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Nonsense-mediated mRNA decay

Yukio Kurihara, Yuko Makita, Mika Kawashima, Tomoya Fujita, Shintaro Iwasaki, Minami Matsui
Plants adapt to alterations in light conditions by controlling their gene expression profiles. Expression of light-inducible genes is transcriptionally induced by transcription factors such as HY5. However, few detailed analyses have been carried out on the control of transcription start sites (TSSs). Of the various wavelengths of light, it is blue light (BL) that regulates physiological responses such as hypocotyl elongation and flowering time. To understand how gene expression is controlled not only by transcript abundance but also by TSS selection, we examined genome-wide TSS profiles in Arabidopsis seedlings after exposure to BL irradiation following initial growth in the dark...
June 18, 2018: Proceedings of the National Academy of Sciences of the United States of America
Shoko Horita, Enver Simsek, Tulay Simsek, Nilgun Yildirim, Hiroyuki Ishiura, Motonobu Nakamura, Nobuhiko Satoh, Atsushi Suzuki, Hiroyuki Tsukada, Tomohito Mizuno, George Seki, Shoji Tsuji, Masaomi Nangaku
BACKGROUND: Congenital NBCe1A deficiency with the SLC4A4 mutation causes severe proximal renal tubular acidosis, which often comprises extrarenal symptoms, such as intellectual disability and developmental delay, glaucoma, cataract and band keratopathy. To date, almost all mutations have been found to be homozygous mutations located in exons. CASE PRESENTATION: We performed direct nucleotide sequencing analysis of exons and exon-intron boundary regions of the SLC4A4 in a patient presenting with severe renal proximal tubule acidosis, glaucoma and intellectual disability and her parents without these signs...
June 18, 2018: BMC Medical Genetics
Jonathan O Nelson, Dominique Förster, Kimberley A Frizzell, Stefan Luschnig, Mark M Metzstein
The nonsense-mediated mRNA decay (NMD) pathway is a cellular quality control and post-transcriptional gene regulatory mechanism and is essential for viability in most multicellular organisms. A complex of proteins has been identified to be required for NMD function to occur, however there is an incomplete understanding of the individual contributions of each of these factors to the NMD process. Central to the NMD process are three proteins, Upf1 (SMG-2), Upf2 (SMG-3), and Upf3 (SMG-4), which are found in all eukaryotes, with Upf1 and Upf2 being absolutely required for NMD in all organisms in which their functions have been examined...
June 14, 2018: Genetics
Andrey V Marakhonov, Vyacheslav Yu Tabakov, Nikolay V Zernov, Elena L Dadali, Inna V Sharkova, Mikhail Yu Skoblov
Here we present a case report of collagen VI related myopathy in a patient, 8 y.o. boy, with intermediate phenotype between severe Ullrich congenital muscular dystrophy and milder Bethlem myopathy. Whole exome sequencing revealed two novel single nucleotide variants in COL6A3 gene: paternal p.Glu2402Ter, resulting in premature translation termination codon and degradation of mRNA from this allele probably due to nonsense-mediated decay, and maternal p.Arg1660Cys leading to amino-acid substitution in N2-terminal domain...
June 9, 2018: Gene
Evangelos D Karousis, Oliver Mühlemann
Nonsense-mediated mRNA decay (NMD) is arguably the best-studied eukaryotic messenger RNA (mRNA) surveillance pathway, yet fundamental questions concerning the molecular mechanism of target RNA selection remain unsolved. Besides degrading defective mRNAs harboring premature termination codons (PTCs), NMD also targets many mRNAs encoding functional full-length proteins. Thus, NMD impacts on a cell's transcriptome and is implicated in a range of biological processes that affect a broad spectrum of cellular homeostasis...
June 11, 2018: Cold Spring Harbor Perspectives in Biology
Markus T Sainio, Emil Ylikallio, Laura Mäenpää, Jenni Lahtela, Pirkko Mattila, Mari Auranen, Johanna Palmio, Henna Tyynismaa
Objective: We used patient-specific neuronal cultures to characterize the molecular genetic mechanism of recessive nonsense mutations in neurofilament light ( NEFL ) underlying early-onset Charcot-Marie-Tooth (CMT) disease. Methods: Motor neurons were differentiated from induced pluripotent stem cells of a patient with early-onset CMT carrying a novel homozygous nonsense mutation in NEFL . Quantitative PCR, protein analytics, immunocytochemistry, electron microscopy, and single-cell transcriptomics were used to investigate patient and control neurons...
June 2018: Neurology. Genetics
Xiu-Qin Yang, Xiao-Yan Jing, Cai-Xia Zhang, Yan-Fang Song, Di Liu
Paired immunoglobulin-like type 2 receptor (PILR)β regulates inflammatory responses to pathogen infection, and therefore plays an important role in host disease resistance/susceptibility. However porcine PILRβ remains poorly characterized. In this study, we obtained the cDNA (V1) of its encoding gene, PILRB, and three alternative splicing (AS) variants (V2-4). The complete coding sequence of V1 was 621 bp long encoding a polypeptide of 206 aa. Compared with V1, V2 and V3 were formed by exon-skipping in the 3'-untranslated region (UTR), while V4 was formed by alternative 3' splice site of exon 3, resulting in a premature termination codon, combined with exon skipping in the 3'-UTR...
