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Nonsense mediated mrna decay

Nazmul Haque, Ryota Ouda, Chao Chen, Keiko Ozato, J Robert Hogg
Control of type I interferon production is crucial to combat infection while preventing deleterious inflammatory responses, but the extent of the contribution of post-transcriptional mechanisms to innate immune regulation is unclear. Here, we show that human zinc finger RNA-binding protein (ZFR) represses the interferon response by regulating alternative pre-mRNA splicing. ZFR expression is tightly controlled during macrophage development; monocytes express truncated ZFR isoforms, while macrophages induce full-length ZFR to modulate macrophage-specific alternative splicing...
March 20, 2018: Nature Communications
Cyril Pottier, Evadnie Rampersaud, Matt Baker, Gang Wu, Joanne Wuu, Jacob L McCauley, Stephan Zuchner, Rebecca Schule, Christin Bermudez, Sumaira Hussain, Anne Cooley, Marielle Wallace, Jinghui Zhang, J Paul Taylor, Michael Benatar, Rosa Rademakers
Homozygous loss-of-function mutations in optineurin (OPTN) are a rare cause of amyotrophic lateral sclerosis (ALS), whereas heterozygous loss-of-function mutations have been suggested to increase ALS disease risk. We report a patient with ALS and frontotemporal dementia (FTD) from the Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium carrying compound heterozygous loss-of-function variants in OPTN. Quantitative real-time mRNA expression analyses revealed a 75-80% reduction in OPTN expression in blood in the OPTN carrier as compared to controls, suggesting at least partial nonsense-mediated decay of the mutant transcripts...
March 20, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Wolf Achim Hassenpflug, Tobias Obser, Julia Bode, Florian Oyen, Ulrich Budde, Sonja Schneppenheim, Reinhard Schneppenheim, Maria Alexandra Brehm
Upshaw-Schulman syndrome (USS) is caused by severe ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency due to homozygous or compound heterozygous mutations in the ADAMTS13 gene. Previous studies suggest three possible disease mechanisms: (1) reduced secretion of ADAMTS13 variants, (2) impaired proteolytic activity, (3) defective biosynthesis due to nonsense-mediated decay. Expression studies have failed to establish a clear genotype/phenotype correlation that could explain the significant variability in the age of onset and patients' clinical courses...
March 19, 2018: Thrombosis and Haemostasis
Ahoura Nozari, Ehsan Aghaei-Moghadam, Aliakbar Zeinaloo, Reza Mollazadeh, Mohammad-Taghi Majnoon, Afagh Alavi, Saghar Ghasemi Firouzabadi, Akbar Mohammadzadeh, Susan Banihashemi, Mehrnoosh Nikzaban, Hossein Najmabadi, Farkhondeh Behjati
Recent achievements in the genetic diagnosis of Dilated Cardiomyopathy (DCM) have disclosed rare variants in numerous genes encoding different types of myocardial proteins. However, the causative gene underlying the pathogenesis of about 60% of familial cases with DCM has not been identified. One novel gene introduced in 2016 for cardiac-restricted DCM is FLNC. In this study, we applied Whole Exome Sequencing (WES) and bioinformatics-based methods to a member of an extended non-consanguineous family with DCM history accompanied with fatal arrhythmia in at least four consecutive generations...
March 15, 2018: Gene
Alan D Marmorstein, Adiv A Johnson, Lori A Bachman, Cynthia Andrews-Pfannkoch, Travis Knudsen, Benjamin J Gilles, Matthew Hill, Jarel K Gandhi, Lihua Y Marmorstein, Jose S Pulido
Autosomal recessive bestrophinopathy (ARB) is caused by mutations in the gene BEST1 which encodes bestrophin 1 (Best1), an anion channel expressed in retinal pigment epithelial (RPE) cells. It has been hypothesized that ARB represents the human null phenotype for BEST1 and that this occurs due to nonsense mediated decay (NMD). To test this hypothesis, we generated induced pluripotent stem cells (iPSCs) from a patient with ARB and her parents. After differentiation to retinal pigment epithelial (iPSC-RPE) cells, both BEST1 mRNA and Best1 protein expression were compared to controls...
