by three (3n) are under strong evolutionary pressure and have a high frequency of in-frame stop codons, which, in the case of intron retention, cause premature termination of mRNA translation and consequent degradation of the mis-spliced mRNA by the nonsense-mediated decay mechanism...
2016: PloS One
Meike J Saul, Stefan Stein, Manuel Grez, Per-Johan Jakobsson, Dieter Steinhilber, Beatrix Suess
UPF1 is a key player in nonsense mediated mRNA decay (NMD) but also involved in posttranscriptional gene regulation. In this study we found that UPF1 regulates the expression of genes with functions in inflammation and myeloid cell differentiation via hnRNP E2. The majority of the UPF1-regulated genes identified in monocytic cells contain a binding site for hnRNP E2 within 5' UTR located introns with hnRNP E2 acting here as splicing regulator. We found that miRNA-328 which is significantly induced during monocytic cell differentiation acts independently from its gene silencing function as RNA decoy for hnRNP E2...
2016: Scientific Reports
Callie P Wigington, Kevin J Morris, Laura E Newman, Anita H Corbett
Polyadenosine RNA binding proteins (Pabs) regulate multiple steps in gene expression. This protein family includes the well-studied Pabs, PABPN1 and PABPC1, as well as the newly characterized Pab, Zinc Finger CCCH-type containing #14, or ZC3H14. Mutations in ZC3H14 are linked to a form of intellectual disability. To probe the function of ZC3H14, we performed a transcriptome-wide analysis of cells depleted of either ZC3H14 the control Pab, PABPN1. Depletion of PABPN1 affected ~17% of expressed transcripts while ZC3H14 affected only ~1% of expressed transcripts...
August 25, 2016: Journal of Biological Chemistry
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