June 4, 2018: Gene
Grace M Wang, Lev Prasov, Hayder Al-Hasani, Colin E R Marrs, Sahil Tolia, Laurel Wiinikka-Buesser, Julia E Richards, Brenda L Bohnsack
Aniridia is a congenital disease that affects almost all eye structures and is primarily caused by loss-of-function mutations in the PAX6 gene. The degree of vision loss in aniridia varies and is dependent on the extent of foveal, iris, and optic nerve hypoplasia and the presence of glaucoma, cataracts, and corneal opacification. Here, we describe a 4-generation family in which 7 individuals across 2 generations carry a novel disease-causing frameshift mutation (NM_000280.4(PAX6):c.565TC>T) in PAX6. This mutation results in an early stop codon in exon 8, which is predicted to cause nonsense-mediated decay of the truncated mRNA and a functionally null PAX6 allele...
2018: Journal of Ophthalmology
Gang Wu, Liying Fan, Michael N Edmondson, Timothy Shaw, Kristy Boggs, John Easton, Michael C Rusch, Thomas R Webb, Jinghui Zhang, Philip M Potter
The recent identification of compounds that interact the spliceosome (sudemycins, spliceostatin A, and meamycin) indicate that these molecules modulate alternative splicing via SF3B1 inhibition. Through whole transcriptome sequencing, we have demonstrated that treatment of Rh18 cells with sudemycin leads to exon skipping as the predominant aberrant splicing event. This was also observed following reanalysis of published RNAseq datasets derived from Hela cells after spliceostatin A exposure. These results are in contrast to previous reports that indicate that intron retention was the major consequence of SF3B1 inhibition...
May 29, 2018: RNA
M Cecilia Poli, Frédéric Ebstein, Sarah K Nicholas, Marietta M de Guzman, Lisa R Forbes, Ivan K Chinn, Emily M Mace, Tiphanie P Vogel, Alexandre F Carisey, Felipe Benavides, Zeynep H Coban-Akdemir, Richard A Gibbs, Shalini N Jhangiani, Donna M Muzny, Claudia M B Carvalho, Deborah A Schady, Mahim Jain, Jill A Rosenfeld, Lisa Emrick, Richard A Lewis, Brendan Lee, Barbara A Zieba, Sébastien Küry, Elke Krüger, James R Lupski, Bret L Bostwick, Jordan S Orange
The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE)...
May 22, 2018: American Journal of Human Genetics
Leila Youssefian, Hassan Vahidnezhad, Andrew Touati, Vahid Ziaee, Amir Hossein Saeidian, Sara Pajouhanfar, Sirous Zeinali, Jouni Uitto
BACKGROUND: Hyaline fibromatosis syndrome (HFS) is a rare heritable multi-systemic disorder with significant dermatologic manifestations. It is caused by mutations in ANTXR2, which encodes a transmembrane receptor involved in collagen VI regulation in the extracellular matrix. Over 40 mutations in the ANTXR2 gene have been associated with cases of HFS. Variable severity of the disorder in different patients has been proposed to be related to the specific mutations in these patients and their location within the gene...
May 25, 2018: BMC Medical Genetics
Kate Krempely, Rachid Karam
Most truncating CDH1 pathogenic alterations confer an elevated lifetime risk of diffuse gastric cancer and lobular breast cancer. However, transcripts containing carboxyl-terminal (C-terminal) premature stop codons have been demonstrated to escape the nonsense-mediated mRNA decay (NMD) pathway, and gastric and breast cancer risks associated with these truncations should be carefully evaluated. A female patient underwent multigene panel testing due to a personal history of invasive lobular breast cancer diagnosed at age 54, which identified the germline CDH1 nonsense alteration, c...
May 24, 2018: Cold Spring Harbor Molecular Case Studies
E Imagawa, Y Yamamoto, S Mitsuhashi, B Isidor, T Fukuyama, M Kato, M Sasaki, S Tanabe, S Miyatake, T Mizuguchi, A Takata, N Miyake, N Matsumoto
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA) (OMIM #617481) is an autosomal recessive disease characterized by progressive microcephaly, plagiocephaly, hypotonia, spastic quadriparesis, global developmental delay, intellectual disability, optic features and abnormal brain MRI. NMIHBA was recently reported to be caused by PRUNE1 mutations. Eight mutations have been reported in 13 unrelated families. Here we report three PRUNE1 mutations in one Caucasian and three Japanese families...