March 14, 2018: Scientific Reports
Thomas D Baird, Ken Chih-Chien Cheng, Yu-Chi Chen, Eugen Buehler, Scott E Martin, James Inglese, J Robert Hogg
The nonsense-mediated mRNA decay (NMD) pathway detects aberrant transcripts containing premature termination codons (PTCs) and regulates expression of 5-10% of non-aberrant human mRNAs. To date, most proteins involved in NMD have been identified by genetic screens in model organisms; however, the increased complexity of gene expression regulation in human cells suggests that additional proteins may participate in the human NMD pathway. To identify proteins required for NMD, we performed a genome-wide RNAi screen against >21,000 genes...
March 12, 2018: ELife
Yonatan Perez, Shay Menascu, Idan Cohen, Rotem Kadir, Omer Basha, Zamir Shorer, Hila Romi, Gal Meiri, Tatiana Rabinski, Rivka Ofir, Esti Yeger-Lotem, Ohad S Birk
RSRC1, whose polymorphism is associated with altered brain function in schizophrenia, is a member of the serine and arginine rich-related protein family. Through homozygosity mapping and whole exome sequencing we show that RSRC1 mutation causes an autosomal recessive syndrome of intellectual disability, aberrant behaviour, hypotonia and mild facial dysmorphism with normal brain MRI. Further, we show that RSRC1 is ubiquitously expressed, and that the RSRC1 mutation triggers nonsense-mediated mRNA decay of the RSRC1 transcript in patients' fibroblasts...
March 7, 2018: Brain: a Journal of Neurology
Andrew D Nguyen, Thi A Nguyen, Jiasheng Zhang, Swathi Devireddy, Ping Zhou, Anna M Karydas, Xialian Xu, Bruce L Miller, Frank Rigo, Shawn M Ferguson, Eric J Huang, Tobias C Walther, Robert V Farese
Frontotemporal dementia (FTD) is the most common neurodegenerative disorder in individuals under age 60 and has no treatment or cure. Because many cases of FTD result from GRN nonsense mutations, an animal model for this type of mutation is highly desirable for understanding pathogenesis and testing therapies. Here, we generated and characterized Grn R493X knockin mice, which model the most common human GRN mutation, a premature stop codon at arginine 493 (R493X). Homozygous Grn R493X mice have markedly reduced Grn mRNA levels, lack detectable progranulin protein, and phenocopy Grn knockout mice, with CNS microgliosis, cytoplasmic TDP-43 accumulation, reduced synaptic density, lipofuscinosis, hyperinflammatory macrophages, excessive grooming behavior, and reduced survival...
March 6, 2018: Proceedings of the National Academy of Sciences of the United States of America
Nur Hidayah Jamar, Paraskevi Kritsiligkou, Chris M Grant
Eukaryotic cells contain translation-associated mRNA surveillance pathways which prevent the production of potentially toxic proteins from aberrant mRNA translation events. We found that loss of mRNA surveillance pathways in mutants deficient in nonsense-mediated decay (NMD), no-go decay (NGD) and nonstop decay (NSD) results in increased protein aggregation. We have isolated and identified the proteins that aggregate and our bioinformatic analyses indicates that increased aggregation of aggregation-prone proteins is a general occurrence in mRNA surveillance mutants, rather than being attributable to specific pathways...
March 1, 2018: Scientific Reports
Ibrahim Sahin, Haktan B Erdem, Huseyin Tan, Abdulgani Tatar
Myotonia congenita is an inherited muscle disease present from childhood that is characterized by impaired muscle relaxation after contraction resulting in muscle stiffness; moreover, skeletal striated muscle groups may be involved. Myotonia congenita occurs due to chloride (Cl) channel mutations that reduce the stabilizing Cl conductance, and it is caused by mutations in the CLCN1 gene. This paper describes four patients from two different healthy consanguineous Turkish families with muscle stiffness and easy fatigability...
February 26, 2018: Acta Neurologica Belgica
Natalia O Kalinina, Svetlana Makarova, Antonida Makhotenko, Andrew J Love, Michael Taliansky
The nucleolus is the most conspicuous domain in the eukaryotic cell nucleus, whose main function is ribosomal RNA (rRNA) synthesis and ribosome biogenesis. However, there is growing evidence that the nucleolus is also implicated in many other aspects of cell biology, such as regulation of cell cycle, growth and development, senescence, telomerase activity, gene silencing, responses to biotic and abiotic stresses. In the first part of the review, we briefly assess the traditional roles of the plant nucleolus in rRNA synthesis and ribosome biogenesis as well as possible functions in other RNA regulatory pathways such as splicing, nonsense-mediated mRNA decay and RNA silencing...
2018: Frontiers in Plant Science
Akihiro Sugai, Taisuke Kato, Akihide Koyama, Yuka Koike, Sou Kasahara, Takuya Konno, Tomohiko Ishihara, Osamu Onodera
Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm and its disappearance from the nucleus are pathological features of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) and are directly involved in the pathogenesis of these conditions. TDP-43 is an essential nuclear protein that readily aggregates in a concentration-dependent manner. Therefore, cells must strictly maintain an appropriate amount of nuclear TDP-43. In one relevant maintenance mechanism, TDP-43 binds to its pre-mRNA and promotes alternative splicing, resulting in mRNA degradation via nonsense-mediated mRNA decay...
2018: Frontiers in Neuroscience
Amjad Khan, Rongrong Wang, Shirui Han, Wasim Ahmad, Xue Zhang
AIMS: To identify the pathogenic mutation underlying microcephaly primary hereditary (MCPH) in a large consanguineous Pakistani family. METHODS: A five-generation family with an autosomal recessive transmission of MCPH was recruited. Targeted next-generation DNA sequencing was carried out to analyze the genomic DNA sample from the proband with MCPH using a previously designed panel targeting 46 known microcephaly-causing genes. Sanger sequencing was performed to verify all identified variants...
February 12, 2018: Genetic Testing and Molecular Biomarkers
Cindy Meyer, Aitor Garzia, Michael Mazzola, Stefanie Gerstberger, Henrik Molina, Thomas Tuschl
TIA1 and TIAL1 encode a family of U-rich element mRNA-binding proteins ubiquitously expressed and conserved in metazoans. Using PAR-CLIP, we determined that both proteins bind target sites with identical specificity in 3' UTRs and introns proximal to 5' as well as 3' splice sites. Double knockout (DKO) of TIA1 and TIAL1 increased target mRNA abundance proportional to the number of binding sites and also caused accumulation of aberrantly spliced mRNAs, most of which are subject to nonsense-mediated decay. Loss of PRKRA by mis-splicing triggered the activation of the double-stranded RNA (dsRNA)-activated protein kinase EIF2AK2/PKR and stress granule formation...
February 15, 2018: Molecular Cell
Saliha Yilmaz, Dilek Uludağ Alkaya, Özgür Kasapçopur, Kenan Barut, Ekin S Akdemir, Cemre Celen, Mark W Youngblood, Katsuhito Yasuno, Kaya Bilguvar, Murat Günel, Beyhan Tüysüz
BACKGROUND: The camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a rare autosomal recessive condition characterized by camptodactyly, noninflammatory arthropathy, coxa vara, and pericarditis. CACP is caused by mutations in the proteoglycan 4 (PRG4) gene, which encodes a lubricating glycoprotein present in the synovial fluid and at the surface of articular cartilage. METHODS: In the present study, we compared the clinical and molecular findings of CACP syndrome in 35 patients from 11 unrelated families...
February 4, 2018: Molecular Genetics & Genomic Medicine
Hiroyuki Ono, Hirotomo Saitsu, Reiko Horikawa, Shinichi Nakashima, Yumiko Ohkubo, Kumiko Yanagi, Kazuhiko Nakabayashi, Maki Fukami, Yasuko Fujisawa, Tsutomu Ogata
Although partial androgen insensitivity syndrome (PAIS) is caused by attenuated responsiveness to androgens, androgen receptor gene (AR) mutations on the coding regions and their splice sites have been identified only in <25% of patients with a diagnosis of PAIS. We performed extensive molecular studies including whole exome sequencing in a Japanese family with PAIS, identifying a deep intronic variant beyond the branch site at intron 6 of AR (NM_000044.4:c.2450-42 G > A). This variant created the splice acceptor motif that was accompanied by pyrimidine-rich sequence and two candidate branch sites...