May 24, 2018: Clinical Genetics
Katarzyna Bartkowska, Beata Tepper, Kris Turlejski, Ruzanna L Djavadian
The exon junction complex (EJC) consists of four core proteins: Magoh, RNA-binding motif 8A (Rbm8a, also known as Y14), eukaryotic initiation factor 4A3 (eIF4A3, also known as DDX48), and metastatic lymph node 51 (MLN51, also known as Casc3 or Barentsz), which are involved in the regulation of many processes occurring between gene transcription and protein translation. Its main role is to assemble into spliceosomes at the exon-exon junction of mRNA during splicing. It is, therefore, a range of functions concerning post-splicing events such as mRNA translocation, translation, and nonsense-mediated mRNA decay (NMD)...
May 23, 2018: Reviews in the Neurosciences
Wanyan Tan, Wei Wang, Qingfeng Ma
Serine/arginine-rich splicing factors (SRSFs) have one or two RNA recognition motifs in the N terminal and a serine/arginine-enriched domain in the C terminal. SRSFs are essential components of spliceosomes and are involved in alternative splicing, spliceosome assembly, mRNA export, and nonsense-mediated mRNA decay. The maintenance of cellular and tissue homeostasis relies on accurate alternative splicing, and various patterns of abnormal alternative splicing can cause different diseases. SRSF4 is associated with many physiological and pathological processes and has applications in the diagnosis and prognosis of specific diseases...
2018: BioMed Research International
Vanessa L Lattimore, John F Pearson, Margaret J Currie, Amanda B Spurdle, Bridget A Robinson, Logan C Walker
PCR-based RNA splicing assays are commonly used in diagnostic and research settings to assess the potential effects of variants of uncertain clinical significance in BRCA1 and BRCA2 . The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium completed a multicentre investigation to evaluate differences in assay design and the integrity of published data, raising a number of methodological questions associated with cell culture conditions and PCR-based protocols. We utilized targeted RNA-seq to re-assess BRCA1 and BRCA2 mRNA isoform expression patterns in lymphoblastoid cell lines (LCLs) previously used in the multicentre ENIGMA study...
2018: Frontiers in Oncology
Liam Spurr, Muzi Li, Nawaf Alomran, Qianqian Zhang, Paula Restrepo, Mercedeh Movassagh, Chris Trenkov, Nerissa Tunnessen, Tatiyana Apanasovich, Keith A Crandall, Nathan Edwards, Anelia Horvath
Imbalanced expression of somatic alleles in cancer can suggest functional and selective features, and can therefore indicate possible driving potential of the underlying genetic variants. To explore the correlation between allele frequency of somatic variants and total gene expression of their harboring gene, we used the unique data set of matched tumor and normal RNA and DNA sequencing data of 5523 distinct single nucleotide variants in 381 individuals across 10 cancer types obtained from The Cancer Genome Atlas (TCGA)...
May 16, 2018: Scientific Reports
Isabel Aznarez, Tomoki T Nomakuchi, Jaclyn Tetenbaum-Novatt, Mohammad Alinoor Rahman, Oliver Fregoso, Holly Rees, Adrian R Krainer
The splicing factor SRSF1 promotes nonsense-mediated mRNA decay (NMD), a quality control mechanism that degrades mRNAs with premature termination codons (PTCs). Here we show that transcript-bound SRSF1 increases the binding of NMD factor UPF1 to mRNAs while in, or associated with, the nucleus, bypassing UPF2 recruitment and promoting NMD. SRSF1 promotes NMD when positioned downstream of a PTC, which resembles the mode of action of exon junction complex (EJC) and NMD factors. Moreover, splicing and/or EJC deposition increase the effect of SRSF1 on NMD...
May 15, 2018: Cell Reports
Francesca Salvatori, Mariangela Pappadà, Giulia Breveglieri, Elisabetta D'Aversa, Alessia Finotti, Ilaria Lampronti, Roberto Gambari, Monica Borgatti
BACKGROUND: Nonsense mutations promote premature translational termination, introducing stop codons within the coding region of mRNAs and causing inherited diseases, including thalassemia. For instance, in β0 39 thalassemia the CAG (glutamine) codon is mutated to the UAG stop codon, leading to premature translation termination and to mRNA destabilization through the well described NMD (nonsense-mediated mRNA decay). In order to develop an approach facilitating translation and, therefore, protection from NMD, ribosomal read-through molecules, such as aminoglycoside antibiotics, have been tested on mRNAs carrying premature stop codons...
May 15, 2018: BMC Biotechnology
Chiara Paolantoni, Simona Ricciardi, Veronica De Paolis, Chinenye Okenwa, Caterina Catalanotto, Maria T Ciotti, Antonino Cattaneo, Carlo Cogoni, Corinna Giorgi
Activity-regulated cytoskeletal associated protein (Arc) is an immediate-early gene critically involved in synaptic plasticity and memory consolidation. Arc mRNA is rapidly induced by synaptic activation and a portion is locally translated in dendrites where it modulates synaptic strength. Being an activity-dependent effector of homeostatic balance, regulation of Arc is uniquely tuned to result in short-lived bursts of expression. Cis -Acting elements that control its transitory expression post-transcriptionally reside primarily in Arc mRNA 3' UTR...
2018: Frontiers in Molecular Neuroscience
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