February 2, 2018: Scientific Reports
Francesca Fiorini, Jean-Philippe Robin, Joanne Kanaan, Malgorzata Borowiak, Vincent Croquette, Hervé Le Hir, Pierre Jalinot, Vincent Mocquet
Up-Frameshift Suppressor 1 Homolog (UPF1) is a key factor for nonsense-mediated mRNA decay (NMD), a cellular process that can actively degrade mRNAs. Here, we study NMD inhibition during infection by human T-cell lymphotropic virus type I (HTLV-1) and characterise the influence of the retroviral Tax factor on UPF1 activity. Tax interacts with the central helicase core domain of UPF1 and might plug the RNA channel of UPF1, reducing its affinity for nucleic acids. Furthermore, using a single-molecule approach, we show that the sequential interaction of Tax with a RNA-bound UPF1 freezes UPF1: this latter is less sensitive to the presence of ATP and shows translocation defects, highlighting the importance of this feature for NMD...
January 30, 2018: Nature Communications
Manjeera Gowravaram, Fabien Bonneau, Joanne Kanaan, Vincent D Maciej, Francesca Fiorini, Saurabh Raj, Vincent Croquette, Hervé Le Hir, Sutapa Chakrabarti
The RNA helicase UPF1 is a key component of the nonsense mediated mRNA decay (NMD) pathway. Previous X-ray crystal structures of UPF1 elucidated the molecular mechanisms of its catalytic activity and regulation. In this study, we examine features of the UPF1 core and identify a structural element that adopts different conformations in the various nucleotide- and RNA-bound states of UPF1. We demonstrate, using biochemical and single molecule assays, that this structural element modulates UPF1 catalytic activity and thereby refer to it as the regulatory loop...
January 25, 2018: Nucleic Acids Research
Annemieke J M H Verkerk, Shimriet Zeidler, Guido Breedveld, Lydia Overbeek, Daphne Huigh, Linda Koster, Herma van der Linde, Celine de Esch, Lies-Anne Severijnen, Bert B A de Vries, Sigrid M A Swagemakers, Rob Willemsen, A Jeannette M Hoogeboom, Peter J van der Spek, Ben A Oostra
Intellectual disability (ID) comprises a large group of heterogeneous disorders, often without a known molecular cause. X-linked ID accounts for 5-10% of male ID cases. We investigated a large, three-generation family with mild ID and behavior problems in five males and one female, with a segregation suggestive for X-linked inheritance. Linkage analysis mapped a disease locus to a 7.6 Mb candidate region on the X-chromosome (LOD score 3.3). Whole-genome sequencing identified a 2 bp insertion in exon 2 of the chromosome X open reading frame 56 gene (CXorf56), resulting in a premature stop codon...
January 26, 2018: European Journal of Human Genetics: EJHG
Hua Tao, Xu Zhou, Qian Xie, Zhonghua Ma, Fuhai Sun, Lili Cui, Yujie Cai, Guoda Ma, Jiawu Fu, Zhou Liu, You Li, Haihong Zhou, Jianghao Zhao, Yanyan Chen, Hui Mai, Ying Chen, Jun Chen, Wei Qi, Chaowen Sun, Bin Zhao, Keshen Li
D-serine is a predominant N-methyl-D-aspartate receptor co-agonist with glutamate, and excessive activation of the receptor plays a substantial role in epileptic seizures. Serine racemase (SRR) is responsible for transforming L-serine to D-serine. In this study, we aimed to investigate the genetic roles of SRR and a neighbouring gene, nonsense-mediated mRNA decay factor (SMG6), in temporal lobe epilepsy (TLE). Here, a total of 496 TLE patients and 528 healthy individuals were successfully genotyped for three SRR tag single nucleotide polymorphisms...
January 24, 2018: Journal of Cellular and Molecular Medicine
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